Clinical trial NCT03888066
Conditions: Hyperkalemia
Keywords: treatment of hyperkalemia chronic kidney disease hypertension hyperkalemia potassium spironolactone heart failure Renin Angiotensin-Aldosterone System Inhibitor (RAASi) RAASi high potassium eplerenone reduced ejection fraction
Sponsor: Vifor Pharma, Inc.
Start date: 2019-04-24; Completion date: 2021-09-02
Enrollment: 1195 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the effects of patiromer compared with placebo on serum K+ in HF patients.

Detailed description:
Prospective Phase 3b multinational, multicenter, double-blind, placebo-controlled, randomized withdrawal, parallel group study that includes screening and up to 12 weeks Run-in Phase (all subjects will have patiromer initiated and RAASi medications, including mineralocorticoid receptor antagonist (MRA) optimized) and a randomized withdrawal Blinded Treatment Phase.

The study population includes subjects with heart failure (HF) with reduced ejection fraction (HFrEF) who are hyperkalemic (serum potassium \[K+\] \> 5.0 mEq/L) while receiving treatment with renin angiotensin aldosterone system inhibitor (RAASi) medications or who are normokalemic (serum K+ 4.0 - 5.0 mEq/L) but have a history of hyperkalemia prior to screening with subsequent reduction or discontinuation of a RAASi medication.

Each subject's participation includes a Run-in Phase (maximum 12 weeks) followed by the Treatment Phase (variable per subject). Study duration for individual subjects will vary, depending on their individual enrollment date. Subjects who prematurely discontinue patiromer/placebo will remain in the study for the collection of clinical events data and will receive usual care.

Arms: arm 1: Subjects will be randomized to receive a daily dose of patiromer with possible dose adjustments based on subsequent local serum potassium levels. arm 2: Subjects will be randomized to receive a daily dose of placebo with possible dose adjustments based on subsequent local serum potassium levels.
Interventions: intervention 1: Patiromer intervention 2: Placebos
Intervention descriptions: intervention 1: The starting dose of patiromer will be 1 packet/day and may be taken either with food or without food. Based upon the patiromer treatment algorithm patiromer may be increased by 1 packet per day in intervals of at least 1 week (± 3 days). For subjects who become hypokalemic, patiromer may be decreased to a minimum of 0 packets/day. Doses of patiromer will be 0 packets/day, 1 packet/day, 2 packets/day, and 3 packets/day (maximum dose). intervention 2: The starting dose of placebo will be 1 packet/day and may be taken either with food or without food. Based upon the placebo treatment algorithm placebo may be increased by 1 packet per day in intervals of at least 1 week (± 3 days). For subjects who become hypokalemic, placebo may be decreased to a minimum of 0 packets/day. Doses of placebo will be 0 packets/day, 1 packet/day, 2 packets/day, and 3 packets/day (maximum dose).

Protocol documents:
Prot_000.pdf: 
 
 
This trial will be conducted in compliance with this protocol, International Council for Harmonisation Good Clinical Practice, and 
applicable regulatory requirements. The information contained in this document is 
 
 proprietary to Vifor Pharma, Inc., 
and is not to be copied, disclosed, or otherwise distributed or used without the prior written permission of Vifor Pharma. 
 
 
 
Clinical Study Protocol 
 
Title: 
A Multicenter, Double-blind, Placebo-controlled, 
Randomized Withdrawal, Parallel Group Study of 
Patiromer for the Management of Hyperkalemia in 
Subjects Receiving Renin-Angiotensin-Aldosterone 
System Inhibitor (RAASi) Medications for the 
Treatment of Heart Failure (DIAMOND) 
 
 
Clinical Protocol Number: 
PAT-CR-302 
 
 
Version Date: 
23 June 2021 
 
 
Version Number: 
4.0 
 
 
Prior Version/ 
Amendments: 
Version 1.0, 14 September 2018 
Version 1.1, 26 February 2019 
Version 1.2 (UK only), 28 November 2019 
Version 1.3 (Germany only), 24 January 2020 
Version 1.4 (Germany only), 8 July 2020 
Version 2.0, 19 October 2020 
Version 3.0, 9 April 2021 (FDA only, not implemented) 
 
 
Phase: 
Phase 3b 
 
 
Investigational Drug: 
Patiromer for Oral Suspension (Veltassa®) 
 
 
IND Number: 
075615 
 
 
EudraCT Number: 
2018-005030-38 
 
 
Sponsor Contact: 
Peter Szecsödy, MD 
VP Global Clinical Development 
 
 
 
 
Sponsor Address: 
Vifor Pharma, Inc. 
200 Cardinal Way 
Redwood City, CA 94063, USA 
 
 


 
 
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SIGNATURE PAGE 
Declaration of Sponsor 
Title: A Multicenter, Double-blind, Placebo-controlled, Randomized Withdrawal, Parallel 
Group Study of Patiromer for the Management of Hyperkalemia in Subjects Receiving 
Renin-Angiotensin-Aldosterone System Inhibitor (RAASi) Medications for the Treatment 
of Heart Failure (DIAMOND) 
Clinical Protocol Number: PAT-CR-302 
Version/Amendment Number/Date: Version 4.0, 23 June 2021 
This study protocol was subject to critical review. The information it contains is consistent 
with current knowledge of the risks and benefits of the investigational product, as well as 
with the moral, ethical and scientific principles governing clinical research as set out in the 
Declaration of Helsinki, and the International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) Guideline for Good Clinical 
Practice as amended. 
 
 
 
Sponsor Medical Expert 
Peter Szecsödy, MD 
VP Global Clinical Development 
Vifor Pharma Ltd. 
 
 
 
Vifor Pharma, Inc. 
200 Cardinal Way 
Redwood City, CA 94063 
USA 
 
Date (day month year) 
 


 
 
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EXECUTIVE SUMMARY OF CHANGES 
(PROTOCOL AMENDMENT VERSION 3.0 TO 4.0) 
The study design was updated to reflect strategic changes made by the Sponsor in 
collaboration with the study Executive Steering Committee.  
• The following changes proposed in Protocol Amendment Version 3.0, which were 
never implemented, have been reverted to the prior wording as per Protocol 
Amendment Version 2.0. All other minor changes have been kept: 
− 
Inclusion Criterion 6 has been reverted to the prior wording as in Protocol 
Amendment 2.0. 
− 
Inclusion Criterion 7 has been reverted to the prior wording as in Protocol 
Amendment 2.0. 
− 
Exclusion Criterion 20 was added in Protocol Amendment 3.0; in the current 
Protocol Amendment 4.0, Exclusion Criterion 20 has been removed.  
− 
Randomization Criterion 1 has been reverted to the prior wording as in Protocol 
Amendment 2.0. 
• The objective of the study was updated to assess the effects of patiromer compared with 
placebo on serum potassium (K+) in heart failure (HF) patients. 
− 
Primary endpoint was changed to: 
o Changes in serum K+ levels from Baseline 
− 
Key secondary endpoints (hierarchically ordered) were changed to: 
1. Hyperkalemia events with a serum K+ value >5.5 mEq/L 
2. Durable enablement to stay on the MRA target dose (as assessed by the between 
treatment group difference of the cumulative frequency of patients not staying 
on the target dose) 
3. Investigator-reported events of hyperkalemia (first and recurrent events) 
4. Hyperkalemia-related hard outcome endpoints (Win Ratio) 
a. Time to cardiovascular (CV) death 
b. Total number of CV hospitalizations 
c. Total number of hyperkalemia toxicity events with serum K+ >6.5 mEq/L 


 
 
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d. Total number of hyperkalemia events with serum K+ >6.0-6.5 mEq/L 
e. Total number of hyperkalemia events with serum K+ >5.0 mEq/L 
5. RAASi Use Score (Win Ratio) 
a. All-cause death 
b. Occurrence of a CV hospitalization 
c. HF medication use and dose for i) an angiotensin-converting enzyme 
inhibitor (ACEi)/angiotensin II receptor blocker (ARB)/angiotensin 
receptor/neprilysin inhibitor (ARNi), ii) an MRA, and iii) a beta-blocker 
• The following endpoints were added as Other Secondary Endpoints: 
− 
Durable enablement to stay on the target dose of ACEi/ARB or ARNi 
− 
Durable hyperkalemia-free enablement to stay on the MRA target dose 
− 
Total number of hyperkalemia toxicity events with serum K+ >6.5 mEq/L 
− 
Total number of hyperkalemia events with serum K+ >6.0-6.5 mEq/L 
− 
Total number of other hyperkalemia events with serum K+ >5.0 mEq/L 
• The following were added as Other Endpoints: 
− 
CV death 
− 
First and recurrent CV hospitalizations 
− 
First and recurrent HF hospitalizations (or equivalent in outpatient clinic) 
− 
Time to first occurrence of HF hospitalization (or equivalent in outpatient clinic) 
− 
Changes in serum K+ from Baseline to individual visits 
• The following endpoints were moved from Primary or Secondary to Other Endpoints: 
− 
Proportion of subjects on ≥50% of target dose of ACEi, ARB, or ARNi and ≥50% 
of target dose of MRA at the End of Study (EoS) Visit 
− 
Total HF hospitalizations (or equivalent in outpatient clinic) 
− 
Kansas City Cardiomyopathy Questionnaire (KCCQ) – changes in overall summary 
score (OSS), clinical summary score (CSS), and total symptom score (TSS) 
(combined with earlier endpoints) 


 
 
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• The following safety endpoint was changed: 
− 
Laboratory parameters other than those defined as efficacy endpoints 
For the full list of changes see Section 19. 


 
 
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INVESTIGATOR AGREEMENT AND SIGNATURE PAGE 
Title: A Multicenter, Double-blind, Placebo-controlled, Randomized Withdrawal, Parallel 
Group Study of Patiromer for the Management of Hyperkalemia in Subjects Receiving 
Renin-Angiotensin-Aldosterone System Inhibitor (RAASi) Medications for the Treatment 
of Heart Failure (DIAMOND) 
Clinical Protocol Number: PAT-CR-302 
Version/Amendment Number/Date: Version 4.0, 23 June 2021 
I have read the attached protocol as specified on this page and agree to abide by all 
provisions set forth therein. 
I agree to comply with the current International Council for Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) Guideline for 
Good Clinical Practice as amended, and applicable local regulations and guidelines. 
I agree to ensure that financial disclosure statements will be completed by: 
• Me (including, if applicable, my spouse (or legal partner) and dependent children) 
• My Sub-investigators 
before the start of the study and to report any changes that affect my financial disclosure 
status for up to 1 year after the study is completed. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of the Sponsor. 
Signature by the Investigator on this Protocol Signature Page documents review, agreement 
and approval of the requirements contained within this protocol. 
 
 
 
Signature of Principal Investigator 
 
Date (day month year) 
 
 
 
Name, Title, Address, Telephone 
Number and Email of Principal 
Investigator 
 
 
 
 
 
 


 
 
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SYNOPSIS 
Protocol Number PAT-CR-302 
Title: 
A Multicenter, Double-blind, Placebo-controlled, Randomized Withdrawal, Parallel 
Group Study of Patiromer for the Management of Hyperkalemia in Subjects 
Receiving Renin-Angiotensin-Aldosterone System Inhibitor (RAASi) Medications 
for the Treatment of Heart Failure 
Short Title: 
DIAMOND 
Study Product(s): 
Patiromer (RLY5016) and placebo 
Study Population: 
Subjects with HF with reduced ejection fraction (HFrEF) who are hyperkalemic 
(serum K+ >5.0 mEq/L) while receiving treatment with RAASi medications or who 
are normokalemic (serum K+ ≥4.0–≤5.0 mEq/L) but have a history of hyperkalemia 
prior to Screening with subsequent reduction or discontinuation of a RAASi 
medication. 
Phase: 
Phase 3b 
Sponsor: 
Vifor Pharma, Inc. 
Protocol Number: 
PAT-CR-302 
Objectives: 
Primary Objective: 
To assess the effects of patiromer compared with placebo on serum K+ in HF patients. 
Design: 
Prospective Phase 3b multinational, multicenter, double-blind, placebo-controlled, 
randomized withdrawal, parallel group study that includes Screening, an up to 12 
weeks Run-in Phase (all subjects will have patiromer initiated and RAASi 
medications, including MRA, optimized) and a randomized withdrawal Blinded 
Treatment Phase. 
Duration: 
Each subject’s participation includes a Run-in Phase (single-blinded, up to 12 weeks) 
followed by the Treatment Phase (double-blinded, variable per subject). Study 
duration for individual subjects will vary, depending on their individual enrollment 
date. Subjects who prematurely discontinue patiromer/placebo will remain in the 
study for the collection of clinical events data, up to and including the common EoS, 
and will receive usual care during the study phase. 
Study Treatments: 
Patiromer or Placebo: 
During the Run-in Phase, subjects who meet all eligibility criteria will initiate 
patiromer, single-blinded, at an oral dose of 1 packet/day (8.4 g/day). The dose will 
be adjusted based on local serum K+ levels in accordance with the patiromer treatment 
algorithm (see Section 6.7.1.1). 
During the Treatment Phase (double-blinded), subjects will be randomized to receive 
patiromer or placebo and will initially continue on the same number of packets as 
established for patiromer during the Run-in Phase but may be up- or down-titrated 
depending on local serum K+ levels (see Treatment Phase and Section 6.7.1.2). 


 
 
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HF Treatments: 
RAAS Inhibitors: 
Since subjects who enter this study will either have hyperkalemia or a previous 
history of hyperkalemia due to the use of RAASi medications, the Run-in Phase is 
intended for the management of serum K+ with patiromer to allow optimization of 
RAASi HF treatments (i.e., ACEi/ARB or ARNi and MRA (spironolactone or 
eplerenone)). The Investigator should evaluate the RAASi treatment(s) that subjects 
are receiving for HF against recommendations from professional society HF 
guidelines and make adjustments in accordance with guideline recommendations; see 
Study Manual for additional details on guideline recommendations and the 
study-specific target doses [1]. For a subject to be eligible for randomization into the 
Treatment Phase, the subject must be on ≥50% of the target dose of an 
ACEi/ARB/ARNi, and ≥50% of the target dose of MRA (spironolactone or 
eplerenone only, see Study Manual [1] for information on the study-specific target 
dose of individual RAASi medications and Section 6.7.2). 
During the Treatment Phase, subjects randomized to either patiromer or placebo will 
initially continue on the doses of RAASi medications (ACEi/ARB/ARNi and/or 
MRA) optimized during the Run-in Phase (see the Procedures section below and 
Section 6.7.1.2 in the protocol for details on the management of hyperkalemia during 
this period). 
Usual Care: 
Whether subjects are treated with patiromer or placebo during the Blinded Treatment 
Phase, usual care in accordance with guideline recommendations will be provided for 
all subjects. Usual care includes recommendations for all aspects of care for HFrEF 
patients (i.e., dietary and exercise recommendations, implantable devices, and 
procedures and medications for the management of HF). Usual care may also include 
patient education. See Section 6.8.4 for additional details regarding concomitant 
medication use. 
Management of K+: 
Serum K+ levels will be monitored and managed throughout the study. The 
management of K+ is different during the Run-in Phase from the Treatment Phase. 
Urgent treatment of hyperkalemia is in accordance with usual care and the 
Investigator’s judgment. See Procedures section of the synopsis for further details. 
Inclusion Criteria: 
The following criteria must be met for each subject prior to entry into the Run-in 
Phase: 
1. Subject provides written informed consent prior to study participation. 
2. Age at least 18 years or greater. 
3. Current New York Heart Association (NYHA) Class II–IV. 
4. Left ventricular ejection fraction ≤40%, measured by any echocardiographic, 
radionuclide, magnetic resonance imaging (MRI), angiographic, or computerized 
tomography method in the last 12 months (without subsequent measured ejection 
fraction >40% during this interval). 
5. Receiving any dose of a beta-blocker for the treatment of HF or unable to tolerate 
beta-blocker (reason documented). 
6. eGFR ≥30 mL/min/1.73 m2 at Screening (based on a single local laboratory 
analysis of serum creatinine and calculation using the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) equation; see Section 9.2). 


 
 
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7. Hyperkalemia at Screening (defined by 2 local serum K+ values of >5.0 mEq/L, 
each obtained from a separate venipuncture, e.g., one in each arm or 2 separate 
venipunctures in the same arm) while receiving ACEi/ARB/ARNi, and/or MRA, 
OR 
Normokalemia at Screening (defined by 2 local serum K+ ≥4.0–≤5.0 mEq/L each 
obtained from a separate venipuncture, e.g., one in each arm or two separate 
venipunctures in the same arm) with a history of hyperkalemia documented by a 
usual care serum K+ measurement >5.0 mEq/L while on RAASi treatment in the 
12 months prior to Screening leading to a subsequent and permanent dose 
decrease or discontinuation of one or more RAASi medications. 
8. Females of child-bearing potential must be non-lactating, must have a negative 
pregnancy test at Screening, and must agree to continue using contraception (see 
Section 9.8) throughout the study and for 4 weeks after study completion. 
9. With hospitalization for HF or equivalent (e.g., emergency room or outpatient 
visit for worsening HF during which the subject received intravenous medications 
for the treatment of HF) within the last 12 months before Screening. 
a) Without atrial fibrillation at Screening, brain natriuretic peptide (BNP*) level 
must be greater than 150 pcg/mL (18 pmol/L) or N-terminal pro b-type BNP 
(NT-proBNP) must be greater than 600 pcg/mL (71 pmol/L) 
b) With atrial fibrillation at Screening, BNP* level must be greater than 
300 pcg/mL (35 pmol/L) or NT-proBNP must be greater than 1,200 pcg/mL 
(142 pmol/L) 
OR 
Without hospitalization for HF or equivalent (e.g., emergency room or outpatient 
visit for worsening HF during which the subject received intravenous medications 
for the treatment of HF) within the last 12 months before Screening. 
a) Without atrial fibrillation at Screening, BNP* level must be greater than 
300 pcg/mL (35 pmol/L) or NT-proBNP must be greater than 1,200 pcg/mL 
(142 pmol/L). 
b) With atrial fibrillation at Screening, BNP* level must be greater than 
600 pcg/mL (71 pmol/L) or NT-proBNP must be greater than 2,400 pcg/mL 
(284 pmol/L). 
*For subjects treated with ARNi (sacubitril/valsartan) in the previous 4 weeks 
before Screening, only NT-proBNP values are to be considered. 
Note: The following table provides the same information of Inclusion Criterion 9 as 
described above. 


 
 
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BNP and NT-proBNP Threshold Levels (Based on Local Laboratory), 
Comorbidities, and Previous Hospitalizations 
 
Subjects with hospitalization for 
HF or equivalent(1) within last 
12 months 
Subjects with no hospitalization 
for HF or equivalent(1) within 
last 12 months 
Subjects presenting 
without atrial fibrillation 
when the blood sample 
was collected 
BNP(2) >150 pcg/mL  
(18 pmol/L) 
or 
NT-proBNP >600 pcg/mL 
(71 pmol/L) 
BNP(2) >300 pcg/mL  
(35 pmol/L) 
or 
NT-proBNP >1,200 pcg/mL 
(142 pmol/L) 
Subjects presenting with 
atrial fibrillation when the 
blood sample was collected 
BNP(2) >300 pcg/mL  
(35 pmol/L) 
or 
NT-proBNP >1,200 pcg/mL 
(142 pmol/L) 
BNP(2) >600 pcg/mL  
(71 pmol/L) 
or 
NT-proBNP >2,400 pcg/mL 
(284 pmol/L) 
1 E.g., emergency room or outpatient visit for worsening HF during which the subject received 
intravenous medications for the treatment of HF. 
2 For subjects treated with ARNi (sacubitril/valsartan) in the previous 4 weeks before Screening only 
NT-proBNP values are to be considered. 
Notes: ARNi=Angiotensin receptor/neprilysin inhibitor; BNP=Brain natriuretic peptide; HF=Heart 
failure; NT-proBNP=N-terminal pro b-type brain natriuretic peptide. 
Exclusion 
Criteria: 
Subjects who meet any of the following criteria during Screening will be excluded: 
1. Current acute decompensated HF within 4 weeks before Screening. Subjects 
with a discharge from a hospitalization for acute decompensation of HF longer 
than 4 weeks before Screening may be included. 
2. Symptomatic hypotension or systolic blood pressure <90 mmHg. 
3. Significant primary aortic or mitral valvular heart disease (except secondary 
mitral regurgitation due to left ventricular dilatation). 
4. Heart transplantation or planned heart transplantation (i.e., currently on a heart 
transplant waiting list) during the study period. 
5. Diagnosis of peripartum or chemotherapy-induced cardiomyopathy or acute 
myocarditis in the previous 12 months. 
6. Implantation of a cardiac resynchronization therapy device in the previous 
4 weeks before Screening. 
7. Restrictive, constrictive, hypertrophic, or obstructive cardiomyopathy. 
8. Untreated ventricular arrhythmia with syncope in the previous 4 weeks. 
9. History of, or current diagnosis of, a severe swallowing disorder, moderate-to-
severe gastroparesis, or major gastrointestinal (GI) surgery (e.g., bariatric 
surgery or large bowel resection). 
10. A major CV event within 4 weeks prior to Screening, including acute myocardial 
infarction, stroke (or transient ischemic attack), a life-threatening atrial or 
ventricular arrhythmia, or resuscitated cardiac arrest. 
11. Note: This exclusion criterion is included in the new Inclusion Criterion 9. 
12. Liver enzymes (alanine aminotransferase, aspartate aminotransferase) >5 times 
upper limit of normal at Screening based on the local laboratory. 


 
 
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13. Diagnosis or treatment of a malignancy in the past 2 years, excluding 
non-melanoma skin cancer and carcinoma in situ of the cervix, prostate cancer 
with Gleason score <7, or a condition highly likely to transform into a 
malignancy during the study. 
14. Presence of any condition (e.g., drug/alcohol abuse; acute illness), in the opinion 
of the Investigator, that places the subject at undue risk, or prevents complete 
participation in the trial procedures, or potentially jeopardizes the quality of the 
study data. 
15. Use of any investigational product for an unapproved indication within 4 weeks 
prior to Screening or currently enrolled in any other type of medical research 
judged not to be scientifically or medically compatible with this study. 
16. Known hypersensitivity to patiromer (RLY5016) or its components. 
17. Note: This exclusion criterion is modified and partially incorporated in the 
Exclusion Criterion 18. 
18. Subjects currently being treated with or having taken any one of the following 
medications in the 7 days prior to Screening: sodium or calcium polystyrene 
sulfonate or sodium zirconium cyclosilicate, or patiromer. 
19. An employee, spouse, or family member of the Sponsor (Vifor Pharma), 
investigational site or the Contract Research Organization (CRO). 
Randomization 
Criteria: 
The following randomization criteria must be met during the up to 12-week 
Run-in Phase to be randomized into the Treatment Phase: 
1. Current MRA dose is at least the target dose* (e.g., spironolactone 50 mg/day, 
eplerenone 50 mg/day) and has been stable for at least 1 week. 
2. Current ACEi/ARB/ARNi is ≥50% of the target dose* and has been stable for at 
least 1 week. 
3. Current patiromer dose is at least 1 packet daily. 
4. Current local serum K+ level is ≥4.0–≤5.0 mEq/L. 
* Study-specific target doses as per Table 4 in the Study Manual. 
Primary and 
Secondary 
Endpoints: 
Primary Endpoint: 
• 
Changes in serum K+ levels from Baseline 
Key Secondary Endpoints (Hierarchically Ordered): 
1. Hyperkalemia events with a serum K+ value >5.5 mEq/L. 
2. Durable enablement to stay on the MRA target dose (of 50 mg daily 
spironolactone or eplerenone, respectively) as assessed by the between treatment 
group difference of the cumulative frequency of patients not staying on that target 
dose. 
Note: Discontinuation of the target dose for at least 14 days (or less if at the EoS) 
is required to confirm this endpoint. 
3. Investigator reported events of hyperkalemia (first and recurrent events). 
4. Hyperkalemia-related hard outcomes endpoints (Win Ratio). 
a. Time to CV death 


 
 
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b. Total number of CV hospitalizations 
c. Total number of hyperkalemia toxicity events with serum K+ >6.5 mEq/L 
d. Total number of hyperkalemia events with serum K+ >6.0-6.5 mEq/L 
e. Total number of hyperkalemia events with serum K+ >5.0 mEq/L 
5. RAASi Use Score (Win Ratio). 
Note: This score (of 0–8 points) will be analyzed at the respective time points for 
each subject in each comparison, and it consists of the following components: 
a. All-cause death 
b. Occurrence of a CV hospitalization 
c. HF medication use and dose for i) an ACEi/ARB/ARNi, ii) an MRA, and iii) 
a beta-blocker 
Other Secondary Endpoints: 
• 
Durable enablement to stay on the target dose of ACE/ARB/ARNi 
Note: Discontinuation of the target dose for at least 14 days (or less if at the EoS) 
is required to confirm this endpoint 
• 
Durable hyperkalemia-free enablement to stay on the MRA target dose (days on 
50mg MRA without presence of hyperkalemia) 
• 
Total number of hyperkalemia toxicity events with serum K+ >6.5 mEq/L 
• 
Total number of hyperkalemia events with serum K+ >6.0-6.5 mEq/L 
• 
Emergency treatment for hyperkalemia (hospitalization or emergency room) 
• 
Total number of hyperkalemia events with serum K+ >5.0 mEq/L 
• 
KCCQ questionnaire, changes in OSS, CSS and TSS 
• 
Investigator reported events of hyperkalemia (first events) 
• 
Proportion of subjects on ≥50% of target dose of ACEi, ARB, or ARNi and 
≥50% of target dose of MRA at the EoS Visit 
• 
Time to first occurrence of CV death or CV hospitalization 
Other Endpoints: 
• 
CV death 
• 
First and recurrent CV hospitalizations 
• 
First and recurrent HF hospitalizations (or equivalent in outpatient clinic) 
• 
Patient-reported outcome: EQ-5D-5L questionnaire 
• 
Proportion of subjects on any dose of MRA at the EoS Visit 
• 
Proportion of subjects on any dose of ACEi, ARB, or ARNi at the EoS Visit 
• 
Change in proteinuria from Screening 
• 
Change in NT-proBNP from Screening 
• 
Change in high sensitivity troponin from Baseline 


 
 
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• 
Functional status by NYHA class 
• 
30-day HF re-hospitalization after a prior HF hospitalization 
• 
Health Economics and Outcomes Research (HEOR) analyses 
• 
Changes in serum K+ from Baseline to individual visits 
Safety Endpoints: 
• 
Adverse events (AEs), including all-cause mortality 
• 
All-cause mortality 
• 
Slope of eGFR change during the study 
• 
Decline in eGFR >50% or end-stage renal disease (ESRD), renal death, or need 
for dialysis 
• 
Laboratory parameters other than those defined as efficacy endpoints 
Procedures: 
See Study Schema for an overview of the study design. The study consists of: 
• 
Screening Phase (the Screening Phase may last up to 10 calendar days) 
• 
Run-in Phase (single-blinded), up to 12 weeks; weekly visits recommended but 
are at the Investigator’s discretion 
• 
Treatment Phase (double-blinded); the scheduled visits are listed below: 
− 
Day 1/Baseline 
− 
Day 3 (±1 day) 
− 
Week 1 (±3 days) 
− 
Week 2 (±3 days) 
− 
Week 6 (±14 days) 
− 
Week 18 (-30 days), first Every 3 Months visit 
− 
Visits every 3 months (-30 days) thereafter through the end of the study 
− 
EoS Visit  
• 
Potassium Assessment Visit (occurs within 2 weeks after patiromer/placebo is 
discontinued) 
Note: Subjects who prematurely discontinue patiromer/placebo during the Blinded 
Treatment Phase remain in the study. 
• 
Follow-up Phone Call (at least 2 weeks after the EoS for the assessment of safety; 
for subjects who discontinue patiromer at the EoS Visit, and attend the Potassium 
Assessment Visit 2 weeks later, a Follow-up Phone Call will not be needed) 
• 
Unscheduled Visit (during the Treatment Period, anytime there are changes to 
ACEi, ARB, ARNi and/or MRA dose or interventions for serum K+ outside the 
desired range, additional Unscheduled Visits should occur weekly until the 
ACEi, ARB, ARNi and/or MRA dose or serum K+ has been stable for at least 
2 consecutive visits) 


 
 
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Screening Phase and Run-in Phase (Single-Blinded, Up to 12 Weeks): 
At the end of the Screening Phase, subjects who satisfy the eligibility criteria will be 
enrolled into the Run-in Phase. The purpose of the Run-in Phase is to select subjects 
who will potentially benefit from treatment and not unnecessarily expose those who 
will not. In addition, the Run-in Phase is for management of serum K+ with patiromer 
to allow optimization of RAASi medications and their dosage (including initiation of 
MRA if not already receiving an MRA). 
All subjects who meet the eligibility criteria for the Run-in Phase (single-blinded) 
will initiate patiromer (1 packet/day). 
Subjects with 2 screening K+ values >5.0 mEq/L are considered hyperkalemic; these 
subjects begin patiromer when they qualify for the Run-in Phase, i.e., on the same 
day Run-in qualification is met or the next day. 
Note: If one screening K+ value is >5.0 mEq/L and one value is ≤5.0 mEq/L, then a 
third peripheral venipuncture is performed within 1 day to obtain clarity, whether 
subject is hyperkalemic or normokalemic (local serum K+ ≥4.0-≤5.0 mEq/L). 
All other subjects are considered normokalemic and serum K+ will be measured again 
latest after the first week during the Run-in Phase. Patiromer will be started at this 
first Run-in Visit only if subjects are still normokalemic or have progressed to 
hyperkalemia; in case of newly observed hypokalemia (local serum K+ <4.0 mEq/L) 
during the first Run-in Week, patiromer must not be given. In subjects with 
hypokalemia serum K+ must be controlled after 3 days. 
During the first week of the Run-in Phase, ACEi/ARB/ARNi and/or MRA doses 
ideally remain unchanged, if clinically indicated. On or after the Run-in Week 1 Visit, 
up-titration of ACEi/ARB/ARNi and/or MRA may be initiated. 
Patiromer is titrated during the Run-in Phase to achieve target local serum K+ level 
of ≥4.0–≤5.0 mEq/L (see below). 
Note: Depending on the actual local serum K+ value this could include patiromer 
0 g/day (i.e., 0 packets/day) during the Run-in Phase. 
• 
If local serum K+ is >5.0 mEq/L, up-titrate patiromer in at least (≥) 1-week 
intervals by 1 packet/day (maximum dose is 3 packets/day) 
− 
If subject is taking maximum dose patiromer (3 packets/day) and local 
serum K+ remains >5.0 mEq/L during the Run-in Phase, then subject is 
Run-in failed 
• 
If local serum K+ is >5.0–≤5.5 mEq/L and the reduction in serum K+ from the 
previous visit was ≥0.4 mEq/L, at the Investigator’s discretion, a dose increase 
of patiromer may not be required 
• 
If local serum K+ is ≥4.3–≤5.0 mEq/L at the first week during the Run-in Phase, 
patiromer must be started at 1 packet/day 
• 
If local serum K+ is ≥4.0–<4.3 mEq/L at the first week during the Run-in Phase, 
patiromer may be started at 1 packet/day; initiation or increase of patiromer dose 
should be made with caution when local serum K+ is ≥4.0–<4.3 mEq/L to avoid 
inducing hypokalemia 
• 
If local serum K+ decreases from >4.3 mEq/L to values <4.3 mEq/L, remaining 
≥4.0 mEq/L, patiromer may be down-titrated by 1 packet/day (minimum dose is 
0 packets/day); in case of a reversal of this decrease from <4.3 mEq/L but 


 
 
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remaining ≥4.0 mEq/L to values ≥4.3 mEq/L at following visits, patiromer may 
be up-titrated by 1 packet/day; subjects must receive at least 1 packet/day at 
serum K+ ≥4.3–≤5.0 mEq/L 
− 
If 1 week after reducing patiromer to 0 packets/day local serum K+ remains 
stable ≥4.0–≤4.3 mEq/L, optimize RAASi dose and resume patiromer at 1 
packet/day before considering these subjects as Run-in failed; initiation or 
increase of patiromer dose should be made with caution when local serum 
K+ is ≥4.0–≤4.3 mEq/L to avoid inducing hypokalemia 
• 
If local serum K+ is <4.0 mEq/L, patiromer must be down-titrated to 0 g/day (i.e., 
0 packets/day), with confirmation of hypokalemia within 3 days and follow-up 
in at least 1-week intervals until serum K+ is ≥4.0 mEq/L. Resume patiromer 
only when local serum K+ rises to >5.0 mEq/L 
− 
If 2 weeks after taking the minimum 0 packets/day, local serum K+ remains 
<4.0 mEq/L during the Run-in Phase, then subject is Run-in failed 
Optimization of ACEi/ARB/ARNi or MRA During Run-in Phase: 
The Investigator should manage ACEi/ARB/ARNi or MRA dose initiation, 
escalation and maintenance with the aim to achieve 100% of target doses as per the 
Study Manual, using clinical judgment to customize ACEi/ARB/ARNi or MRA 
addition or dose escalation based on subject response; see Section 6.7.2, 
Section 6.8.2, and Study Manual [1] for a summary of practice guideline 
recommendations.  
Initiation or escalation of ACEi/ARB/ARNi or MRA dose should be made with 
caution when local serum K+ is >5.0 mEq/L. Assessment of serum K+ will occur at 
each visit. The patiromer dose is titrated based on the subject’s K+ level as presented 
above. 
Subjects may be randomized anytime (but no later than 12 weeks) during the Run-in 
Phase when they meet all of the following randomization criteria: 
• 
Current MRA dose is at least the target dose* (e.g., spironolactone 50 mg/day, 
eplerenone 50 mg/day) and has been stable for at least 1 week 
• 
Current ACEi/ARB/ARNi is ≥50% of the target dose* and has been stable for at 
least 1 week 
• 
Current patiromer dose is at least 1 packet daily 
Current local serum K+ level is ≥4.0–≤5.0 mEq/L 
* Study-specific target doses as per Table 4 in the Study Manual. 
Subjects are Run-in failed from the study if: 
• 
After completing 12 weeks of Run-in do not meet the randomization criteria 
• 
1 week after taking the maximum 3 packets/day dose of patiromer, local serum 
K+ remains >5.0 mEq/L 
• 
2 weeks after taking the minimum 0 packets/day, local serum K+ remains 
<4.0 mEq/L 
Run-in failed subjects cannot be randomized but may be rescreened once, after 
3 months (Section 8.1.1.1). 
Treatment Phase (Double-Blinded): 


 
 
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After the Run-in Phase (single-blinded), eligible subjects will be randomized in a 1:1 
ratio, to treatment with patiromer or placebo double-blinded; see Study Schema. 
Randomized subjects will begin their assigned treatment (patiromer or placebo), 
double-blinded, using the same number of packets established for patiromer at the 
end of the Run-in Phase and will continue the ACEi/ARB/ARNi and MRA regimen 
being administered at the end of the Run-in Phase. Anytime during the Treatment 
Phase when subjects are on less than the target dose of either ACEi/ARB/ARNi or 
MRA, up-titration should be attempted if serum K+ remains in the normokalemic 
range (serum K+ 4.0–5.0 mEq/L) and no other contravening conditions are present. 
After randomization, serum K+ will be measured prior to initiation of assigned 
patiromer/placebo, double-blinded, on Treatment Day 1/Baseline (if not already 
obtained that day), and at each subsequent scheduled and unscheduled visit during 
the Treatment Phase. 
Protocol allowed interventions for the management of hyperkalemia during the 
Treatment Phase include the following: 
• 
Up-titration of patiromer/placebo if on <3 packets per day 
• 
Down-titration or discontinuation of ACEi, ARB, ARNi and/or MRA 
• 
Initiate or increase diuretics 
• 
Dietary K+ restriction 
If local K+ is >5.5 mEq/L one or more of these interventions must be initiated either 
individually or in combination following the recommendations by practice 
guidelines. Repeat the K+ measurement within 7 days; if local K+ 
remains >5.5 mEq/L consider repeating the intervention or using other interventions 
in the order described above. 
If local K+ is between ≥5.0 mEq/L and ≤5.5 mEq/L one or more of these interventions 
may be initiated per Investigator discretion. 
Urgent treatment of hyperkalemia should be in accordance with usual care and the 
Investigator’s judgment. As described in Section 6.8.4.1, the only K+ binding 
medications permitted for use during the study are temporary use of sodium or 
calcium polystyrene sulfonate as well as sodium zirconium cyclosilicate for up to 
7 days or until local serum K+ <5.0 mEq/L, whichever occurs first. Patiromer/placebo 
must be withheld during temporary use of permitted K+ binding medications. 
If hypokalemia develops during the Treatment Phase, study drug should be 
down-titrated (lowest acceptable dose is 0 packets/day) until local serum K+ ≥4.0 
mEq/L. 
Samples will be collected at each scheduled visit, at minimum, for the measurement 
of serum K+ and creatinine (for calculation of eGFR). Subject reported outcome will 
be assessed using the KCCQ and EQ-5D-5L questionnaire. See Schedule of Events 
for full details of protocol required procedures and laboratory assessments at the 
applicable visits (and timings of each visit). 


 
 
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Monitoring Changes in Renal Function: 
Throughout the study, creatinine will be measured at each study visit (and may be 
measured at unscheduled visits). Subjects must be monitored for changes in renal 
function (eGFR and creatinine), especially during periods of medication changes or 
adjustments and when the subject has a change in clinical status. See Section 6.7.4 
for suggested guidance on medication adjustments based on changes in renal 
function. 
Sample Size: 
The sample size of 410 subjects per treatment arm (total of 820 subjects) has been 
calculated to provide 90% power to detect a difference between the control group 
(placebo) and the active group (patiromer) on the mean change in K+ levels from 
Baseline. This sample size calculation was based upon the following assumptions: 
alpha level of 5% (2-sided), a difference between group means of 0.116 a standard 
deviation (SD) of 0.5 and a 5% rate of loss to follow-up 
Study Sites: 
Approximately 375 sites 
Statistical 
Methods: 
The mean change in serum K+ levels from Baseline is analyzed by means of a mixed 
model for repeated measures (MMRM) approach including all available follow-up 
data. A Gaussian linear model for repeated measures with treatment, geographic 
region, sex, baseline Type 2 diabetes mellitus (T2DM) status, and visit as factors, and 
baseline K+ level, baseline eGFR as covariates. The error terms are assumed to follow 
a multivariate normal distribution with unstructured covariance.  
Sensitivity analyses for the primary endpoint will explore changes in treatment effect 
over follow-up time by including treatment by visit interactions in the above-
mentioned model. In addition, sensitivity analyses accounting for potentially 
informative missingness will be based upon a Win Ratio approach.  
Secondary efficacy endpoints will be tested in the order listed (i.e., fixed-sequence 
method to preserve the family-wise error rate) and summarized descriptively through 
the calculation of point estimates by treatment group along with 95% ICIs for the 
treatment differences. Other endpoints will be summarized using the calculation of 
point estimates by treatment group along with 95% CIs for the treatment differences 
and descriptive methods as appropriate. 
Safety evaluations include AEs and serious adverse events (SAEs) (including 
all-cause mortality); slope of eGFR change during the study; decline in eGFR >50% 
or ESRD, renal death, or need for dialysis; and serum K+ level. Safety variables will 
be summarized using the safety set. 
No interim analysis is planned. 
See Section 12 for additional information. 
 


 
 
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STUDY SCHEMA 
 
= Randomized (see Section 5.4 for the Randomization Criteria); the assigned patiromer or placebo treatment begins and RAASi  medication continues from the Run-in Phase 
ACEi = angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blocker; ARNi = angiotensin receptor/neprilysin inhibitor; BNP=brain natriuretic peptide; EoS = end of study; HF = heart failure; HFrEF = heart 
failure with reduced ejection fraction; LVEF = left ventricular ejection fraction; MRA = mineralocorticoid receptor antagonist; NT-proBNP=N-terminal pro b-type brain natriuretic peptide; RAASi = renin-angiotensin-
aldosterone system inhibitor; sK+ = serum potassium
a. For BNP and NT-proBNP inclusion criteria in relation to the presence or not of hospitalization for HF within 12 months and the presence or not of atrial fibrillation   when blood samples were collected see Section 5.2.
b. Hyperkalemia or normokalemia defined by 2 local serum K+ values each obtained from a separate venipuncture, e.g., one in each arm. If 1 serum potassium value is hyperkalemic (>5.0 mEq/L) and 1 value is 
normokalemic (≤5.0 mEq/L), then a third peripheral venipuncture is performed within 1 day to obtain clarity whether a subject ishyperkalemic or normokalemic.
c.   Start at 8.4 g/day and up-titrate as necessary up to 25.2 g/day. Hyperkalemic subjects start patiromer immediately; normokalemic subjects start at Week 1 or later. Subject must return within 1 week ( 3 days) after 
patiromer initiation or dose adjustments to assess potassium levels.
d. Initiate/optimize selected MRA; up-titrate to 50 mg/day. For subjects not on an MRA, the Investigator determines which MRA to initiate, and also determines the starting dose. For subjects who are on <50 mg/day of 
MRA, double their current dose up to 50 mg/day. Assess tolerance to the 50 mg target dose
e.   If there are changes to ACEi, ARB, ARNi  and/or MRA dose or serum potassium varies outside the intended range, unscheduled weekly or monthly visits should occur until stability returns.
f.    If the Potassium Assessment Visit is at 2 weeks after the EoS Visit, then Follow-up phone call is not required.
Placebo (withdraw patiromer)
Patiromer Continued
Day 3
Week 1
Every 3-Month Visits
sK+ ≥4.0 to ≤5.0 
mEq/L
R
Day 1/
Baseline
EoS Visit
Potassium Assessment Visit (within 2 weeks of 
patiromer/placebo discontinuation)
and/or 
Follow-up Phone Call (at least 2 weeks after the EoS Visit)f
Treatment Phase
(double blinded)
R
Run-in Phase 
(single, blinded, up to 
12 weeks)
• Initiate patiromerc
• Optimize 
ACE/ARB/ARNi
• Initiate/optimize             
MRAd
sK+ >5.0 mEq/L
Week 2e
Subjects must meet the 
following criteria:
•
On RAASi
•
HFrEF (LVEF ≤40%)
•
eGFR ≥30 mL/min/1.73 m2
•
BNP and NT-proBNP 
threshold levels dependent 
upon presence or not of 
hospitalization for HF (or 
equivalent) within 12 
months  and upon presence 
or not of atrial fibrillation  
when blood samples were 
collecteda
Week 6e
Week18e
Screening Phase
(up to 10 business days)
Hyperkalemicb
Normokalemicb


 
 
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SCHEDULE OF EVENTS 
Procedures 
Screening 
Phase 
Run-in Phase 
(Single-Blinded) 
Treatment Phase (Double-Blinded) 
 
Screening 
Visits(1) 
Run-in Visits(2) 
(Up To 12 wks) 
Day 1/ 
Baseline 
Day 3 
(±1 D) 
Week 
1 
(±3 D) 
Week 
2 
(±3 D) 
Week 6 
(±14 D) 
Week 18 
(-30 D), First 
Every 3 
Months Visit 
Every 3 Months 
Visits After Week 
18 Until EoS 
(-30 D) 
EoS/ET 
Visit 
PA 
Visit(3) 
(Up to 
2 Wks) 
Follow-up 
Phone Call (at 
Least 2 Wks 
After EoS)(4) 
U Visit(5) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
IWRS entry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X(24) 
Eligibility criteria 
X 
X(6) 
X(6) 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
NYHA class 
X 
 
X 
 
 
 
 
X 
X 
X 
X 
 
 
Medical/surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
X 
 
 
X(7) 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
BP and heart rate 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
12-lead ECG(22) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
K+(8) 
L(9) 
L 
L&C 
L 
L 
L 
L 
L&C 
L&C 
L&C 
L&C 
 
L 
Serum chemistry 
L(10)&C(11) 
L(12,13) 
C 
L(13) 
L(13) 
L(13) 
L(13) 
C 
C 
C 
C 
 
L 
Hematology 
C 
 
 
 
 
 
 
C 
C 
C 
C 
 
C(7) 
Urinalysis 
C 
 
C 
 
 
 
 
 
 
C 
 
 
 
Urine ACR 
 
C(14) 
 
C(15) 
 
C(15) 
 
C(15) 
C(15) 
C(15) 
 
 
 
Urine or serum pregnancy test(16) 
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
BNP/NT-proBNP(22,23) 
L&C(11) 
 
 
 
 
 
 
C 
C 
C 
 
 
 
High sensitivity troponin 
 
 
C 
 
 
 
 
 
 
C 
 
 
 
MRA levels(17) 
 
 
C 
 
C 
 
 
C(18) 
C(18) 
C 
 
 
 
Adverse events/special situations 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications and 
procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
KCCQ and EQ-5D-5L(19) 
X 
 
X 
 
 
 
 
X(18) 
X(18) 
X 
 
 
 


 
 
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Procedures 
Screening 
Phase 
Run-in Phase 
(Single-Blinded) 
Treatment Phase (Double-Blinded) 
 
Screening 
Visits(1) 
Run-in Visits(2) 
(Up To 12 wks) 
Day 1/ 
Baseline 
Day 3 
(±1 D) 
Week 
1 
(±3 D) 
Week 
2 
(±3 D) 
Week 6 
(±14 D) 
Week 18 
(-30 D), First 
Every 3 
Months Visit 
Every 3 Months 
Visits After Week 
18 Until EoS 
(-30 D) 
EoS/ET 
Visit 
PA 
Visit(3) 
(Up to 
2 Wks) 
Follow-up 
Phone Call (at 
Least 2 Wks 
After EoS)(4) 
U Visit(5) 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Drug accountability 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X(24) 
Dispense patiromer/placebo(20) 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X(24) 
Reimburse MRA(21) 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
X 
1 
Screening activities may take place over different calendar days if needed, but not exceeding 10 calendar days. 
2 
Subjects with 2 screening K+ values >5.0 mEq/L are considered hyperkalemic; these patients begin patiromer when they qualify for the Run-in Phase (i.e., on the same day Run-in qualification is met or the 
next day). All other subjects are considered normokalemic and will begin patiromer latest by the end of the first week during the Run-in Phase only if they are still normokalemic or progressed to 
hyperkalemia. Note: Depending on the actual local serum K+ value this could include patiromer 0 g/day (i.e., 0 packets/day). During the Run-in Phase, after any adjustments of patiromer (up or down) subjects 
must return within 1 week ±3 days to assess their serum K+ level. See Section 6.7.1.1 for details. 
3 
Occurs after discontinuation of patiromer during the Run-in Phase (Run-in Phase failed) and after discontinuation from patiromer/placebo during Treatment Phase; see Section 8.6. 
4 
If the PA Visit is 2 weeks after the EoS Visit, then the Follow-up Phone Call is not required. 
5 
Any other study assessments (see Section 8.8) may be performed at the discretion of the Investigator during an unscheduled visit. 
6 
See Section 5.4 for the assessment of the randomization criteria. 
7 
Assessment is optional. 
8 
If hemolysis of the local sample is detected or is suspected (see Section 9.1.1), or the initial 2 screening blood samples reveal inconsistent values not allowing to clearly define hyperkalemia or normokalemia, 
a repeat (third) K+ measurement from a separate blood draw will be performed within 1 day. 
9 
Collect 2 local samples at Screening, each obtained from a separate venipuncture (e.g., one in each arm or 2 separate venipunctures in the same arm) to determine normokalemia or hyperkalemia in both blood 
samples; in case of deviant results, another blood sample is to be taken within 1 day to confirm normokalemia or hyperkalemia. 
10 Only locally measured creatinine for the calculation of eGFR for assessment of Inclusion Criterion 6 and alanine aminotransferase and aspartate aminotransferase for assessment of Exclusion Criterion 12. 
11 Central laboratory values only to be collected when subject meets all other eligibility criteria. 
12 Locally measured magnesium level at 1 week after starting patiromer, followed by periodic measurements during Run-in Phase to early detect rare cases of hypomagnesemia. 
13 Only locally measured serum creatinine for the calculation of eGFR. 
14 Urine sample containers will be dispensed at Screening to subjects who qualify for entry into the Run-in Phase and subjects will be provided proper training and instructions on the use of the containers. Urine 
ACR is collected and measured latest at the end of the initial week during the Run-in Phase only and not assessed at other Run-in Phase Visits. 
15 Urine sample containers will be dispensed at the prior visit and subjects will be provided proper training and instructions on the use of the containers. See Section 9.6. 
16 Only for women of child-bearing potential. Serum pregnancy tests will be locally measured. 
17 MRA must be taken in the morning before blood withdrawal for analysis of MRA levels. 
18 Performed at 3 months (i.e., Week 18), 6 months, 12 months, and then every 12 months thereafter. 
19 Subjects will complete the KCCQ and EQ-5D-5L questionnaire before study staff performs any clinic or study assessments. 
20 During Run-in Phase, only patiromer is dispensed. After randomization, patiromer/placebo dose on Day 1/Baseline will be the same number of packets established for patiromer at the end of the Run-in 
Phase. Throughout the study patiromer or patiromer/placebo will be dispensed as needed. 
21 Only if needed for subjects who initiate spironolactone or eplerenone during the Run-in Phase; see Section 6.7.2 and Section 6.8.2. 
22 Screening 12-lead ECG and BNP/NT-proBNP needs to be assessed on the same day. 
23 For subjects treated with ARNi (sacubitril/valsartan) in the previous 4 weeks before Screening only NT-proBNP values are to be considered. 
24 Applicable only if IMP is dispensed at an unscheduled visit. 


 
 
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Notes: ACEi=Angiotensin-converting enzyme inhibitor; ACR=Albumin-to-creatinine ratio; ARB=Angiotensin II receptor blocker; ARNi=Angiotensin receptor/neprilysin inhibitor; BNP=Brain natriuretic peptide; 
BP=Blood pressure; C=Central laboratory; D=Day(s); ECG=Electrocardiogram; eGFR=Estimated glomerular filtration rate; EoS=End of study; ET=Early termination; IMP=Investigational medicinal 
Product; IWRS=Interactive web response system; K+=Potassium; KCCQ=Kansas City Cardiomyopathy Questionnaire; L=Local; MRA=Mineralocorticoid receptor antagonist; NT-proBNP=N-terminal pro 
b-type brain natriuretic peptide; NYHA=New York Heart Association; PA=Potassium assessment; U=Unscheduled. 


 
 
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TABLE OF CONTENTS 
Page 
SIGNATURE PAGE ..........................................................................................................2 
EXECUTIVE SUMMARY OF CHANGES (PROTOCOL AMENDMENT 
VERSION 3.0 TO 4.0) ...............................................................................................3 
INVESTIGATOR AGREEMENT AND SIGNATURE PAGE .....................................6 
SYNOPSIS ..........................................................................................................................7 
STUDY SCHEMA ...........................................................................................................18 
SCHEDULE OF EVENTS ..............................................................................................19 
TABLE OF CONTENTS ................................................................................................22 
LIST OF TABLES ...........................................................................................................27 
LIST OF ABBREVIATIONS .........................................................................................28 
1. 
INTRODUCTION AND BACKGROUND ............................................................30 
1.1 
Background of the Disease and Treatment Options ..............................................30 
1.2 
Summary of Clinical Data .....................................................................................32 
2. 
RATIONALE ...........................................................................................................34 
3. 
STUDY OBJECTIVES AND ENDPOINTS ..........................................................36 
3.1 
Primary Objective ..................................................................................................36 
3.2 
Primary Endpoint ...................................................................................................36 
3.3 
Key Secondary Endpoints (Hierarchically Ordered) .............................................36 
3.4 
Other Secondary Endpoints ...................................................................................37 
3.5 
Other Endpoints .....................................................................................................37 
3.6 
Safety Endpoints ....................................................................................................38 
4. 
INVESTIGATIONAL PLAN .................................................................................39 
4.1 
Overall Study Design .............................................................................................39 
4.2 
Duration of Subject Participation and Study .........................................................42 
5. 
SELECTION AND WITHDRAWAL OF SUBJECTS ........................................43 
5.1 
Number of Subjects................................................................................................43 
5.2 
Inclusion Criteria ...................................................................................................43 
5.3 
Exclusion Criteria ..................................................................................................45 
5.4 
Randomization Criteria ..........................................................................................46 
5.5 
Discontinuing Patiromer/Placebo or Withdrawal of Subjects ...............................46 
5.5.1 
Discontinuation from Patiromer/Placebo............................................................46 
5.5.2 
Withdrawal from Study ......................................................................................47 
5.5.2.1 
Withdrawal of Consent ....................................................................................47 
5.5.2.2 
Investigator-Withdrawn Subject ......................................................................47 
5.5.2.3 
All Early Withdrawal Subjects ........................................................................48 


 
 
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6. 
STUDY TREATMENTS .........................................................................................49 
6.1 
Treatment Blinding ................................................................................................49 
6.1.1 
Unblinding ..........................................................................................................49 
6.2 
Dosage Forms/Formulation ...................................................................................50 
6.2.1 
Patiromer for Oral Suspension (Patiromer) or Placebo (Microcrystalline 
Cellulose) ............................................................................................................50 
6.3 
Drug Dosage and Administration ..........................................................................50 
6.3.1 
Treatment Arms ..................................................................................................50 
6.3.2 
Dosing and Administration Guidelines...............................................................50 
6.3.2.1 
Patiromer/Placebo ............................................................................................50 
6.4 
Package and Labeling ............................................................................................51 
6.5 
Study Treatment Allocation ...................................................................................52 
6.6 
Site Supply, Storage, Accountability .....................................................................53 
6.6.1 
Site Supply ..........................................................................................................53 
6.6.2 
Storage ................................................................................................................53 
6.6.3 
Accountability .....................................................................................................53 
6.7 
Drug Dose Modification ........................................................................................53 
6.7.1 
Management of Serum K+ ..................................................................................53 
6.7.1.1 
Management of Serum K+ in the Run-in Phase (Single-Blinded) ...................53 
6.7.1.2 
Management of Serum K+ in the Treatment Phase (Double-Blinded) ............55 
6.7.2 
Optimization of ACEi/ARB/ARNi or MRA Medications During 
Run-in Phase .......................................................................................................56 
6.7.3 
Temporary Interruption or Dose Reduction of HF Medications ........................58 
6.7.4 
Management of eGFR Level...............................................................................58 
6.7.5 
Usual Care...........................................................................................................58 
6.8 
Prohibited Therapy, Special Considerations, and Concomitant Treatment ...........59 
6.8.1 
Prohibited Medications .......................................................................................59 
6.8.2 
MRA ...................................................................................................................59 
6.8.2.1 
Potential Interactions with Spironolactone ......................................................59 
6.8.2.2 
Potential Interactions with Eplerenone ............................................................60 
6.8.3 
Caution Regarding the Use of NSAIDs or COX-2 Inhibitors ............................60 
6.8.4 
Concomitant Medications ...................................................................................60 
6.8.4.1 
Permitted K+ Binding Medications ..................................................................61 
6.8.4.2 
Magnesium Supplements .................................................................................61 
7. 
RISKS/PRECAUTIONS .........................................................................................62 
7.1 
Precautions .............................................................................................................62 
7.2 
Adverse Reactions .................................................................................................62 
8. 
STUDY PROCEDURES .........................................................................................63 
8.1 
Screening and Run-in Phase Procedures (Single-Blinded, Up to 12 Weeks) ........63 
8.1.1 
Screening Procedures ..........................................................................................63 
8.1.1.1 
Rescreening of Subjects ...................................................................................64 
8.1.2 
Run-in Phase (Single-Blinded) Procedures ........................................................65 
8.2 
Treatment Phase (Double-Blinded) Procedures.....................................................67 


 
 
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8.2.1 
Day 1/Baseline Visit ...........................................................................................67 
8.2.2 
Day 3 Visit (±1 Day) ..........................................................................................68 
8.2.3 
Week 1 Visit (±3 Days) ......................................................................................69 
8.2.4 
Week 2 Visit (±3 Days) ......................................................................................70 
8.2.5 
Week 6 Visit (±14 Days) ....................................................................................71 
8.2.6 
Week 18 Visit (-30 Days) and Every 3 Months Visit Until Event-Driven 
EoS (-30 Days)....................................................................................................71 
8.3 
Unscheduled Visit Procedures ...............................................................................73 
8.4 
EoS Visit Procedures .............................................................................................74 
8.5 
Early Termination Procedures ...............................................................................75 
8.6 
Potassium Assessment Visit Procedures (Up to 2 Weeks After Withdrawal 
from Patiromer/Placebo Treatment) ......................................................................75 
8.7 
Follow-up Phone Call (at Least 2 Weeks After EoS/ET Visit and Run-in 
Failure) ...................................................................................................................76 
8.8 
Allowed Adaptations in Case of Extraordinary Events, e.g., COVID-19 .............76 
9. 
STUDY ASSESSMENTS ........................................................................................78 
9.1 
Potassium ...............................................................................................................78 
9.1.1 
Preventing, Identifying, and Handling Hemolyzed Samples ..............................78 
9.1.2 
Deviant Serum Potassium Levels During Screening Process .............................78 
9.2 
Laboratory Tests ....................................................................................................79 
9.2.1 
MRA Level .........................................................................................................79 
9.3 
Vital Signs ..............................................................................................................80 
9.3.1 
Heart Rate ...........................................................................................................80 
9.3.2 
Blood Pressure ....................................................................................................80 
9.4 
Physical Examination.............................................................................................80 
9.5 
ECG Assessment ....................................................................................................80 
9.6 
Urine Collection for ACR ......................................................................................81 
9.7 
Patient-Reported Outcomes ...................................................................................81 
9.8 
Contraception in Women of Child-Bearing Potential ............................................82 
9.9 
Assessment of Left Ventricular Ejection Fraction .................................................82 
9.10 
HEOR Assessments ...............................................................................................82 
10. EVALUATION, RECORDING, AND REPORTING OF ADVERSE 
EVENTS ....................................................................................................................83 
10.1 
Definition of Adverse Events.................................................................................83 
10.2 
Adverse Event Reporting Period ...........................................................................83 
10.3 
Eliciting Adverse Events........................................................................................84 
10.4 
Assessing Adverse Events .....................................................................................84 
10.4.1 
Intensity/Severity ................................................................................................84 
10.4.2 
Causality and Reporting......................................................................................84 
10.4.3 
Outcome Categorization .....................................................................................85 
10.5 
Recording and Reporting .......................................................................................86 
10.5.1 
Persistent or Recurrent Adverse Events..............................................................86 
10.5.2 
Diagnosis Versus Signs and Symptoms .............................................................86 


 
 
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10.5.3 
Pre-existing Medical Conditions ........................................................................86 
10.5.4 
Clinical Laboratory Evaluations .........................................................................86 
10.5.5 
Abnormal Vital Signs and Other Abnormalities.................................................88 
10.6 
Adverse Drug Reaction and Reference Safety Information ..................................88 
10.6.1 
Adverse Drug Reaction .......................................................................................88 
10.6.2 
Reference Safety Information .............................................................................88 
10.7 
Serious Adverse Event ...........................................................................................89 
10.7.1 
Definition of Serious Adverse Event ..................................................................89 
10.7.1.1 
Situations That Are Not Considered SAEs ......................................................89 
10.7.2 
Serious Adverse Event Reporting .......................................................................90 
10.7.2.1 
Study Endpoints ...............................................................................................92 
10.7.3 
SUSARs ..............................................................................................................93 
10.7.3.1 
SUSAR Reporting ............................................................................................93 
10.8 
Special Situations ...................................................................................................93 
10.8.1 
Definition of Special Situations ..........................................................................93 
10.8.2 
Special Situation Recording and Reporting ........................................................94 
10.8.3 
Pregnancy Exposure and Birth Events................................................................94 
10.8.3.1 
Definition of Pregnancy Exposure and Birth Events .......................................94 
10.8.3.2 
Pregnancy Exposure and Birth Events Recording and Reporting ...................95 
11. STUDY COMMITTEES .........................................................................................96 
11.1 
DSMB ....................................................................................................................96 
11.2 
Event Adjudication Committee..............................................................................96 
11.3 
Steering Committee ...............................................................................................96 
12. STATISTICAL ANALYSIS ...................................................................................97 
12.1 
Statistical Methods .................................................................................................97 
12.2 
Sample Size and Power Calculations .....................................................................97 
12.3 
Randomization .......................................................................................................97 
12.4 
Analysis Sets ..........................................................................................................97 
12.4.1 
Randomized Set ..................................................................................................97 
12.4.2 
Full Analysis Set .................................................................................................97 
12.4.3 
Safety Set ............................................................................................................97 
12.4.4 
Run-in Phase Set .................................................................................................98 
12.5 
Background and Demographic Characteristics ......................................................98 
12.6 
Study Medication ...................................................................................................98 
12.7 
Concomitant Therapy.............................................................................................98 
12.8 
Efficacy Evaluations ..............................................................................................98 
12.8.1 
Primary................................................................................................................98 
12.8.2 
Key Secondary Endpoints (Hierarchically Ordered) ..........................................99 
12.8.3 
Other Secondary Endpoints ..............................................................................101 
12.8.4 
Other Endpoints ................................................................................................101 
12.8.5 
Subgroups of Interest ........................................................................................102 
12.9 
Safety Evaluations ...............................................................................................103 
12.10 Interim Analyses ..................................................................................................103 


 
 
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13. STUDY ETHICAL CONSIDERATIONS ...........................................................104 
13.1 
Ethical Conduct of the Study ...............................................................................104 
13.2 
Informed Consent.................................................................................................104 
13.3 
IRB or EC/IEC .....................................................................................................105 
14. QUALITY CONTROL AND QUALITY ASSURANCE ...................................106 
14.1 
Quality Management: Critical Processes and Data ..............................................106 
14.1.1 
Critical Processes ..............................................................................................106 
15. REPORTING AND RECORDING OF DATA ...................................................108 
15.1 
Source Documentation .........................................................................................108 
15.2 
Case Report Forms/Electronic Data Record ........................................................109 
15.3 
Records Retention ................................................................................................109 
15.4 
Site Documentation ..............................................................................................110 
16. PROCEDURE FOR MODIFICATION OF PROTOCOL OR PREMATURE 
TERMINATION OF THE STUDY .....................................................................111 
16.1 
Protocol Deviations ..............................................................................................111 
16.2 
Protocol Amendments ..........................................................................................111 
16.3 
Study Termination ...............................................................................................111 
17. POLICY FOR PUBLICATION AND PRESENTATION OF DATA ..............112 
18. REFERENCES .......................................................................................................113 
19. SUMMARY OF CHANGES: PROTOCOL AMENDMENT VERSION 3.0 
TO 4.0 ......................................................................................................................117 
 


 
 
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LIST OF TABLES 
Page 
Table 1 
Protocol Allowed Interventions for the Management of Hyperkalemia 
During the Blinded Treatment Phase .........................................................41 
Table 2 
BNP and NT-proBNP Threshold Levels (Based on Local Laboratory), 
Comorbidities, and Previous Hospitalizations ...........................................44 
Table 3 
Example of ACEi/ARB/ARNi or MRA Optimization During 
Run-in Phase ..............................................................................................57 
Table 4 
Rescreening of Subjects .............................................................................65 
Table 5 
List of Central Laboratory Assays .............................................................79 
 


 
 
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LIST OF ABBREVIATIONS 
ACEi 
Angiotensin-converting enzyme inhibitor 
ACR 
Albumin-to-creatinine ratio 
ADR 
Adverse drug reactions 
AE 
Adverse event 
ARB 
Angiotensin II receptor blocker 
ARNi 
Angiotensin receptor/neprilysin inhibitor 
BNP 
Brain natriuretic peptide 
BP 
Blood pressure 
CI 
Confidence interval 
CKD 
Chronic kidney disease 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
COX-2 
Cyclooxygenase-2 
CRO 
Contract Research Organization 
CV 
Cardiovascular 
DSMB 
Data and Safety Monitoring Board 
EAC 
Event Adjudication Committee 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
eGFR 
Estimated glomerular filtration rate 
EoS 
End of study 
ESRD 
End-stage renal disease 
ET 
Early termination 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GWTG-HF 
Get With The Guidelines-Heart Failure 
HEOR 
Health Economics and Outcomes Research 
HF 
Heart failure 
HFrEF 
Heart failure with reduced ejection fraction 


 
 
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HR 
Hazard ratio 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IMP(s) 
Investigational medicinal product(s) 
IRB 
Institutional Review Board 
IWRS 
Interactive web response system 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
KDOQI 
Kidney Disease Outcomes Quality Initiative 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model for repeated measures 
MRA 
Mineralocorticoid receptor antagonist 
MRI 
Magnetic resonance imaging 
NSAIDs 
Nonsteroidal anti-inflammatory drugs 
NT-proBNP 
N-terminal pro b-type brain natriuretic peptide 
NYHA 
New York Heart Association 
PT 
Preferred term 
RAASi 
Renin-angiotensin-aldosterone system inhibitor 
RSI 
Reference Safety Information 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SE 
Standard error 
SOC 
System organ class 
SS 
Safety set 
SUSAR 
Suspected unexpected serious adverse reaction 
T2DM 
Type 2 diabetes mellitus 
TEAE(s) 
Treatment-emergent adverse event(s) 
US 
United States 
WBC 
White blood cell count 


 
 
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1. INTRODUCTION AND BACKGROUND 
1.1 
Background of the Disease and Treatment Options 
Twenty-six (26) million people worldwide have a diagnosis of HF [5]. In their Heart 
Disease and Stroke Statistics—2017 Update, the American Heart Association (AHA) 
reported data from National Health and Nutrition Examination Survey 2011–2014, which 
estimates that 6.5 million Americans ≥20 years of age have HF. Projections show that with 
improved survival and the aging of the population, the prevalence of HF in the US will 
increase 46% from 2012 to 2030, resulting in more than 8 million people ≥18 years of age 
with HF. Currently, HF accounts for nearly 1 million annual hospitalizations in the US and 
more than 3 million physician office visits. By 2030, 1 in every 33 US citizens will have a 
diagnosis of HF. Accordingly, it is in the public interest that therapies which have shown 
reductions in CV mortality, reductions in HF hospitalizations, and improvements in patient 
quality of life be used and optimally implemented [6,7,8]. Renal insufficiency is common 
in HF and is independently associated with increased all-cause and CV mortality [9]. 
However, in patients with advanced chronic kidney disease (CKD) (eGFR <30 
mL/min/1.73 m2) evidence-based strategies for improving CV outcomes remain almost 
unavailable [10]. 
HF mortality remains high. Approximately 50% of people diagnosed with HF will die 
within 5 years, but mortality rates have improved in the past 20 years, and this has been 
primarily because of evidence-based approaches to treating HF risk factors and 
comorbidities, as well as use of ACEi, beta-blocker, MRA, coronary revascularization, 
implantable cardioverter-defibrillators, and cardiac resynchronization therapeutic 
strategies [6]. 
However, evidence suggests that these treatments are not being implemented as 
recommended in HF treatment guidelines. Data from the Get With The Guidelines-Heart 
Failure (GWTG-HF) registry suggests that approximately 47% of individuals admitted to 
the hospital with HF should have had initiation of at least 1 new medication on discharge. 
The 
GWTG-HF 
registry 
2008–2013 
collected 
prescribing, 
indications, 
and 
contraindications for ACEi or ARB, beta-blocker, MRA, hydralazine/isosorbide dinitrate, 
and anticoagulants. The difference between a patient’s medication regimen at hospital 
admission and that which was recommended by HF quality measures at discharge was 
calculated. Among 158,922 patients from 271 hospitals with a primary discharge diagnosis 
of HF, initiation of ACEi/ARB was indicated in 18.1% of all patients, 55.5% of whom had 
not been receiving ACEi/ARB at admission. Beta-blockers were indicated in 20.3%, 50.5% 
of whom had not been receiving beta-blockers at admission, and initiation of MRA was 
indicated in 24.1%, 87.4% of whom had not been receiving MRA at admission. A quarter 
of patients hospitalized with HF needed to start more than 1 medication to meet HF quality 
measures, and a significant proportion of these patients were not taking these medications 
at admission, excluding them from the mortality and morbidity benefits attributed to these 
treatments which have earned Class I recommendations in the HF treatment guidelines 
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Similar findings have been seen in the European Society of Cardiology Heart Failure 
Long-Term Registry. In patients with chronic HFrEF, renin-angiotensin system blockers, 
beta-blockers, and MRA were used in 92.2, 92.7, and 67.0% of patients, respectively. 
About 70% of patients did not receive the target dosage of these drugs [14]. Among reasons 
for non-adherence or not achieving the target dose with ACEi, ARB, or MRA were 
contraindication or lack of tolerance, most often due to worsening renal function, 
symptomatic hypotension, or hyperkalemia. The reduction in renal function associated with 
HF, older age, and comorbidities such as diabetes mellitus hampers K+ excretion and so 
makes patients with HF more likely to develop hyperkalemia. Additionally, the 
guideline-recommended pharmacologic treatments, which include multiple neurohormonal 
antagonists of the renin-angiotensin-aldosterone system (RAAS), increase the risk of 
hyperkalemia, especially when used in combination [15]. 
Despite advances in treatment of CV diseases, evidence-based strategies for improving CV 
outcomes in patients with advanced CKD remain almost unavailable [10]. This is in part 
because the efficacy and safety studies that support drug approval typically exclude patients 
with more advanced CKD; although criteria vary, typically patients with Stages 4 and 5 
CKD are excluded from CV outcome studies. As a consequence, very few adequately 
powered CV outcome trials that focus specifically on patients with advanced CKD have 
been done [16]. 
Patients with severe renal insufficiency have generally been excluded from the RAASi 
outcomes trials. Thus, eGFR <30 mL/min/1.73 m2, i.e., CKD Stages 4 and 5 (Europe), 
constitutes contraindications or cautions when initiating RAASi medication [17]. For 
example, cautious use or avoidance of MRAs is recommended in HFrEF patients with 
eGFR <30 mL/min/1.73 m2 or serum K+ >5 mEq/L [12,13]. 
New K+ binders might also enable study of patients that have been excluded or 
underrepresented in RAASi clinical trials, e.g., those with eGFR <30 mL/min/1.73 m2 or 
serum K+ >5.0–5.5 mEq/L [18]. K+ binders may be used to study the potential benefit of 
RAASi in populations not studied in the past due to the risk of hyperkalemia, for example, 
in patients with eGFR <30 mL/min/1.73 m2. Also, K+ binders may enable investigating the 
benefit of higher doses MRA therapy [19]. 
Epstein et al, 2015 examined renin-angiotensin-aldosterone-system inhibitor (RAASi) dose 
levels in a US patient population. They investigated the impact of hyperkalemia on RAASi 
dose and the association between dose levels and clinical outcomes [20]. Patients were 
classified by comorbidities CKD, HF, or diabetes and RAASi dose level at index date, as 
determined by prescription information (supramaximal = above labeled dose; maximal = 
labeled dose; submaximal = less than labeled dose; or discontinued). One-third (32.8%) of 
all qualifying subjects experienced at least 1 hyperkalemic event (serum K+ >5.0 mEq/L). 
Among subjects with HF and Stage 3–4 CKD, maximum doses were prescribed in 19% of 
subjects; 64% of subjects were prescribed submaximal doses, and 16% of patients 
discontinued treatment with RAASi medications as of the index date. Analysis of RAASi 
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subjects had changes in their dose following an episode of elevated serum K+, with dose 
changes occurring more frequently after moderate-to-severe hyperkalemia events 
(serum K+ >5.5 mEq/L). Patients on a maximum dose of a RAASi were down-titrated to a 
submaximal dose or discontinued the RAASi nearly half the time (47%) after 
moderate-to-severe hyperkalemia events and 38% of the time after mild events. Among 
patients on submaximal doses of RAASi, moderate-to-severe hyperkalemia events were 
followed by submaximal dose maintenance in 55% of patients and discontinuation in 27% 
of patients, compared with dose maintenance in 61% after mild hyperkalemia events and 
discontinuation in 24% after mild events. Nearly 60% of subjects with HF who 
discontinued RAASi experienced an adverse outcome or mortality compared with 52.3% 
of patients on submaximal doses and 44.3% of patients on maximum doses (all 
comparisons p<0.05). Patients on submaximal doses or who discontinued RAASi therapy 
showed consistently worse outcomes compared with patients on maximum doses, 
irrespective of comorbidity status (CKD, HF, diabetes mellitus) or patient age [20], 
suggesting that patients may benefit from continuing maximal, guideline-directed doses of 
medications, if hyperkalemia can be managed. 
Although these data are taken from a retrospective database analysis with many limitations, 
they are consistent with other observational and retrospective studies [11,14,21,22,23] that 
have reported a meaningful gap between recommendations in guidelines and real-world 
practice. Closing this gap between the number of guideline-RAASi-eligible patients with 
HFrEF and the actual number receiving RAASi may provide an opportunity to further 
reduce CV mortality, hospitalizations for CV events (including HF), and healthcare costs. 
New treatments for hyperkalemia may offer a solution to intolerance or contraindication 
due to hyperkalemia while on RAASi medications and may help close this gap. Veltassa® 
(patiromer) for Oral Suspension is a non-absorbed, polymeric K+ binder that is approved 
for the treatment of hyperkalemia [24]. 
1.2 
Summary of Clinical Data 
In a Phase 3 study (RLY5016-301) CKD patients on RAASi with serum K+ levels 
≥5.1-<6.5 mEq/L (n=243) received patiromer (8.4 g daily initially) for 4 weeks (Initial 
Treatment Phase); the primary efficacy endpoint was mean change in serum K+ from 
Baseline to Week 4. Eligible patients (those with Baseline K+ ≥5.5-<6.5 mEq/L and levels 
≥3.8–<5.1 mEq/L at the end of Week 4) entered an 8-week randomized withdrawal phase 
and were randomly assigned to continue patiromer or switch to placebo; the primary 
efficacy endpoint was the change in the serum K+ over the first 4 weeks of that phase. One 
hundred two (102) patients (42%) had HF (per the Investigator’s assessment). A 
prespecified analysis of these subjects demonstrated a mean (±standard error (SE)) change 
in serum K+ from Baseline to Week 4 of -1.06±0.05 mEq/L (95% confidence interval (CI), 
-1.16, -0.95; p<0.001); 76% (95% CI, 69, 84) achieved target serum K+ (3.8-<5.1 mEq/L). 
In the randomized withdrawal phase, the median increase in serum K+ from Baseline of that 
phase was greater with placebo (n=22) than patiromer (n=27) (p<0.001); recurrent 
hyperkalemia (serum K+ ≥5.5 mEq/L) occurred in 52% on placebo and 8% on patiromer 


 
 
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(p<0.001). By the end of the randomized withdrawal phase, 55% of HF patients on placebo 
and 100% of HF patients on patiromer were still receiving RAASi [25]. These findings 
support the use of patiromer to manage hyperkalemia in HF patients. 
In addition, the effect of treatment with patiromer for up to 52 weeks was evaluated in an 
open-label study of 304 hyperkalemic patients with CKD and Type 2 diabetes mellitus on 
RAASi therapy (Study RLY5016-205). This study demonstrated that the treatment effect 
on serum K+ was maintained during continued therapy. Patiromer was well tolerated over 
this longer treatment period, supporting its use in the management of more chronic 
hyperkalemia seen with RAASi treatment of HF in some subjects [26]. 


 
 
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2. RATIONALE 
Patients with HF and CKD are among those at the highest risk of severe outcomes of 
COVID-19 infection. Treatment practices for this patient population have been adapted to 
reduce risks of exposure to infection during hospital visits, disrupting clinical care and 
impacting the conduct of randomized clinical trials such as the DIAMOND study. Priority 
has been to protect the safety of the patients in the trial, and to respect the need of the 
healthcare system to prioritize efforts to contain the pandemic. This has led to fewer 
patients enrolled in the trial than anticipated.  
Due to the changing treatment landscape in HFrEF, the lower-than-expected recruitment 
rate due to the COVID-19 pandemic and the consecutively lower-than-expected event rates, 
the Sponsor with recommendations from the Executive Steering Committee of the study 
decided to change the study objectives and the primary and secondary endpoints. The 
decision was made to maximize the scientific value of the data already collected in 
DIAMOND, while at the same time ensuring the safety and wellbeing of patients. It also 
took into account the way the unprecedented demands of the COVID-19 pandemic had 
altered clinical care during this period. 
It is therefore hypothesized that patiromer can be used to treat hyperkalemia that develops 
in high-risk HFrEF patients while receiving treatment with RAASi. This is expected to 
result in improved adherence to guideline RAASi treatment, and less hyperkalemic events 
are expected compared with the current standard of care in these patients, which includes 
RAASi dose reduction or discontinuation. 
We hypothesize that patiromer can be used to treat hyperkalemia that develops in high-risk 
HFrEF patients while receiving treatment with RAASi. This is expected to result in 
improved adherence to guideline RAASi treatment, and we expect reductions in CV 
mortality and hospitalizations for CV events compared with current standard of care to 
manage hyperkalemia in these patients, which includes RAASi dose reduction or 
discontinuation. 
Therefore, the present multinational, multicenter, double-blind, placebo-controlled, 
randomized withdrawal, parallel group study of subjects with HFrEF who have developed 
hyperkalemia (serum K+ >5.0 mEq/L) while being treated with RAASi medications is 
re-designed to determine if patiromer treatment will result in better K+ control compared 
with placebo treatment. 
The selection criteria for the present study will provide a cohort of subjects who have risk 
factors for hyperkalemia (e.g., CKD, diabetes mellitus, older age), who have demonstrated 
hyperkalemia and who pose the greatest therapeutic dilemma to clinicians, since they have 
the highest risk of developing hyperkalemia but stand to benefit most from these RAASi 
therapies [27]. 


 
 
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The study includes a single-blinded Run-in Phase and a double-blinded Treatment Phase. 
During the Run-in Phase, doses of RAASi medications will be adjusted consistent with 
guideline therapy, including initiation and up-titration of an MRA. Serum K+ will be 
managed through treatment with patiromer in all subjects during the Run-in Phase. Doses 
of patiromer will be adjusted according to a Sponsor-provided algorithm to maintain serum 
K+ 4.0–5.0 mEq/L. Mortality is increased on the lower end of the serum K+ “normal range” 
with K+ values as high as 4.1 mEq/L, so a lower limit of 4.0 mEq/L was chosen for the 
target range [8,28,29]. The 4.0–5.0 mEq/L target range will allow optimization of HF 
treatment while managing serum K+ in all subjects before randomization. After the Run-in 
Phase, subjects are randomized 1:1 to either continued patiromer treatment (patiromer 
group) or the withdrawal of patiromer (placebo group); subjects and site study personnel 
will be blinded to treatment assignment. 
We hypothesize that the ability of patiromer to treat hyperkalemia will allow better 
adherence to HF guidelines in the patiromer arm than in the placebo arm and that this 
difference will lead to a difference in the serum K+ changes from Baseline compared with 
placebo. 


 
 
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3. STUDY OBJECTIVES AND ENDPOINTS 
3.1 
Primary Objective 
• To assess the effects of patiromer on serum K+ in HF patients compared with placebo 
3.2 
Primary Endpoint 
• Changes in serum K+ levels from Baseline 
Note: All analyses will be restricted to serum K+ levels and not substituted by plasma 
values as they are known to be systematically lower. Both central laboratory and local 
laboratory values will be used at all visits; however, if both values are available at one 
visit, then central laboratory values will be used. 
3.3 
Key Secondary Endpoints (Hierarchically Ordered) 
1. Hyperkalemia events with a serum K+ value >5.5 mEq/L 
2. Durable enablement to stay on the MRA target dose (of 50 mg daily spironolactone or 
eplerenone, respectively) as assessed by the between treatment group difference of the 
cumulative frequency of patients not staying on that target dose 
Note: Discontinuation of the target dose for at least 14 days (or less if at the EoS) is 
required to confirm this endpoint. 
3. Investigator reported events of hyperkalemia (first and recurrent events) 
4. Hyperkalemia-related hard outcomes endpoints (Win Ratio) 
a. Time to CV death 
b. Total number of CV hospitalizations 
c. Total number of hyperkalemia toxicity events with serum K+ >6.5 mEq/L 
d. Total number of hyperkalemia events with serum K+ >6.0-6.5 mEq/L 
e. Total number of hyperkalemia events with serum K+ >5.0 mEq/L 
5. RAASi Use Score (Win Ratio) 
Note: This score (of 0–8 points) will be analyzed at the respective time points for each 
patient in each comparison, and it consists of the following components: 
a. All-cause death 
b. Occurrence of a CV hospitalization 


 
 
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c. HF medication use and dose for i) an ACEi/ARB/ARNi, ii) an MRA, and ii) a beta-
blocker 
3.4 
Other Secondary Endpoints 
• Durable enablement to stay on the target dose of ACE/ARB/ARNi 
Note: Discontinuation of the target dose for at least 14 days (or less if at the EoS) is 
required to confirm this endpoint 
• Durable hyperkalemia-free enablement to stay on the MRA target dose (days on 50mg 
MRA without presence of hyperkalemia) 
• Total number of hyperkalemia toxicity events with serum K+ >6.5 mEq/L 
• Total number of hyperkalemia events with serum K+ >6.0-6.5 mEq/L 
• Emergency treatment for hyperkalemia (hospitalization or emergency room) 
• Total number of hyperkalemia events with serum K+ >5.0 mEq/L 
• KCCQ questionnaire, changes in OSS, CSS and TSS  
• Investigator reported events of hyperkalemia (first events) 
• Proportion of subjects on ≥50% of target dose of ACEi, ARB, or ARNi and ≥50% of 
target dose of MRA at the EoS Visit 
• Time to first occurrence of CV death or CV hospitalization  
3.5 
Other Endpoints 
• CV death 
• First and recurrent CV hospitalizations 
• First and recurrent HF hospitalizations (or equivalent in outpatient clinic) 
• Patient-reported outcome: EQ-5D-5L questionnaire 
• Proportion of subjects on any dose of MRA at the EoS Visit 
• Proportion of subjects on any dose of ACEi, ARB, or ARNi at the EoS Visit 
• Change in proteinuria from Screening 
• Change in NT-proBNP from Screening 


 
 
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• Change in high sensitivity troponin from Baseline 
• Functional status by NYHA class 
• 30-day HF re-hospitalization after a prior HF hospitalization 
• HEOR analyses 
• Changes in serum K+ from Baseline to individual visits 
3.6 
Safety Endpoints 
• AEs, including all-cause mortality 
• All-cause mortality 
• Slope of eGFR change during the study 
• Decline in eGFR >50% or ESRD, renal death, or need for dialysis 
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4. INVESTIGATIONAL PLAN 
4.1 
Overall Study Design 
See Study Schema for an overview of the study design. The study consists of: 
• Screening Phase (the Screening Phase may last up to 10 calendar days) 
• Run-in Phase (single-blinded), up to 12 weeks; weekly visits recommended but are at 
the Investigator’s discretion 
• Treatment Phase (double-blinded); the scheduled visits are listed below: 
− 
Day 1/Baseline 
− 
Day 3 (±1 day) 
− 
Week 1 (±3 days) 
− 
Week 2 (±3 days) 
− 
Week 6 (±14 days) 
− 
Week 18 (−30 days), first Every 3 Months visit 
− 
Visits every 3 months (−30 days) thereafter through the end of the study 
− 
EoS Visit 
• Potassium Assessment Visit (occurs within 2 weeks after patiromer or placebo is 
discontinued) 
Note: Subjects who prematurely discontinue patiromer/placebo during the Blinded 
Treatment Phase remain in the study. 
• Follow-up Phone Call (at least 2 weeks after the EoS for the assessment of safety; for 
subjects who discontinue patiromer at the EoS Visit, and attend the Potassium 
Assessment Visit 2 weeks later, a Follow-up Phone Call will not be needed) 
• Unscheduled Visit (during the Treatment Period, anytime there are changes to ACEi, 
ARB, ARNi and/or MRA dose or interventions for serum K+ outside the desired range, 
additional Unscheduled Visits should occur weekly until the ACEi, ARB, ARNi and/or 
MRA dose or serum K+ has been stable for at least 2 consecutive visits) 
Screening Phase and Run-in Phase (Single-Blinded, Up to 12 Weeks): 
At the end of the Screening Phase, subjects who satisfy the eligibility criteria will be 
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will potentially benefit from treatment and not unnecessarily expose those who will not. In 
addition, the Run-in Phase is for management of serum K+ with patiromer to allow 
optimization of RAASi medications and their dosage (including initiation of MRA if not 
already receiving an MRA). 
All subjects who meet the eligibility criteria for the Run-in Phase will initiate patiromer 
(1 packet/day), single-blinded. 
Subjects with 2 Screening K+ values >5.0 mEq/L are considered hyperkalemic; these 
patients begin patiromer when they qualify for the Run-in Phase, i.e., on the same day 
Run-in qualification is met or the next day. 
Note: If one screening K+ value is >5.0 mEq/L and one value is ≤5.0 mEq/L, then a third 
peripheral venipuncture is performed within 1 day to obtain clarity, whether subject is 
hyperkalemic or normokalemic (local serum K+ ≥4.0–≤5.0 mEq/L). 
All other subjects are considered normokalemic and serum K+ will be measured again latest 
after the first week during the Run-in Phase. Patiromer will be started at this first Run-in 
Visit only if subjects are still normokalemic or have progressed to hyperkalemia; in case of 
newly observed hypokalemia (local serum K+ <4.0 mEq/L) during the first Run-in Week, 
patiromer must not be given. In subjects with hypokalemia serum K+ must be controlled 
after 3 days. During the first week of Run-in, ACEi/ARB/ARNi and/or MRA doses ideally 
remain unchanged, if clinically indicated. On or after the Run-in Week 1 Visit, up-titration 
of ACEi/ARB/ARNi and/or MRA may be initiated. 
Patiromer is titrated during Run-in Phase to achieve target local serum K+ level of 
≥4.0-≤5.0 mEq/L; see Section 6.7.1.1 for patiromer titration algorithm. Note: Depending 
on the actual local serum K+ value this could include patiromer 0 g/day (i.e., 0 packets/day) 
during the Run-in Phase. 
Optimization of ACEi/ARB/ARNi or MRA During Run-in Phase: 
The Investigator should manage ACEi/ARB/ARNi or MRA dose initiation, escalation and 
maintenance with the aim to achieve 100% of target doses as per the Study Manual, using 
clinical judgment to customize ACEi/ARB/ARNi or MRA addition or dose escalation 
based on subject response; see Section 6.7.2, Section 6.8.2, and Study Manual [1] for a 
summary of practice guideline recommendations.  
Initiation or escalation of ACEi/ARB/ARNi or MRA dose should be made with caution 
when local serum K+ is >5.0 mEq/L. Assessment of serum K+ will occur at each visit. The 
patiromer dose is titrated based on the subject’s K+ level. 
Subjects may be randomized anytime (but no later than 12 weeks) during the Run-in Phase 
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Treatment Phase (Double-Blinded): 
After the Run-in Phase (single-blinded), eligible subjects will be randomized in a 1:1 ratio, 
to treatment with patiromer or placebo double-blinded; see Study Schema. 
Randomized subjects will begin their assigned treatment (patiromer or placebo) using the 
same number of packets established for patiromer at the end of the Run-in Phase and will 
continue the ACEi/ARB/ARNi and MRA regimen being administered at the end of the 
Run-in Phase.  
Anytime during the Treatment Phase when subjects are on less than the target dose of either 
ACEi/ARB/ARNi or MRA, up-titration should be attempted if serum K+ remains in the 
normokalemic range (serum K+ ≥4.0–≤5.0 mEq/L) and no other contravening conditions 
are present. 
After randomization, serum K+ will be measured prior to initiation of assigned 
patiromer/placebo, double-blinded, on Treatment Day 1/Baseline (if not already obtained 
that day), and at each subsequent scheduled and unscheduled visit during the Treatment 
Phase. See Table 1 for the allowed interventions for the management of hyperkalemia 
during the Treatment Phase. 
Table 1 
Protocol Allowed Interventions for the Management of Hyperkalemia 
During the Blinded Treatment Phase 
1. Up-titration of patiromer/placebo if on <3 packets per day 
2. Down-titration or discontinuation of ACEi, ARB, ARNi and/or MRA 
3. Initiate or increase diuretics 
4. Dietary K+ restriction 
Notes: ACEi=Angiotensin-converting enzyme inhibitor; ARB=Angiotensin II receptor blocker; ARNi=Angiotensin receptor/neprilysin 
inhibitor; K+=Potassium; MRA=Mineralocorticoid receptor antagonist. 
 
If local K+ is >5.5 mEq/L, one or more of these interventions must be initiated either 
individually or in combination following the recommendations by practice guidelines. 
Repeat the K+ measurement within 7 days; if local K+ remains >5.5 mEq/L consider 
repeating the intervention or using other interventions in the order presented in Table 1. 
If local K+ is between >5.0 mEq/L and 5.5 mEq/L, one or more of these interventions may 
be initiated per Investigator discretion. 
Urgent treatment of hyperkalemia should be in accordance with usual care and the 
Investigator’s judgment. As described in Section 6.8.4.1, the only K+ binding medications 
permitted for use during the study are temporary use of sodium or calcium polystyrene 
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<5.0 mEq/L, whichever occurs first. Patiromer/placebo must be withheld during temporary 
use of permitted K+ binding medications. 
If hypokalemia develops during the Treatment Phase, study drug should be down-titrated 
(lowest acceptable dose is 0 packets/day) until local serum K+ ≥4.0 mEq/L. 
Samples will be collected at each scheduled visit, at minimum, for the measurement of 
serum K+ and creatinine (for calculation of eGFR). Subject reported outcome will be 
assessed using the KCCQ and EQ-5Q-5L. See Schedule of Events for full details of 
protocol required procedures and laboratory assessments at the applicable visits (and 
timings of each visit). 
4.2 
Duration of Subject Participation and Study 
Each eligible subject’s participation includes a Screening Phase (within a maximum of 
10 calendar days), Run-in Phase (single-blinded, up to 12 weeks) followed by the 
Treatment Phase (double-blinded, variable per subject). Study duration for individual 
subjects will vary, depending on their individual enrollment date. The common EoS will 
occur when 820 subjects have completed the Week 6 visit. Recruitment will be stopped 
when it is projected that a sufficient number of subjects have been enrolled in order for 
820 subjects to reach the Week 6 visit. Sites will be notified of the common EoS date prior 
to study closure and should advise ongoing study subjects of the study termination date 
thereafter; see Section 8.4 for detailed description of the EoS procedures. 
Patients who prematurely discontinue patiromer/placebo will remain in the study for the 
collection of composite endpoint event data up to and including the common EoS and will 
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5. SELECTION AND WITHDRAWAL OF SUBJECTS 
5.1 
Number of Subjects 
For detailed justification of the sample size please refer to Section 12.2. 
5.2 
Inclusion Criteria 
The following criteria must be met for each subject prior to entry in the Run-in Phase: 
1. Subject provides written informed consent prior to study participation 
2. Age at least 18 years or greater 
3. Current NYHA Class II–IV 
4. Left ventricular ejection fraction ≤40%, measured by any echocardiographic, 
radionuclide, MRI, angiographic, or computerized tomography method in the last 12 
months (without subsequent measured ejection fraction >40% during this interval) 
5. Receiving any dose of a beta-blocker for the treatment of HF or unable to tolerate beta-
blockers (reason documented) 
6. eGFR ≥30 mL/min/1.73 m2 at Screening (based on a single local laboratory analysis of 
serum creatinine and calculation using the CKD-EPI equation; see Section 9.2) 
7. Hyperkalemia at Screening (defined by 2 local serum K+ values of >5.0 mEq/L, each 
obtained from a separate venipuncture, e.g., one in each arm or two separate 
venipunctures in the same arm) while receiving an ACEi/ARB/ARNi, and/or an MRA 
OR 
Normokalemia at Screening (defined by 2 local serum K+ ≥4.0–≤5.0 mEq/L, each 
obtained from a separate venipuncture, e.g., one in each arm or two separate 
venipunctures in the same arm) with a history of hyperkalemia documented by a usual 
care serum K+ measurement >5.0 mEq/L while on RAASi treatment in the 12 months 
prior to Screening leading to a subsequent and permanent dose decrease or 
discontinuation of one or more RAASi medications 
8. Females of child-bearing potential must be non-lactating, must have a negative 
pregnancy test at Screening, and must agree to continue using contraception (see 
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9. With hospitalization for HF or equivalent (e.g., emergency room or outpatient visit for 
worsening HF during which the patient received intravenous medications for the 
treatment of HF) within the last 12 months before Screening 
a) Without atrial fibrillation at Screening, BNP level must be greater than 150 pcg/mL 
(18 pmol/L) or NT-proBNP must be greater than 600 pcg/mL (71 pmol/L) 
b) With atrial fibrillation at Screening, BNP level must be greater than 300 pcg/mL 
(35 pmol/L) or NT-proBNP must be greater than 1,200 pcg/mL (142 pmol/L) 
OR 
Without hospitalization for HF or equivalent (e.g., emergency room or outpatient visit 
for worsening HF during which the subject received intravenous medications for the 
treatment of HF) within the last 12 months before Screening 
a) Without atrial fibrillation at Screening, BNP level must be greater than 300 pcg/mL 
(35 pmol/L) or NT-proBNP must be greater than 1,200 pcg/mL (142 pmol/L) 
b) With atrial fibrillation at Screening, BNP level must be greater than 600 pcg/mL 
(71 pmol/L) or NT-proBNP must be greater than 2,400 pcg/mL (284 pmol/L) 
Note: Table 2 provides the same information of Inclusion Criterion 9 as described in the 
text above. 
Table 2 
BNP and NT-proBNP Threshold Levels (Based on Local Laboratory), 
Comorbidities, and Previous Hospitalizations 
 
Subjects with hospitalization for 
HF or equivalent(1) within last 
12 months 
Subjects with no hospitalization for 
HF or equivalent(1) within last 
12 months 
Subjects presenting without 
atrial fibrillation when the 
blood sample was collected 
BNP(2) >150 pcg/mL  
(18 pmol/L) 
or 
NT-proBNP >600 pcg/mL 
(71 pmol/L) 
BNP(2) >300 pcg/mL  
(35 pmol/L) 
or 
NT-proBNP >1,200 pcg/mL 
(142 pmol/L) 
Subjects presenting with 
atrial fibrillation when the 
blood sample was collected 
BNP(2) >300 pcg/mL  
(35 pmol/L) 
or 
NT-proBNP >1,200 pcg/mL 
(142 pmol/L) 
BNP(2) >600 pcg/mL  
(71 pmol/L) 
or 
NT-proBNP >2,400 pcg/mL 
(284 pmol/L) 
1 E.g., urgent emergency room or outpatient visit for worsening HF during which the subject received intravenous medications for the 
treatment of HF. 
2 For subjects treated with ARNi (sacubitril/valsartan) in the previous 4 weeks before Screening only NT-proBNP values are to be 
considered. 
Notes: ARNi=Angiotensin receptor/neprilysin inhibitor; BNP=Brain natriuretic peptide; HF=Heart failure; NT-proBNP=N-terminal 
pro b-type brain natriuretic peptide. 
 


 
 
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5.3 
Exclusion Criteria 
Subjects who meet any of the following criteria during Screening will be excluded: 
1. 
Current acute decompensated HF within 4 weeks before Screening. Subjects with a 
discharge from a hospitalization for acute decompensation of HF longer than 4 weeks 
before Screening may be included 
2. 
Symptomatic hypotension or systolic blood pressure <90 mmHg 
3. 
Significant primary aortic or mitral valvular heart disease unrelated to HF (except 
secondary mitral regurgitation due to left ventricular dilatation) 
4. 
Heart transplantation or planned heart transplantation (i.e., currently on a heart 
transplant waiting list) during the study period 
5. 
Diagnosis of peripartum or chemotherapy-induced cardiomyopathy or acute 
myocarditis in the previous 12 months 
6. 
Implantation of a cardiac resynchronization therapy device in the previous 4 weeks 
before Screening 
7. 
Restrictive, constrictive, hypertrophic, or obstructive cardiomyopathy 
8. 
Untreated ventricular arrhythmia with syncope in the previous 4 weeks before 
Screening 
9. 
History of, or current diagnosis of, a severe swallowing disorder, moderate-to-severe 
gastroparesis, or major GI surgery (e.g., bariatric surgery or large bowel resection) 
10. A major CV event within 4 weeks prior to Screening, including acute myocardial 
infarction, stroke (or transient ischemic attack), a life-threatening atrial or ventricular 
arrhythmia, or resuscitated cardiac arrest 
11. Note: This exclusion criterion is included in the new Inclusion Criterion 9 
12. Liver enzymes (alanine aminotransferase, aspartate aminotransferase) >5 times upper 
limit of normal at Screening based on the local laboratory 
13. Diagnosis or treatment of a malignancy in the past 2 years, excluding non-melanoma 
skin cancer and carcinoma in situ of the cervix, prostate cancer with Gleason score 
<7, or a condition highly likely to transform into a malignancy during the study 
14. Presence of any condition (e.g., drug/alcohol abuse; acute illness), in the opinion of 
the Investigator, that places the subject at undue risk, or prevents complete 
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15. Use of any investigational product for an unapproved indication within 4 weeks 
before Screening or currently enrolled in any other type of medical research judged 
not to be scientifically or medically compatible with this study 
16. Known hypersensitivity to patiromer (RLY5016) or its components 
17. Note: This exclusion criterion is modified and partially incorporated in the Exclusion 
Criterion 18 
18. Subjects currently being treated with or having taken any one of the following 
medications in the 7 days prior to Screening: sodium or calcium polystyrene sulfonate 
or sodium zirconium cyclosilicate, or patiromer 
19. An employee, spouse, or family member of the Sponsor (Vifor Pharma), 
investigational site or the CRO 
5.4 
Randomization Criteria 
Subject may be randomized anytime (but no later than 12 weeks) during the Run-in Phase 
when they meet all of the following criteria: 
1. 
Current MRA dose is at least the target dose* (e.g., spironolactone 50 mg/day, 
eplerenone 50 mg/day) and has been stable for at least 1 week. 
2. 
Current ACEi/ARB/ARNi is ≥50% of the target dose* and has been stable for at least 
1 week. 
3. 
Current patiromer dose is at least 1 packet daily. 
4. 
Current local serum K+ level is ≥4.0–≤5.0 mEq/L. 
* Study-specific target doses as per Table 4 in the Study Manual. 
5.5 
Discontinuing Patiromer/Placebo or Withdrawal of Subjects 
5.5.1 
Discontinuation from Patiromer/Placebo 
The management of ACEi/ARB/ARNi and/or MRA are at the discretion of the Investigator 
during the Blinded Treatment Phase. If one or more ACEi/ARB/ARNi and/or MRA are 
adjusted, patiromer/placebo may be adjusted accordingly, based on changes in local serum 
K+ levels. The lowest dose of patiromer/placebo is 0 packets/day. It is recommended to 
discuss with the subject a study treatment interruption (dose level 0 packets/day) rather than 
a permanent patiromer/placebo discontinuation, which should only occur when it is 
requested by the Investigator or the subject. 
Subjects who discontinue from patiromer/placebo treatment after randomization and prior 
to completion of the study will be encouraged to return within 2 weeks, or as soon as 
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discontinue from patiromer/placebo treatment after randomization and prior to the common 
EoS will continue in the study for collection of composite endpoint events. These subjects 
will be treated in accordance with the standard of care per the Investigator’s judgment. 
Note: Subjects who discontinue from patiromer during the Run-in Phase will also be 
encouraged to return for a Potassium Assessment Visit within 2 weeks, or as soon as 
possible thereafter. 
5.5.2 
Withdrawal from Study 
5.5.2.1 
Withdrawal of Consent 
Within the provisions of informed consent and good clinical judgment with respect to the 
subject’s safety, every attempt should be made to have subjects complete both the 
Treatment Phase and the Potassium Assessment Visit after discontinuation of 
patiromer/placebo. Subjects will be informed that they will be free to withdraw from the 
study at any time. However, should a subject withdraw, every effort will be made to 
determine the reason why the subject has withdrawn his/her consent. Although subjects 
will not be obliged to give a reason for withdrawing consent, the Investigator will use best 
efforts to obtain the reason, while fully respecting the subject’s rights. Reasons for 
withdrawal of consent, when provided by the subject, will be recorded in the eCRF, and 
every effort should be made by the site to ensure that the subject completes the procedures 
described for early termination (ET) (Section 8.5). Every effort will be made to contact a 
subject who fails to attend a study visit, in order to ensure that the subject is in satisfactory 
health. 
The subject who wishes to withdraw consent will be offered the opportunity to withdraw 
consent only partially and to accept any or all of the following: 
• Providing information about his/her own health status by telephone or other means until 
the common EoS date 
• Allowing Primary Care physicians or family to be contacted to provide information 
about the subject’s health status 
• Allowing 1 final contact at the end of the study (at or after the EoS) 
5.5.2.2 
Investigator-Withdrawn Subject 
The Investigator and/or the Medical Monitor may exercise his or her medical judgment to 
terminate a subject’s participation in the study if they determine that the subject’s continued 
participation in the study is a potential safety concern, related to e.g., subject’s 
non-adherence to the study protocol, subject’s non-compliance to study medication, any 
medical condition that the Investigator or Sponsor determines may jeopardize the subject’s 
safety if he or she continues in the study, subject’s excessive drug/alcohol abuse. The 
Investigator may also terminate a subject’s participation due to any condition preventing 
complete participation in the trial procedures, or potentially jeopardizing the quality of the 
study data. The Investigator will immediately inform the Medical Monitor of plans for early 


 
 
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withdrawal of a subject from the study. Investigator-withdrawn subjects will also be offered 
the opportunity to consent to the 3 options described above. All subjects withdrawn early 
from the study for any reason will complete the procedures described for ET (Section 8.5) 
and be followed for safety after receiving the last dose of study medications. Randomized 
subjects withdrawn from the study for any reason will not be replaced. 
5.5.2.3 
All Early Withdrawal Subjects 
For any subject who early terminates from the study (including subjects who withdraw their 
consent), survival information may be ascertained via public database search at the end of 
the study. 


 
 
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6. STUDY TREATMENTS 
6.1 
Treatment Blinding 
The Run-in Phase is single-blinded for the subject. 
To minimize the potential for bias during the Treatment Phase, treatment randomization 
information will be kept confidential by an unblinded biostatistician and will not be 
released to the Investigator or Investigator site personnel until the study database has been 
locked. The blind will be maintained for subjects, site personnel, Sponsor and vendor staff, 
except for unblinded staff required for the development of the final randomization schedule 
and for production of unblinded materials for the Data and Safety Monitoring Board 
(DSMB) and Sponsor’s Drug Safety staff in situations where unblinding is necessary to 
comply with regulatory requirements. 
Clinical Trial Supply Management will have access to overall patiromer/placebo usage for 
management of patiromer/placebo packaging and distribution activities and oversight of 
patiromer/placebo stock levels at drug depots and study sites. 
If the Investigator or site study staff becomes aware of a subject’s study treatment 
assignment, efforts should be made to not disclose treatment assignments to other study 
staff, subjects, or their caregivers. Blinded Sponsor staff will also remain blinded to 
treatment assignment. 
The Investigational Pharmacist or the qualified designee as assigned by the Principal 
Investigator will exclusively be responsible for investigational medicinal product (IMP) 
handling and should not be involved in any other study procedures (see Section 6.5 for 
more details). 
Subjects will be instructed to refrain from discussion of their study drugs with the site staff 
(except with the Investigational Pharmacist or the qualified designee as assigned by the 
Principal Investigator) or other subjects, and that any questions regarding the study drug 
should be directed to the Investigational Pharmacist or the qualified designee as assigned 
by the Principal Investigator only. 
6.1.1 
Unblinding 
In the case of a medical emergency, the Investigator may request that the blind be broken 
if it is considered important to the management of the medical emergency. In such cases, 
the Investigator will be unblinded via the interactive web response system (IWRS). The 
Investigator should make every reasonable attempt to notify study Medical Monitor before 
breaking the blind. The Investigator may inform the subject and/or his/her treating 
physician of the treatment assignment. 
Other situations where unblinding may be necessary are for study-specific suspected 
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authorities. In these cases, Sponsor’s Drug Safety personnel must know the subject’s 
treatment allocation to ensure compliance with reporting requirements. 
6.2 
Dosage Forms/Formulation 
6.2.1 
Patiromer for Oral Suspension (Patiromer) or Placebo 
(Microcrystalline Cellulose) 
Patiromer or placebo (microcrystalline cellulose) will be provided to the subject blinded, 
as a powder for oral suspension in packets. 
Information on patiromer is provided below: 
Active Ingredient: 
Patiromer sorbitex calcium 
Chemical Name: 
Calcium, hydrolyzed divinylbenzene-Me 2-fluoro-2-propenoate-
1,7-octadiene polymer sorbitol complexes 
Generic Name: 
Patiromer sorbitex calcium, powder for oral suspension 
Trade Name: 
Veltassa 
Strength: 
Each packet contains 8.4 g patiromer 
Excipients: 
Xanthan gum 
Dosage Form: 
Powder for oral suspension 
Manufacturer: 
Patheon Inc. or OM Pharma S.A. 
Labeling: 
Almac or Catalent 
Storage: 
2–8ºC (see the Pharmacy Manual for additional details) 
All IMPs used in this study have been manufactured in accordance with current Good 
Manufacturing Practice. 
6.3 
Drug Dosage and Administration 
6.3.1 
Treatment Arms 
All enrolled subjects will be treated with patiromer single-blinded during the Run-in Phase. 
After the Run-in Phase, eligible subjects will be randomized in a 1:1 ratio to treatment with 
patiromer or placebo in a double-blinded fashion. 
6.3.2 
Dosing and Administration Guidelines 
6.3.2.1 
Patiromer/Placebo 
The starting dose will be 1 packet/day and may be taken either with food or without food. 
Based upon the K+ management algorithms (Section 6.7.1.1 and Section 6.7.1.2), 


 
 
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patiromer/placebo may be increased by 1 packet per day in intervals of at least 1 week 
(±3 days). For subjects who become hypokalemic (K+ <4.0 mEq/L), patiromer/placebo 
must be decreased to a minimum of 0 packets/day (see Section 6.7.1.1). If serum K+ 
increases 
from 
<4.0–≥4.0 
mEq/L 
and 
remains 
between 
≥4.0–≤5.0 
mEq/L, 
patiromer/placebo must not be resumed yet. Resume patiromer/placebo only when K+ >5.0 
mEq/L to prevent re-inducing or aggravating hypokalemia. Doses of patiromer/placebo will 
be 0 packets/day, 1 packet/day, 2 packets/day, and 3 packets/day (maximum dose). 
Patiromer/placebo are for oral administration only. Each dose must be prepared 
immediately prior to administration. Patiromer/placebo should be taken at least 3 hours 
before or 3 hours after administration of other orally administered medications. 
Patiromer/placebo should be taken once daily, and preferably at the same time of day, 
consistently. An accidentally missed dose can be taken later on the same day but shall not 
be taken the next day. At the discretion of the Investigator, the following drugs may be 
co-administered with patiromer/placebo: allopurinol, amlodipine, amoxicillin, apixaban, 
aspirin, atorvastatin, cephalexin, cinacalcet, clopidogrel, digoxin, furosemide, glipizide, 
lisinopril, lithium, metoprolol, phenytoin, rivaroxaban, spironolactone, trimethoprim, 
valsartan, verapamil, and warfarin (see the Investigator’s Brochure (IB), Version 13.0, 
dated 15 July 2020, for additional information [30]). 
Patiromer/placebo suspension must not be heated (e.g., microwaved) or added to heated 
foods or liquids. Patiromer/placebo must not be taken in its dry form but must be mixed 
with water, apple, or cranberry juice only. Prepare patiromer/placebo doses following the 
steps below: 
• Measure 1/3 cup (approximately 80 mL) of water. Pour half of the water into a glass, 
then add the contents of the prescribed number of patiromer/placebo packets and stir. 
Add the remaining half of the water and stir thoroughly. The powder will not dissolve, 
and the mixture will look cloudy. Add more water to the mixture as needed for desired 
consistency 
• Drink the mixture immediately. If powder remains in the glass after drinking, add more 
water, stir, and drink immediately. Repeat as needed to ensure the entire dose is 
administered 
6.4 
Package and Labeling 
Patiromer powder for oral suspension or placebo will be provided by the Sponsor in a 
blinded manner as kits labeled for clinical trial use only. Each Run-in kit contains packets 
of patiromer, and these kits are only dispensed during the Run-in Phase (single-blinded for 
the subject). Each Treatment kit contains packets of either patiromer or placebo, and these 
kits are only dispensed in during the Treatment Phase (double-blinded). Additional details 
are provided in the Pharmacy Manual. 


 
 
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All packaging and labeling will be performed according to Good Manufacturing Practice 
guidelines. The study drug will be labeled in accordance with local regulations for 
investigational products. 
6.5 
Study Treatment Allocation 
Each eligible subject will be assigned (blinded) to 1 of the 2 treatment groups via IWRS: 
• Patiromer 
• Placebo 
Upon enrollment into the Run-in Phase of the study, each subject will be provided with 
instructions on proper dosing of patiromer and individualized instructions on when to take 
patiromer and other concomitant medications after considering the subject’s current 
medication regimen, patiromer instructions regarding administration, and subject 
preference; see Section 7.1. The subject will be instructed to follow the agreed dosing 
instructions for the remainder of the study to encourage compliance. The Investigator will 
determine if the study drug dosing instruction requires changes at each visit and any 
changes will be communicated to the subject. 
For subjects who qualify for the Blinded Treatment Phase, subjects will be randomized to 
either patiromer or placebo on Day 1/Baseline via IWRS. The study drug will be dispensed 
to subjects by the Investigational Pharmacist, or the qualified designee as assigned by the 
Principal Investigator. 
Subjects will also be instructed to discard all used/empty packets but to bring back any 
unopened packets to the next visit for compliance assessment during both the Run-in and 
Blinded Treatment Phases. Subjects will be instructed to return the unopened (unused) 
patiromer/placebo packets in the outer packaging (boxes) in which they were originally 
provided. The Investigational Pharmacist or the qualified designee as assigned by the 
Principal Investigator will assess compliance based on returned unopened packets during 
the entire study to confirm that the subject is taking patiromer/placebo according to the 
protocol instructions. 
Compliance will be documented and assessed on the basis of the prescribed number of 
patiromer/placebo packets, the duration of treatment, and the quantity of dispensed and 
returned unused packets. The Investigational Pharmacist or the qualified designee as 
assigned by the Principal Investigator will inform the study personnel if any compliance 
issues (e.g., <80% of expected usage) are identified so that the subject can be retrained on 
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6.6 
Site Supply, Storage, Accountability 
6.6.1 
Site Supply 
Once a site has been approved to receive study drug, the site will be supplied with an initial 
shipment of patiromer/placebo sufficient for 1 to 2 subjects. The need for drug resupply 
will be assessed on a regular basis taking into account the number of subjects enrolled, the 
number of subjects in Screening at the site, and the overall enrollment into the study. 
6.6.2 
Storage 
The Investigational Pharmacist or qualified designee as assigned by the Principal 
Investigator will verify and acknowledge receipt of each shipment of patiromer/placebo. 
Patiromer/placebo will be shipped and stored under refrigeration (2–8 degrees Celsius); see 
the Pharmacy Manual for additional details. Upon dispensation to a subject, 
patiromer/placebo should ideally be kept refrigerated at 2°C to 8°C (36°F to 46°F) if 
possible, but if stored at ambient room temperature (<25°C (<77°F)) patiromer/placebo 
must be used within 3 months of being taken out of the refrigerator [24]. All study drugs 
will be stored in a secure location. No subject other than those enrolled in this specific 
clinical study are allowed to take patiromer/placebo provided for this study. 
Patiromer/placebo provided for this study must not be utilized for any laboratory or animal 
research. 
6.6.3 
Accountability 
All investigational product dispensed to subjects must be accurately recorded on the 
Investigational Product Accountability Records maintained at the Study Site by the 
Investigational Pharmacist or the qualified designee as assigned by the Principal 
Investigator. Subjects will be instructed to return all containers of investigational product 
dispensed to them (including unused packets and all containers) at each scheduled visit. All 
used containers will be retained at the site by the Investigational Pharmacist/qualified 
designee as assigned by the Principal Investigator for the Study Monitor’s verification. 
Investigational product accountability and compliance for all investigational products will 
be performed by the Investigational Pharmacist or the qualified designee as assigned by the 
Principal Investigator at each scheduled study visit. 
6.7 
Drug Dose Modification 
6.7.1 
Management of Serum K+ 
6.7.1.1 
Management of Serum K+ in the Run-in Phase (Single-Blinded) 
During the Screening Phase, subjects who satisfy the eligibility criteria will be enrolled into 
the Run-in Phase. The purpose of the Run-in Phase is for management of serum K+ with 
patiromer to allow optimization of RAASi medications (including initiation of MRA if not 
already receiving an MRA). 
All subjects who meet the eligibility criteria for the Run-in Phase (single-blinded) will 
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Subjects with 2 Screening K+ values >5.0 mEq/L are considered hyperkalemic; these 
subjects begin patiromer when they qualify for the Run-in Phase, i.e., on the same day 
Run-in qualification is met or the next day. 
All other subjects are considered normokalemic and serum K+ will be measured again latest 
after the first week during the Run-in Phase. Patiromer will be started at this Week 1 Run-in 
Visit only if subjects are still normokalemic or have progressed to hyperkalemia; in case of 
newly observed hypokalemia (local serum K+ <4.0 mEq/L) during the first Run-in Week, 
patiromer must not be given. In subjects with hypokalemia serum K+ must be controlled 
after 3 days. 
Note: If one screening K+ value is >5.0 mEq/L and one value is ≤5.0 mEq/L, then a third 
peripheral venipuncture is performed within 1 day to obtain clarity, whether subject is 
hyperkalemic or normokalemic (local serum K+ ≥4.0-≤5.0 mEq/L). 
During the first Run-in Week, ACEi/ARB/ARNi and/or MRA doses ideally remain 
unchanged, if clinically indicated. On or after the initial first week visit during the Run-in 
Phase, up-titration of ACEi/ARB/ARNi and/or MRA may be initiated. 
Patiromer is titrated during Run-in Phase to achieve target local serum K+ level of 
≥4.0-≤5.0 mEq/L (see below). 
Note: Depending on the actual local serum K+ value this could include patiromer 0 g/day 
(i.e., 0 packets/day) during the Run-in Phase. 
• If local serum K+ is >5.0 mEq/L, up-titrate patiromer in at least (≥) 1-week intervals by 
1 packet/day (maximum dose is 3 packets/day) 
− 
If subject is taking maximum dose patiromer (3 packets/day) and local serum K+ 
remains >5.0 mEq/L during the Run-in Phase, then subject is Run-in failed 
• If local serum K+ is >5.0–≤5.5 mEq/L and the reduction in serum K+ from the previous 
visit was ≥0.4 mEq/L, at the Investigator’s discretion, a dose increase may not be 
required 
• If local serum K+ is ≥4.3–≤5.0 mEq/L at the first week during the Run-in Phase, 
patiromer must be started at 1 packet/day 
• If local serum K+ is ≥4.0–<4.3 mEq/L at the first week during the Run-in Phase, 
patiromer may be started at 1 packet/day; initiation or increase of patiromer dose should 
be made with caution when local serum K+ is ≥4.0–<4.3 mEq/L to avoid inducing 
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• If local serum K+ decreases from >4.3 mEq/L to values <4.3 mEq/L, remaining 
≥4.0 mEq/L, patiromer may be down-titrated by 1 packet/day (minimum dose is 0 
packets/day); in case of a reversal of this decrease from <4.3 mEq/L but remaining 
≥4.0 mEq/L to values ≥4.3 mEq/L at following visits, patiromer may be up-titrated by 
1 packet/day; subjects must receive at least 1 packet/day at serum K+ ≥4.3–≤5.0 mEq/L 
− 
If 1 week after reducing patiromer to 0 packets/day local serum K+ remains stable 
≥4.0–≤4.3 mEq/L, optimize RAASi dose and resume patiromer at 1 packet/day 
before considering these subjects as Run-in failed; initiation or increase of 
patiromer dose should be made with caution when local serum K+ is 
≥4.0-≤4.3 mEq/L to avoid inducing hypokalemia 
• If local serum K+ is <4.0 mEq/L, patiromer must be down-titrated to 0 g/day (i.e., 
0 packets/day), with confirmation of hypokalemia within 3 days and follow-up in at 
least (≥) 1-week intervals until serum K+ is ≥4.0 mEq/L. Resume patiromer only when 
local serum K+ rises to >5.0 mEq/L 
− 
If 2 weeks after taking the minimum 0 packets/day, local serum K+ remains 
<4.0 mEq/L during the Run-in Phase, then subject is Run-in failed 
Once a subject meets all randomization criteria (see Section 5.4), they may be randomized 
into the Treatment Phase (double-blinded). 
6.7.1.2 
Management of Serum K+ in the Treatment Phase (Double-Blinded) 
After the Run-in Phase (single-blinded), eligible subjects will be randomized in a 1:1 ratio, 
to treatment with patiromer or placebo (double-blinded); see Study Schema. 
Randomized subjects will begin their assigned treatment (patiromer or placebo), 
double-blinded, using the same number of packets established for patiromer at the end of 
the Run-in Phase and will continue the ACEi/ARB/ARNi and MRA regimen being 
administered at the end of the Run-in Phase.  
For subjects who are on less than the target dose of either ACEi/ARB/ARNi or MRA, up-
titration should continue if serum K+ remains in the normokalemic range (serum K+ ≥4.0–
≤5.0 mEq/L). 
After randomization, serum K+ will be measured prior to initiation of assigned 
patiromer/placebo, double-blinded, on Treatment Day 1/Baseline, and at each subsequent 
visit during the Treatment Phase. 
The Investigator may initiate an unscheduled visit at their discretion throughout the 
Treatment Phase. 
Protocol allowed interventions for the management of hyperkalemia during the Treatment 
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1. Up-titration of patiromer/placebo if on <3 packets per day 
2. Down-titration or discontinuation of ACEi, ARB, ARNi and/or MRA 
3. Initiate or increase diuretics 
4. Dietary K+ restriction 
If local K+ is >5.5 mEq/L, one or more of these interventions must be initiated either 
individually or in combination following the recommendations by practice guidelines. 
Repeat the K+ measurement within 7 days; if local K+ remains >5.5 mEq/L consider 
repeating the intervention or using other interventions in the order described above. 
If local K+ is between >5.0 mEq/L and ≤5.5 mEq/L, one or more of these interventions may 
be initiated per Investigator discretion. 
Urgent treatment of hyperkalemia is in accordance with usual care and the Investigator’s 
judgment. As described in Section 6.8.4.1, the only K+ binding medications permitted for 
use during the study are temporary use of sodium or calcium polystyrene sulfonate and 
sodium zirconium cyclosilicate for up to 7 days or until serum K+ is <5.0 mEq/L, or 
whichever occurs first. Patiromer/placebo must be withheld during temporary use of 
permitted K+ binding medications. 
If hypokalemia develops during the Treatment Phase, study drug should be down-titrated 
(lowest acceptable dose is 0 packets/day) until local serum K+ ≥4.0 mEq/L. 
The Investigator reinitiates patiromer/placebo treatment after a temporary interruption of 
dosing per treatment algorithm described in Section 6.7.1.1. 
6.7.2 
Optimization of ACEi/ARB/ARNi or MRA Medications During 
Run-in Phase 
Because subjects will enter the Run-in Phase on a variety of different ACEi/ARB/ARNi 
and/or MRA medications, the Investigator will determine how to optimize each subject’s 
ACEi/ARB/ARNi and/or MRA with the goal of achieving the best guideline-recommended 
HF treatment regimen for the subject and meeting the randomization criteria. The 
Investigator should manage ACEi/ARB/ARNi or MRA dose initiation or escalation to 
achieve 100% of target doses as recommended by the Study Manual [1] using clinical 
judgment to customize ACEi/ARB/ARNi or MRA addition or dose escalation based on 
subject response; see Study Manual for summary of practice guideline recommendations 
and the study-specific target doses.  
Initiation or escalation of ACEi/ARB/ARNi or MRA dose should be made with caution 
when local serum K+ is >5.0 mEq/L. Assessment of serum K+ will occur at each visit. 
Patiromer dose will be titrated as described in Section 6.7.1.1 to achieve and/or maintain 
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Subjects may be randomized anytime (but no later than 12 weeks) during the Run-in Phase 
when they meet all of the randomization criteria; see Section 5.4. Subjects who do not meet 
all of the Randomization criteria within 12 weeks are Run-in failures and may be rescreened 
after 3 months (Section 8.1.1.1). 
Note: For the purpose of this study, maximum tolerated dose of ACEi/ARB/ARNi or MRA 
is not defined by hyperkalemia, but one that is limited by other health considerations, such 
as renal function decline or symptoms of hypotension. If intolerance of ACEi/ARB/ARNi 
or MRA is due to K+ level, patiromer should be titrated as described in Section 6.7.1.1 and 
ACEi/ARB/ARNi or MRA dose increase should be attempted. 
Table 3 describes an example of how ACEi/ARB/ARNi or MRA could be optimized during 
the Run-in Phase of the study. 
Table 3 
Example of ACEi/ARB/ARNi or MRA Optimization During 
Run-in Phase 
Optimization of ACEi/ARB/ARNi: 
For subjects initiating an ACEi/ARB/ARNi, the Investigator decides which ACEi/ARB/ARNi will be 
started and its dose. 
ACEi/ARB/ARNi can be up-titrated by 50% of the prior dose to achieve target doses(1) in 1-week intervals, 
as tolerated. 
If the local serum K+ is >5.0 mEq/L to ≤5.5 mEq/L, increase the patiromer dose by 1 packet/day (if on 
<3 packets/day); the ACEi/ARB/ARNi dose may be escalated and the patient evaluated at the next 
scheduled visit. If local serum K+ is >5.5 mEq/L, the patiromer dose must be increased by 1 packet/day (if 
on <3 packets/day) and optionally maintaining the same ACEi/ARB/ARNi dose or decreasing 
ACEi/ARB/ARNi dose. When patiromer titration results in local serum K+ ≤5.0–≥4.0 mEq/L, 
ACEi/ARB/ARNi dose may be escalated if needed. See Section 6.7.1.1 for titration of patiromer during 
Run-in Phase. 
Optimization of MRA: 
For subjects who are not on an MRA at study entry, the Investigator determines which MRA to initiate, 
e.g., spironolactone and at which starting dose; 25 mg/day, or 25 mg/every other day, or 12.5 mg/day, at 
the Investigator’s discretion. 
For subjects who are on <50 mg/day of MRA, double their current dose up to 50 mg/day. Assess tolerance 
to the 50 mg target dose.Patiromer dose is titrated based on the subject’s serum K+ level as described in 
Section 6.7.1.1. 
The subject can be randomized when: 
• 
MRA dose is at least 50 mg/day and has been stable for at least 1 week 
• 
ACEi/ARB/ARNi dose is ≥50% of target dose(1) and has been stable for at least 1 week 
• 
Local serum K+ is ≥4.0–≤5.0 mEq/L 
• 
Patiromer dose is at least 1 packet/day 
1 Study-specific target doses as per Table 4 in the Study Manual. 
Notes: ACEi=Angiotensin-converting enzyme inhibitor; ARB=Angiotensin II receptor blocker; ARNi=Angiotensin receptor/neprilysin 
inhibitor; MRA=Mineralocorticoid receptor antagonist. 
 


 
 
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6.7.3 
Temporary Interruption or Dose Reduction of HF Medications 
During the Treatment Phase, temporary interruption or dose reduction of HF medications 
is allowed, with documentation of the reason for the change. HF medications may be 
reinitiated at the time that is deemed appropriate by the Investigator, and HF medications 
may be titrated as needed. 
6.7.4 
Management of eGFR Level 
Throughout the treatment period, creatinine will be measured at each study visit (and may 
be measured at Unscheduled Visits). Subjects should be monitored for changes in renal 
function, especially during periods of medication changes or adjustments. Acute reductions 
in glomerular filtration rate have been seen with the initiation of MRA, similar to those 
seen with initiation of ACEi and ARB that have been attributed to transient changes in 
glomerular hemodynamics [31,32]. These changes typically do not impact long-term renal 
function. In this study, use of the Kidney Disease Outcomes Quality Initiative (KDOQI) 
recommendations for the detection and management of decreases in eGFR when initiating 
or up-titrating ACEi/ARB/ARNi or MRA [33] should be considered. 
Based on KDOQI guidelines: 
• An early decline in eGFR is defined as >15% reduction from Baseline (Screening) 
within 4 weeks of initiation of ACEi/ARB/ARNi or MRA. 
• For decreases in eGFR up to 30%, no changes to ACEi/ARB/ARNi or MRA dosing 
need to be made, and eGFR may be followed routinely. 
• Decreases in eGFR >30%, however, should prompt a search for other etiologies of 
abrupt renal function decline, including prerenal and postrenal causes, toxic reactions, 
and renal artery disease. 
• For a decline in eGFR from ≥31–50%, the ACEi/ARB/ARNi or MRA dose should be 
decreased and the eGFR followed weekly. If the eGFR does not return to within 30% 
of Baseline within 4 weeks, ACEi/ARB/ARNi or MRA should be discontinued. 
• ACEi/ARB/ARNi or MRA should be discontinued for a decline in eGFR >50% and 
eGFR should be followed at least weekly until eGFR has returned to within 15% of the 
Baseline value, and biweekly thereafter until stabilized. 
• An eGFR decline >50% must be reported as an AE; see Section 10.5 for reporting of 
AEs. 
6.7.5 
Usual Care 
During the Treatment Phase, all subjects will receive usual care in accordance with 
guideline recommendations; see Study Manual. Usual care includes recommendations for 
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implantable devices, and procedures and medications for the management of HF and blood 
pressure). Usual care may also include patient education. See Section 6.8.4 for additional 
details regarding concomitant medication use. 
6.8 
Prohibited Therapy, Special Considerations, and Concomitant 
Treatment 
6.8.1 
Prohibited Medications 
During the entire study, the following medications will be prohibited while being treated 
with patiromer/placebo as these drugs may increase the risk of constipation and/or 
hyperkalemia: 
• Colesevelam (increased risk of constipation) 
• Colestipol (increased risk of constipation) 
• Cholestyramine (increased risk of constipation) 
• Drospirenone (increased risk of hyperkalemia) 
• Aliskiren or any direct renin inhibitor (increased risk of hyperkalemia) 
• K+ sparing diuretics such as triamterene and amiloride (increased risk of hyperkalemia) 
• K+ supplements (increased risk of hyperkalemia) 
6.8.2 
MRA 
In the study only 2 MRAs are allowed — spironolactone and eplerenone. For subjects who 
are already taking MRA at entry into the Run-in Phase, the MRA dose will be managed by 
the Investigator; see Section 6.7.2. In case subjects enter the Run-in Phase with 
spironolactone or eplerenone (any brand), subjects should stay on their initially prescribed 
MRA as long as they follow the guideline recommendations. In case subjects enter the 
Run-in Phase with an MRA other than spironolactone or eplerenone (any brand), subjects 
will have to switch to either of the 2 allowed MRAs to qualify for the Treatment Phase (see 
Randomization Criteria Section 5.4). A change from spironolactone to eplerenone is 
allowed if indicated due to medical reasons. For subjects who are not taking an MRA at 
entry into the Run-in Phase, and the Investigator prescribes spironolactone as the MRA, 
spironolactone may be reimbursed by the Sponsor, but only for these subjects who initiated 
spironolactone during the Run-in Phase. 
Reimbursement of eplerenone might be considered by the Sponsor only in medically 
indicated cases (e.g., male subjects who develop breast discomfort or gynecomastia). 
6.8.2.1 
Potential Interactions with Spironolactone 
For subjects receiving spironolactone, the following interactions described in the 
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Digoxin: 
The half-life of digoxin has been shown to be increased by spironolactone, which may 
result in increased serum levels of digoxin and may lead to subsequent digitalis toxicity. 
To avoid over- or under-digitalization, subjects taking digoxin should be carefully 
monitored when also taking spironolactone. 
Lithium: 
The renal clearance of lithium is reduced by diuretic agents, which can lead to a high risk 
of lithium toxicity. Generally, lithium should not be taken with diuretics [34]. 
6.8.2.2 
Potential Interactions with Eplerenone 
Because eplerenone metabolism is predominantly mediated via CYP3A4, eplerenone is 
contraindicated in all patients with concomitant administration of strong CYP3A4 
inhibitors (e.g., ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, 
ritonavir, and nelfinavir). 
Digoxin: 
The systemic exposure of digoxin has been shown to be increased by 16% when 
co-administered with eplerenone, which may lead to subsequent digitalis toxicity. Caution 
is recommended when digoxin is dosed near the upper limit of the therapeutic window. 
Lithium 
No interaction study has been performed with eplerenone and lithium. If this treatment 
combination is considered necessary, then plasma lithium concentrations should be 
monitored. 
6.8.3 
Caution Regarding the Use of NSAIDs or COX-2 Inhibitors 
Nonsteroidal anti-inflammatory drugs (NSAIDs) or cyclooxygenase-2 (COX-2) inhibitors 
are not recommended by treatment guidelines for patients with HF, as they increase the risk 
of HF worsening and HF hospitalization. If new medications for mild to moderate pain 
relief are required, NSAIDs and COX-2 inhibitors (except low dose aspirin) should be 
avoided and alternatives such as acetaminophen should be used. 
6.8.4 
Concomitant Medications 
Information on concomitant medication (prescription, over-the-counter, herbal and 
naturopathic remedies, etc.) will be collected beginning at Screening and continuing for the 
duration of the study (including EoS/ET Visit, Follow-up Phone Call, and Potassium 
Assessment Visit; see Section 8.5 and Section 8.6). 
In general, subjects should continue on the same medications and regimens that were 
ongoing at the study entry with the exception of ACEi/ARB/ARNi and MRA medications 
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possible during the study. Medications that the Investigator deems indicated for treatment 
of any intercurrent illness or a pre-existing condition that are not on the prohibited 
medication list or do not form an exclusion criterion for participation in this study will 
generally be allowed. 
6.8.4.1 
Permitted K+ Binding Medications 
Only temporary use of sodium or calcium polystyrene sulfonate as well as sodium 
zirconium cyclosilicate is permitted for up to 7 days or until K+ is <5.0 mEq/L, whichever 
occurs first. During this period patiromer/placebo must be withheld. During the study, the 
Medical Monitor should be notified when a subject has been treated with K+ binding 
medications other than patiromer/placebo. 
6.8.4.2 
Magnesium Supplements 
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 
based on the Investigator’s decision and per standard of care. 


 
 
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7. RISKS/PRECAUTIONS 
7.1 
Precautions 
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 
co-administered with patiromer: allopurinol, amlodipine, amoxicillin, apixaban, aspirin, 
atorvastatin, cephalexin, cinacalcet, clopidogrel, digoxin, furosemide, glipizide, lisinopril, 
lithium, metoprolol, phenytoin, rivaroxaban, spironolactone, eplerenone, trimethoprim, 
valsartan, verapamil, and warfarin. 
Patiromer binds K+ and other cations. In conducted clinical trials with patiromer, 
magnesium was the only other cation with mean decreases in serum levels. Serum 
magnesium values <1.4 mg/dL (0.58 mmol/L) occurred in 9% of subjects treated with 
patiromer. Mean decreases in serum magnesium were 0.17 mg/dL (0.070 mmol/L) or less. 
Serum magnesium levels should be monitored in all subjects according to this protocol, and 
magnesium supplementation should be considered in those with low serum magnesium 
levels at the Investigator’s discretion and per standard of care. 
Studies in healthy adults on K+-controlled diets demonstrated that about 73 mg of calcium 
is absorbed from a maximal 25.2 g daily dose of patiromer. Patiromer at 25.2 g/day 
increased urinary calcium levels by 72.9±23.4 mg/day in healthy individuals who are on a 
1,000 mg/day calcium diet. Based on these findings, Investigators should evaluate the 
benefit/risk of continued supplemental calcium in addition to patiromer in each subject in 
the overall context of the subject’s calcium intake, calcium balance, vitamin D status and 
bone health and adjust accordingly [35]. 
7.2 
Adverse Reactions 
The majority of the adverse reactions reported from clinical trials conducted with patiromer 
were GI disorders, with the most frequently reported adverse reactions being constipation 
(5.9%), diarrhea (4.9%), nausea (2.1%), flatulence (2.1%), and hypomagnesemia (4.1%) 
[30]. GI disorder reactions were generally mild to moderate in nature, did not appear to be 
dose related, generally resolved spontaneously or with treatment, and none were reported 
as serious. Hypomagnesemia was mild to moderate, with no subject developing a serum 
magnesium level <1.0 mg/dL (0.41 mmol/L). 


 
 
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8. STUDY PROCEDURES 
For a detailed schedule of assessments (including all protocol required assessments, visits 
and visit windows) please refer to the Study Schema. 
8.1 
Screening and Run-in Phase Procedures (Single-Blinded, Up to 
12 Weeks) 
8.1.1 
Screening Procedures 
Before any study-specific procedures are performed, the subject will receive an explanation 
of all study procedures and must sign and date a written Informed Consent Form (ICF) 
approved by an Institutional Review Board (IRB) or equivalent Ethics Committee (EC) 
(see Section 13.2 for additional requirements). The timing of the Screening Visit (and all 
subsequent visits) must take into account planned absences at the research facility and the 
need for study visits according to the Schedule of Events. Due to the expected waiting 
period of certain assessments (e.g., central laboratory parameters), screening activities can 
be held over different calendar days, but not exceeding 10 calendar days. 
The subjects will be instructed to arrive at the scheduled time for each Screening Visit to 
allow for completion of all assessments including measurement of the K+ level by the local 
laboratory. At the Screening Visit, subjects will be assigned a unique subject number, 
which will be generated during Screening Visit registration in IWRS. 
Subjects are first screened to identify those who satisfy the eligibility criteria (see 
Section 5.2 and Section 5.3, and Screening activities below). Once a subject meets all 
eligibility criteria, they will begin the Run-in Phase (see Section 8.1.2). 
The following activities will be performed at Screening: 
• Subject signs ICF 
• Completion of the KCCQ and EQ-5D-5L questionnaire (must be performed by subjects 
after signing of the ICF but before all other assessments) 
• IWRS registration 
• Review inclusion and exclusion criteria 
• Collect demographic information 
• Assess NYHA class 
• Review medical/surgical history 
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• Measure weight and height 
• Measure resting heart rate (pulse) after the subject has been sitting quietly for 5 minutes 
• Measure blood pressure after the subject has been sitting quietly for 5 minutes 
(see Section 9.3.2) 
• Perform 12-lead ECG 
• Collect blood samples (measured locally and/or by central laboratory; see Table 5): 
− 
The following serum chemistry assessments will be measured locally; only when 
the subject meets all eligibility criteria will serum chemistry samples be sent to the 
central laboratory: 
• Creatinine, eGFR 
• Alanine aminotransferase, aspartate aminotransferase 
• BNP or NT-proBNP 
− 
K+ level (measured locally) 
• 2 samples, each obtained from a separate venipuncture (e.g., one in each arm) 
− 
Hematology (central laboratory only) 
• Collect urine samples for the evaluation of (see Table 5): 
− 
Urinalysis 
− 
Urine or serum pregnancy test 
• Dispense urine sample containers for the visit at Week 1 during the Run-in Phase and 
provide proper training/instructions on use (see Section 9.6) 
• Assess AEs/special situations 
• Record concomitant medications and procedures 
8.1.1.1 
Rescreening of Subjects 
Subjects who screen failed may be rescreened twice. The first rescreening must be at least 
2 weeks after initial screen failure. If the subject also fails on the second attempt (first 
rescreening), another screening attempt is allowed but must be at least 6 months after the 
first rescreening. All Screening procedures described in Section 8.1.1 will be repeated. If a 
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Subjects who Run-in failed may be rescreened once, earliest after 3 months from the date 
of Run-in failure. All screening procedures described in Section 8.1.1 will be repeated. 
Subjects can be screened maximum three times in total as shown in Table 4. 
Table 4 
Rescreening of Subjects 
Scenario # 
1st Screen 
2nd Screen 
3rd Screen 
1 
Screen Fail 
Screen Fail 
  
2 
Screen Fail 
Run-in Fail 
  
3 
Screen Fail 
Randomized 
  
4 
Run-in Fail 
Screen Fail 
  
5 
Run-in Fail 
Run-in Fail 
  
6 
Run-in Fail 
Randomized 
  
7 
Screen Fail 
Screen Fail 
Screen Fail 
8 
Screen Fail 
Screen Fail 
Run-in Fail 
9 
Screen Fail 
Screen Fail 
Randomized 
10 
Screen Fail 
Run-in Fail 
Screen Fail 
11 
Screen Fail 
Run-in Fail 
Run-in Fail 
12 
Screen Fail 
Run-in Fail 
Randomized 
 
8.1.2 
Run-in Phase (Single-Blinded) Procedures 
The purpose of the Run-in Phase is intended for the management of serum K+ with 
patiromer (see Section 6.7.1.1) to allow optimization of ACEi/ARB/ARNi and MRA as 
tolerated (see Section 6.7.2). The frequency of subject weekly visits during the Run-in 
Phase is at the discretion of the Investigator. 
Subjects with 2 Screening K+ values >5.0 mEq/L are considered hyperkalemic; these 
patients begin patiromer (single-blinded) when they qualify for the Run-in Phase (i.e., on 
the same day Run-in qualification is met or the next day). 
All other subjects are considered normokalemic and serum K+ will be measured again latest 
at 1 week during the Run-in Phase. Patiromer will be started at the first week during the 
Run-in Phase only if subjects are still normokalemic or have progressed to hyperkalemia; 
in case of newly observed hypokalemia during the first week of the Run-in Phase, patiromer 
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In subjects with hypokalemia serum K+ must be controlled after 3 days to evaluate the 
effects of up-titrated ACEi/ARB/ARNi and/or MRA. Note: Depending on the actual local 
serum K+ value this could include patiromer 0 g/day (i.e., 0 packets/day) during the Run-in 
Phase. 
Except where noted, the following activities will be performed during all visits during the 
Run-in Phase: 
• IWRS entry 
• Measure resting heart rate (pulse) after the subject has been sitting quietly for 5 minutes 
• Measure blood pressure after the subject has been sitting quietly for 5 minutes (see 
Section 9.3.2) 
• Measure weight 
• Collect blood samples for evaluation of: 
− 
K+ level (measured locally) 
• Review local laboratory K+ results and adjust study medications according to 
Section 6.7.1.1 
− 
Magnesium level (measured locally) starting at 1 week after initiating the use of 
patiromer; consider periodic measurements of serum magnesium levels based on 
your clinical assessment of clinical signs of hypomagnesemia 
− 
Serum creatinine, eGFR (measured locally) 
• Collect and measure urine albumin-to-creatinine ratio (ACR) (at first week during 
Run-in Phase only, not assessed at other Run-in Phase Visits; see Section 9.6) 
• Assess AEs/special situations 
• Assess ACEi/ARB/ARNi and MRA doses and determine if titration is needed (see 
Section 6.7.2) 
• Record concomitant medications and procedures 
• Investigational Pharmacist or qualified designee as assigned by the Principal 
Investigator performs the following: 
− 
Perform drug accountability 
− 
Dispense patiromer based on kit number(s) assigned by IWRS, if needed 


 
 
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• Reimburse MRA (only for subjects who are initiating spironolactone or eplerenone; see 
Section 6.7.2 and Section 6.8.2) if needed 
• Assess if subject meets randomization criteria; if yes, the visit becomes the 
Day 1/Baseline Visit; see Section 8.2 
• For subjects who Run-in fail a follow-up (K+ assessment) visit needs to be completed; 
see Section 8.6 
8.2 
Treatment Phase (Double-Blinded) Procedures 
Subjects who meet all randomization criteria (see Section 5.4) within the 12 weeks of the 
Run-in Phase (single-blinded) may be randomized on the same day in which they qualify, 
and all assessments performed at the visit in the Run-in Phase when they qualified will be 
considered the Baseline assessments and will not be repeated. The qualifying Run-in Phase 
visit will become the Day 1/Baseline Visit. 
If a subject cannot be randomized on the same day the randomization criteria were met, 
then the subject should be randomized within 1 week and all assessments described in 
Section 8.2.1 will be repeated on the day of randomization. 
8.2.1 
Day 1/Baseline Visit 
The following activities will be performed at the Day 1/Baseline Visit: 
• Confirm subject meets all randomization criteria 
• IWRS randomization to patiromer or placebo (assignment blinded) 
• Perform KCCQ and EQ-5D-5L questionnaire (see Section 9.7) 
• Assess NYHA class 
• Measure resting heart rate (pulse) after the subject has been sitting quietly for 5 minutes 
• Measure blood pressure after the subject has been sitting quietly for 5 minutes (see 
Section 9.3.2) 
• Measure weight 
• Collect blood samples for evaluation of (see Table 5): 
− 
K+ level (measured locally and by central laboratory) 
− 
Serum chemistry including creatinine, eGFR (central laboratory) 
− 
MRA level (see Section 9.2.1) 


 
 
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− 
High sensitivity troponin 
• Collect urine samples for the evaluation of 
− 
Urinalysis 
− 
Urine or serum pregnancy test 
• Dispense urine sample containers for Day 3 Visit and provide proper 
training/instructions on use (see Section 9.6) 
• Assess AEs/special situations 
• Record concomitant medications and procedures 
• Investigational Pharmacist or qualified designee as assigned by the Principal 
Investigator performs the following: 
− 
Perform drug accountability 
− 
Dispense patiromer/placebo based on kit number(s) assigned by IWRS and collect 
all packets or kits dispensed during the Run-in Phase 
8.2.2 
Day 3 Visit (±1 Day) 
The following activities will be performed at the Day 3 Visit: 
• IWRS entry 
• Measure resting heart rate (pulse) after the subject has been sitting quietly for 5 minutes 
• Measure blood pressure after the subject has been sitting quietly for 5 minutes (see 
Section 9.3.2) 
• Measure weight 
• Collect blood samples for evaluation of: 
− 
K+ level (measured locally) 
o Review local K+ results and adjust study medications according to 
Section 6.7.1.2 
− 
Serum creatinine, eGFR (measured locally) 
• Collect and measure urine ACR (see Section 9.6) 
• Assess AEs/special situations 


 
 
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• Record concomitant medications and procedures 
• Investigational Pharmacist or qualified designee as assigned by the Principal 
Investigator performs the following: 
− 
Perform drug accountability 
− 
Dispense patiromer/placebo based on kit number(s) assigned by IWRS as needed 
• Reimburse MRA (only for subjects who are initiating spironolactone or eplerenone; see 
Section 6.7.2 and Section 6.8.2) if needed 
8.2.3 
Week 1 Visit (±3 Days) 
The following activities will be performed at the Week 1 Visit: 
• IWRS entry 
• Measure resting heart rate (pulse) after the subject has been sitting quietly for 5 minutes 
• Measure blood pressure after the subject has been sitting quietly for 5 minutes (see 
Section 9.3.2) 
• Measure weight 
• Collect blood samples for evaluation of (see Table 5): 
− 
K+ level (measured locally) 
o Review K+ results and adjust study medications according to Section 6.7.1.2 
− 
Serum creatinine, eGFR (measured locally) 
− 
MRA level (see Section 9.2.1) 
• Dispense urine sample containers and provide proper training/instructions on use (see 
Section 9.6) 
• Assess AEs/special situations 
• Record concomitant medications and procedures 
• Investigational Pharmacist or qualified designee as assigned by the Principal 
Investigator performs the following: 
− 
Perform drug accountability 
− 
Dispense patiromer/placebo based on kit number(s) assigned by IWRS as needed 


 
 
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• Reimburse MRA (only for subjects who are initiating spironolactone or eplerenone; see 
Section 6.7.2 and Section 6.8.2) if needed 
8.2.4 
Week 2 Visit (±3 Days) 
If at Week 2 there are changes to ACEi, ARB, ARNi and/or MRA dose or serum K+ varies 
outside the intended range, unscheduled weekly visits should occur until stability (i.e., 
at 2 consecutive visits) returns. 
The following activities will be performed at the Week 2 Visit: 
• IWRS entry 
• Measure resting heart rate (pulse) after the subject has been sitting quietly for 5 minutes 
• Measure blood pressure after the subject has been sitting quietly for 5 minutes (see 
Section 9.3.2) 
• Measure weight 
• Collect blood samples for evaluation of: 
− 
K+ level (measured locally) 
o Review K+ results and adjust study medications according to Section 6.7.1.2 
− 
Serum creatinine, eGFR (measured locally) 
• Collect and measure urine ACR (see Section 9.6) 
• Assess AEs/special situations 
• Record concomitant medications and procedures 
• Investigational Pharmacist or qualified designee as assigned by the Principal 
Investigator performs the following: 
− 
Perform drug accountability 
− 
Dispense patiromer/placebo based on kit number(s) assigned by IWRS as needed 
• Reimburse MRA (only for subjects who are initiating spironolactone or eplerenone; see 
Section 6.7.2 and Section 6.8.2) if needed 


 
 
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8.2.5 
Week 6 Visit (±14 Days) 
If there are changes to ACEi, ARB, ARNi and/or MRA dose or serum K+ varies outside 
the intended range, unscheduled weekly or monthly visits should occur until stability (i.e., 
at 2 consecutive visits) returns. 
The following activities will be performed at the Week 6 Visit: 
• IWRS entry 
• Measure resting heart rate (pulse) after the subject has been sitting quietly for 5 minutes 
• Measure blood pressure after the subject has been sitting quietly for 5 minutes (see 
Section 9.3.2) 
• Measure weight 
• Collect blood samples for evaluation of: 
− 
K+ level (measured locally) 
o Review K+ results and adjust study medications according to Section 6.7.1.2 
− 
Serum creatinine, eGFR (measured locally) 
• Dispense urine sample containers and provide proper training/instructions on use 
(Week 10 Visit only; see Section 9.6) 
• Assess AEs/special situations 
• Record concomitant medications and procedures 
• Investigational Pharmacist or qualified designee as assigned by the Principal 
Investigator performs the following: 
− 
Perform drug accountability 
− 
Dispense patiromer/placebo based on kit number(s) assigned by IWRS as needed 
• Reimburse MRA (only for subjects who are initiating spironolactone or eplerenone; see 
Section 6.7.2 and Section 6.8.2) if needed 
8.2.6 
Week 18 Visit (-30 Days) and Every 3 Months Visit Until Event-
Driven EoS (-30 Days) 
The following activities will be performed at the Week 18 Visit (i.e., first of the Every 
3 Months visits) and at each subsequent visit that will occur every 3 months until the EoS: 


 
 
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• IWRS entry 
• Perform KCCQ and EQ-5D-5L questionnaire at 3 (i.e., Week 18), 6, and 12 months 
and every 12 months thereafter (see Section 9.7) 
• Assess NYHA class 
• Measure resting heart rate (pulse) after the subject has been sitting quietly for 5 minutes 
• Measure blood pressure after the subject has been sitting quietly for 5 minutes (see 
Section 9.3.2) 
• Measure weight 
• Collect blood samples for evaluation of (see Table 5): 
− 
K+ level (measured locally and by central laboratory) 
o Review K+ results and adjust study medications according to Section 6.7.1.2 
− 
Serum chemistry including creatinine, eGFR (central laboratory) 
− 
Hematology (central laboratory) 
− 
BNP or NT-proBNP (central laboratory) 
− 
MRA level at 3 (i.e., Week 18), 6, and 12 months and every 12 months thereafter 
(see Section 9.2.1) 
• Collect and measure urine ACR (see Section 9.6) 
• Dispense urine sample containers (see Section 9.6) 
• Assess AEs/special situations 
• Record concomitant medications and procedures 
• Investigational Pharmacist or qualified designee as assigned by the Principal 
Investigator performs the following: 
− 
Perform drug accountability 
− 
Dispense patiromer/placebo based on kit number(s) assigned by IWRS as needed 
• Reimburse MRA (only for subjects who are initiating spironolactone or eplerenone; see 
Section 6.7.2 and Section 6.8.2) if needed. 


 
 
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8.3 
Unscheduled Visit Procedures 
An unscheduled visit may occur at the discretion of the Investigator. 
During the Double-Blinded Treatment Period, anytime there are changes to ACEi, ARB, 
ARNi and/or MRA dose or interventions for serum K+ outside the desired range, additional 
Unscheduled Visits should occur weekly until the ACEi, ARB, ARNi and/or MRA dose or 
serum K+ has been stable for at least 2 consecutive visits. 
At an unscheduled visit during any phase of the study, the following activities will be 
performed: 
• IWRS entry, in case IMP is to be re-dispensed 
• Measure resting heart rate (pulse) after the subject has been sitting quietly for 5 minutes 
• Measure blood pressure after the subject has been sitting quietly for 5 minutes (see 
Section 9.3.2) 
• Measure weight 
• Collect blood samples for evaluation of: 
− 
K+ level (measured locally) 
− 
Serum creatinine, eGFR (measured locally) 
• Assess AEs/special situations 
• Record concomitant medications and procedures 
Any other study assessments (see Section 8.8) may be performed at the discretion of the 
Investigator during an unscheduled visit. 
The following activities are optional during an unscheduled visit: 
• Perform physical examination 
• Collect blood sample for the evaluation of hematology (central laboratory) 
• Investigational Pharmacist or qualified designee as assigned by the Principal 
Investigator performs the following: 
− 
Perform drug accountability 
− 
Dispense patiromer/placebo based on kit number(s) assigned by IWRS 


 
 
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• Reimburse MRA (only for subjects who are initiating spironolactone or eplerenone; see 
Section 6.7.2 and Section 6.8.2) if needed 
8.4 
EoS Visit Procedures 
The common EoS date will be set by the Sponsor. The common EoS will occur when 
820 subjects have completed the Week 6 visit. Recruitment will be stopped, and subjects 
called in by the sites for the EoS visit when it is projected that a sufficient number of 
subjects have been enrolled in order for 820 subjects to reach the Week 6 visit. All 
randomized subjects, including those who prematurely discontinued patiromer/placebo, 
will complete the EoS Visit within the timeline provided by the Sponsor around the 
common EoS date. Investigational sites will be notified of the study termination date as 
soon as possible after the decision is taken and should advise ongoing study subjects of the 
study termination date thereafter. All randomized subjects with final dose of 
patiromer/placebo within 1 week of the EoS Visit will complete a Potassium Assessment 
Visit within 2 weeks or as soon as possible thereafter to assess serum K+ levels and to 
collect AE data (see Section 8.6). 
The following assessments will be performed at the EoS Visit: 
• IWRS entry 
• Perform KCCQ and EQ-5D-5L questionnaire (see Section 9.7) 
• Assess NYHA class 
• Perform physical examination 
• Measure resting heart rate (pulse) after the subject has been sitting quietly for 5 minutes 
• Measure blood pressure after the subject has been sitting quietly for 5 minutes (see 
Section 9.3.2) 
• Measure weight 
• Collect blood samples for evaluation of (see Table 5): 
− 
K+ level (measured locally and by central laboratory) 
− 
Serum chemistry including creatinine, eGFR (central laboratory) 
− 
Hematology (central laboratory) 
− 
BNP/NT-proBNP 
− 
High sensitivity troponin 


 
 
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− 
MRA level (see Section 9.2.1) 
• Collect urine samples for the evaluation of (see Table 5): 
− 
Urinalysis 
− 
Assess urine ACR (see Section 9.6) 
− 
Urine or serum pregnancy test 
• Assess AEs/special situations 
• Record concomitant medications and procedures 
• Investigational Pharmacist or qualified designee as assigned by the Principal 
Investigator performs drug accountability and collects all packets or kits dispensed 
during the Treatment Phase 
8.5 
Early Termination Procedures 
For subjects who prematurely withdraw from the study (before the common EoS date) and 
who do not allow any further contact (full withdrawal of consent), every effort should be 
made by the site to ensure that the subject completes the ET Visit, which should be 
performed on the day of the withdrawal or as soon as possible thereafter. The assessments 
performed at the ET Visit will be the same as the EoS Visit (see Section 8.4). 
8.6 
Potassium Assessment Visit Procedures (Up to 2 Weeks After 
Withdrawal from Patiromer/Placebo Treatment) 
All subjects who discontinue patiromer/placebo treatment during the study, including 
Run-in Failures/Randomization failures, or whose final patiromer/placebo dose is within 
1 week of the EoS Visit, will complete a Potassium Assessment Visit within 2 weeks or as 
soon as possible thereafter to assess serum K+ and to collect AE data. 
The following activities will be performed at the Potassium Assessment Visit: 
• Assess NYHA class 
• Measure resting heart rate (pulse) after the subject has been sitting quietly for 5 minutes 
• Measure blood pressure after the subject has been sitting quietly for 5 minutes (see 
Section 9.3.2) 
• Measure weight 
• Collect blood samples for evaluation of (see Table 5): 
− 
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− 
Serum chemistry including creatinine, eGFR (central laboratory) 
− 
Hematology (central laboratory) 
• Assess AEs/special situations 
• Record concomitant medications and procedures 
8.7 
Follow-up Phone Call (at Least 2 Weeks After EoS/ET Visit and 
Run-in Failure) 
For subjects who performed the Potassium Assessment Visit <2 weeks after ET or EoS a 
Follow-up Phone Call at least 2 weeks after ET or EoS will be done. Subjects determined 
as Run-in failed during the Run-in Phase will also have a Follow-up Phone Call after 
2 weeks if the Potassium Assessment Visit was performed <2 weeks after Run-in failure. 
Assessments performed over the phone call: 
• Assess AEs/special situations with an onset date up to 2 weeks after ending study 
participation 
• Concomitant medication assessment for any drugs used to treat an AE with an onset 
date up to 2 weeks after ending study participation 
8.8 
Allowed Adaptations in Case of Extraordinary Events, e.g., 
COVID-19 
Extraordinary events may call for specific measures to maintain subject safety and 
guarantee conduct of clinical investigations according to established general and specific 
guidelines and regulations to meet agreed regulatory, quality, and scientific expectations. 
For this, the following adaptations are considered for specific situations: 
• Site visits are not possible within the defined time window, possibly leading to delayed 
− Physical examination: consultation by local physician, follow-up assessment and 
guidance on drug adaptations via phone, remote visits at subject’s home (e.g., home 
nursing) 
− Laboratory assessments: consultation by local physician, visit at local laboratory 
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− Adaptation of IMP: dispense sufficient amount of IMP at previous visit, delivery to 
subject’s home by qualified designee as assigned by the Principal Investigator, or 
consider handover of IMP to relatives if allowed and in compliance with the 
applicable ICH Good Clinical Practice (GCP) and other applicable laws and 
regulations, phone call by treating physician to guide dose adaptation of drugs 
including RAASi medication, if needed 
− On-site monitoring: accept delayed on-site monitoring, conduct remote monitoring 
− On-site auditing: accept delayed on-site auditing, conduct remote auditing 
− AE/SAE/special situation reporting: frequent phone call visits 
• Site visits are not possible within the defined time window, possibly leading to no 
− Physical examination: consultation by local physician, follow-up clinical 
assessment via phone remote visits at subject’s home (e.g., home nursing) 
− Laboratory assessments: consultation by local physician, local laboratory for blood 
analysis, or via home nursing 
− Adaptation of IMP: dispense sufficient amount of IMP at previous visit, delivery to 
subject’s home by qualified designee as assigned by the Principal Investigator, or 
consider handover of IMP to relatives if allowed and in compliance with the 
applicable ICH GCP and other applicable laws and regulations, phone call by 
treating physician to guide dose adaptation of drugs including RAASi medication, 
if needed 
− On-site monitoring: accept delayed on-site monitoring, conduct remote monitoring 
− On-site auditing: accept delayed on-site auditing, conduct remote auditing 
− AE/SAE/special situation reporting: frequent phone call visits 


 
 
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9. STUDY ASSESSMENTS 
9.1 
Potassium 
Serum K+ levels will be assessed locally and/or by central laboratory at all study visits 
including Unscheduled Visits (Schedule of Events). Detailed instructions on how to draw 
blood and prepare specimens for analysis are provided in the Laboratory Manual. 
The definition of hyperkalemia follows the European Society of Cardiology expert 
consensus document on the management of hyperkalemia in patients with cardiovascular 
disease [36]. Hyperkalemia is considered for all serum K+ values >5.0 mEq/l with the 
gradings of mild hyperkalemia (serum K+ >5.0 mEq ≤5.5 mEq/l), moderate hyperkalemia 
(serum K+ >5.5 mEq ≤6.0 mEq/l) and severe hyperkalemia (serum K+ >6.0 mEq). 
9.1.1 
Preventing, Identifying, and Handling Hemolyzed Samples 
Hemolysis of blood specimens may result in spuriously high K+ levels, potentially leading 
to inappropriate up-titrating of patiromer/placebo or inappropriate down-titration or 
discontinuation of ACEi/ARB/ARNi or MRA in this study. 
The Laboratory Manual provides detailed descriptions of the recommended phlebotomy, 
sample preparation and transportation procedures to minimize hemolysis. Upon receipt of 
each blood sample for K+ analysis, the central laboratory will perform a semiquantitative 
test to assess for evidence of hemolysis. Predefined criteria will be established for 
determining whether the test result is indicative of potential hemolysis. These criteria and 
the criteria for removing serum K+ values from 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 K+ value. 
If a blood sample has been identified as hemolyzed by the site personnel (i.e., visual 
inspection) before it has been sent to the central laboratory, a repeat blood draw can be 
performed if the subject is still at the site. 
When a blood sample, which will be used by the site for patiromer/placebo titration and 
subject management, is hemolyzed (e.g., by visual inspection of the local laboratory serum 
sample), the site will repeat the K+ measurement from a separate blood draw within 1 day 
in order to ensure accurate decision-making regarding management of K+. 
9.1.2 
Deviant Serum Potassium Levels During Screening Process 
At Screening, serum K+ is measured twice to assure correct identification of hyperkalemic 
and normokalemic subjects. Should the 2 serum K+ levels differ substantially with one 
value being ≤5.0 and the other >5.0 mEq/L, then a separate blood draw within 1 day, latest 
the next calendar day will be performed. 


 
 
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9.2 
Laboratory Tests 
All laboratory assessments will be performed by central laboratory unless specified in the 
Schedule of Events. 
See Table 5 for the list of central laboratory assays. 
Table 5 
List of Central Laboratory Assays 
Serum Chemistry Panel 
Hematology 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Amylase 
Aspartate aminotransferase 
Bicarbonate 
Bilirubin (total) 
Blood urea nitrogen 
Calcium 
Creatine kinase 
Creatinine (with eGFR) 
Glucose 
Inorganic phosphate 
Iron 
Lactate dehydrogenase 
Magnesium 
Potassium 
Sodium 
Total cholesterol 
Total protein 
Uric acid 
WBC count 
Red blood cell count 
Hemoglobin 
Hematocrit (packed cell volume) 
Mean cell volume 
Mean cell hemoglobin 
Mean cell hemoglobin concentration 
Platelet count 
Differential WBC 
Urine 
Specific gravity 
pH 
Protein 
Glucose 
Creatinine 
Spot urine for albumin and creatinine (for ACR) 
Other 
BNP/NT-proBNP 
High sensitivity troponin 
MRA level (see Section 9.2.1) 
Pregnancy test (urine)(1) 
1 If needed, serum pregnancy test will be locally measured. 
Notes: ACR=Albumin-to-creatinine 
ratio; 
BNP=Brain 
natriuretic peptide; 
eGFR=Estimated 
glomerular 
filtration 
rate; 
MRA=Mineralocorticoid receptor antagonist; NT-proBNP=N-terminal pro b-type brain natriuretic peptide; WBC=White blood 
cell. 
 
To qualify for the study, subject must have eGFR ≥20 mL/min/1.73 m2 at Screening from 
a single local laboratory analysis of serum creatinine and calculation using the CKD-EPI 
creatinine equation. If the local laboratory does not provide an eGFR value using the 
CKD-EPI creatinine equation, the National Kidney Foundation online eGFR calculator 
(https://www.kidney.org/professionals/kdoqi/gfr_calculator) may be used. 
For subjects who develop anuria during the study, urine assessments will not be required. 
9.2.1 
MRA Level 
Blood samples from subjects receiving an MRA will be analyzed for MRA levels. Please 
refer to the Laboratory Manual for additional information. MRA must be taken in the 
morning before blood withdrawal for analysis of MRA levels. 


 
 
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9.3 
Vital Signs 
The subject should avoid eating, smoking, or exercising for 30 minutes before vital sign 
measurements are taken. The subject should rest, sitting quietly, for approximately 
5 minutes prior to the measurements. 
9.3.1 
Heart Rate 
Heart rate is to be measured for a full 60 seconds or as provided using the oscillometric 
blood pressure device. 
9.3.2 
Blood Pressure 
Blood pressure will be performed using an oscillometric device after resting for 5 minutes. 
Blood pressure data for each visit should be recorded in the respective eCRF. 
9.4 
Physical Examination 
Physical examination will be performed as indicated in the Schedule of Events. The 
following body systems are to be examined: 
• Cardiovascular 
• Lungs and chest, including respirations 
• Head and neck 
• Abdomen 
• Musculoskeletal 
• Skin 
• Neurological 
Any new clinically significant physical examination abnormality identified during the 
study will be reported as an AE. 
9.5 
ECG Assessment 
If the Investigator is concerned regarding any K+ value, a retest of K+ level and/or ECG 
evaluation for electrophysiological manifestations can be initiated by the Investigator at 
their discretion. 
The subject should be resting quietly for a minimum of 5 minutes prior to obtaining the 
ECG. 
If a K+-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 


 
 
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depending on the subject’s clinical situation: intravenous calcium gluconate, intravenous 
insulin and glucose, inhaled beta2-agonists. In such 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. 
9.6 
Urine Collection for ACR 
Urine samples will be collected as indicated in the Schedule of Events. The urine sample 
containers will be dispensed at the visit prior to the study visit where urine ACR is assessed 
and subjects will be provided with training and instructions on proper use of the urine 
containers. For the Run-in Phase Week 1 Visit assessment of urine ACR, the urine sample 
containers will be dispensed at the Screening Visit. For the Blinded Treatment Phase, at the 
Day 3 Visit, the urine sample container will be dispensed at the Day 1/Baseline Visit (see 
Section 8). Note: Urine ACR is collected and measured at the Run-in Phase Week 1 Visit 
only and not assessed at other Run-in Phase Visits. 
The subject will be collecting the urine samples at home. Two urine samples will be 
collected: (1) the first morning void the day prior to, and (2) the first morning void the day 
of the study visit where urine samples will be collected from the subject. At an ET Visit, a 
single spot urine specimen may be collected at the clinic if time permits. Detailed 
description of the urine collection process for ACR measurements is provided in the 
Laboratory Manual. 
For subjects who develop anuria during the study, urine assessments will not be required. 
9.7 
Patient-Reported Outcomes 
Patient-reported outcomes KCCQ and 5Q-5L questionnaires will be completed by the 
subjects before study staff performs any clinic or study assessments to avoid biasing the 
subjects’ responses. The study coordinators will review the subject’s responses 
immediately after completion of the questionnaires by subject to ensure that all questions 
are answered. The site will use the KCCQ and 5Q-5L questionnaires to complete the 
corresponding modules in the electronic data capture (EDC) system. The original 
questionnaires must be retained as source documentation. 
KCCQ 
The KCCQ is a self-administered instrument that is composed of 23 items, which quantifies 
the frequency, severity, and recent change in physical function and symptoms. Subjects 
will complete the KCCQ as indicated in the Schedule of Events. 
EQ-5D-5L Questionnaire 
The EQ-5D-5L questionnaire is composed of 5 questions each with 5 levels (e.g., no 
problems, slight problems, moderate problems, severe problems, and extreme problems) 
representing 5 health domains: mobility, self-care, usual activities, pain/discomfort, and 
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records the subject’s self-rated health status on a graduated scale that ranges from 0–100, 
with higher scores indicating higher health-related quality of life. Subjects will complete 
the EQ-5D-5L questionnaire as indicated in the Schedule of Events. 
9.8 
Contraception in Women of Child-Bearing Potential 
For females of child-bearing potential, urine or serum pregnancy test is performed at 
Screening, Day 1/Baseline Visit, and EoS/ET Visit. 
Methods of birth control in sexually active subjects approved for use during this study 
include: 
• Hormonal birth control (oral, skin patch, or injection for at least 28 days prior to the 
first Screening Visit) 
• Removal of the uterus or tubal ligation (already performed at least 6 months before 
screening) 
• Intrauterine device (already performed at least 6 months before screening) 
• Male partner who has had a vasectomy 
• Condom with spermicidal foam/gel/film/cream/suppository 
Females of non-child-bearing potential must be postmenopausal with amenorrhea for 
12 consecutive months before the Screening Visit or serum follicle stimulating hormone 
levels consistent with postmenopausal status as per the Investigator’s judgment. 
9.9 
Assessment of Left Ventricular Ejection Fraction 
The date for the left ventricular ejection fraction measurement used to determine eligibility 
must be <12 months before the Screening date. The left ventricular ejection fraction may 
have been measured by echocardiographic, radionucleotide, MRI, angiographic, or 
computerized tomography methods. If the assessment results in a range of values, then the 
average value is to be used. 
9.10 HEOR Assessments 
The objective is to select and include HEOR parameters as exploratory endpoints in the 
study protocol with the aim of analyzing both health-related quality of life and healthcare 
resource utilization. The choice of HEOR endpoints will be agreed and validated by payers 
and evaluators of Health Technology Assessment bodies from the US and Europe. The 
former will allow us to design a cost-effectiveness model, fed with clinical and HEOR data 
from DIAMOND, which will be potentially adaptable to the payers requirements in the US 
and those from five key European countries. The HEOR analysis will be described in a 
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10. EVALUATION, RECORDING, AND REPORTING OF ADVERSE 
EVENTS 
10.1 Definition of Adverse Events 
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 [36]. 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 10.3), including signs or symptoms 
associated with an underlying condition that were not present prior to the AE reporting 
period; (2) a pre-existing condition that has worsened in severity or frequency or changed 
in character after the subject signs the ICF 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, 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. 
For the purposes of this protocol, events that will not be considered AEs include: 
• Anticipated fluctuating signs or symptoms of a pre-existing medical condition (e.g., 
tremor in a subject with Parkinson’s disease; migraine episodes) that have not worsened 
in severity or frequency or changed in character during the AE reporting period 
• Surgeries or medical procedures are not AEs, however, the medical condition (new or 
worsened) that led to the surgery or medical procedure is the reported AE (e.g., for 
appendicitis resulting in appendectomy, appendicitis would be reported as the AE) 
• Overdose without clinical signs or symptoms (see Section 10.8) 
• Pregnancy (see Section 10.8.3.2 for reporting obligations) 
10.2 Adverse Event Reporting Period 
AEs, including SAEs, will be collected throughout the study period, beginning from the 
time the subject signs the ICF until the 2 weeks after the EoS. For screen-failed subjects 
the AE reporting period ends at the time of screen failure. All AEs persisting at the time of 
study completion will be followed by the Investigator through contact with the subject until 
resolution or stabilization, or the subject is lost to follow-up and cannot be contacted. The 
outcome must be documented in the subject’s source documents. The Investigator must 
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Investigator’s assessment there was a reasonable possibility that the SAE was related to 
patiromer/placebo or any study procedures. 
10.3 Eliciting Adverse Events 
If the subject reports an AE, it is the Investigator’s responsibility to acquire sufficient 
information in order to assess causality. This may require additional laboratory testing, 
physical examinations, telephone contacts, etc. 
In order to avoid bias in eliciting AEs, subjects should be asked a non-leading question, 
such as “How are you feeling?” It is also important to question the subject in a non-leading 
way about changes in their health or concomitant medication usage since their last visit. 
This information should be collected prior to completion of assessments at all study visits. 
In addition, any symptoms/conditions reported during assessments and deemed to be 
clinically significant by the Investigator will be assessed as AEs. 
10.4 Assessing Adverse Events 
10.4.1 Intensity/Severity 
The medical assessment of intensity will be determined by using the following definitions: 
• Mild: The AE is easily tolerated and does not interfere with usual activity 
• Moderate: The AE interferes with daily activity, but the subject is still able to function 
• Severe: The AE is incapacitating, and the subject is unable to work or complete usual 
activity 
A new event will be documented each time the intensity of an event has changed. 
It is important to note the distinctions between severe AEs and serious AEs (SAEs). 
Severity is a classification of intensity of a specific event (as in mild, moderate, or severe); 
however, the event itself may be of relatively minor medical significance (such as severe 
headache). An SAE, however, is an AE that meets any of the regulatory specified criteria 
required for designation as seriousness described in Section 10.7.1 (i.e., a headache may be 
severe (interferes significantly with subject's usual function) but would not be classified as 
serious unless it met one of the criteria for SAEs). 
10.4.2 Causality and Reporting 
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 will each assess relatedness of the AE to the 
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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 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 
For causality assessment purposes “reasonable possibility” is meant to convey that, based 
on the Investigator’s medical judgment of the available information, there are facts or 
arguments to suggest a positive causal relationship. 
10.4.3 Outcome Categorization 
Outcome is classified as: recovered/resolved (i.e., without sequelae); recovered/resolved 
with sequelae; not recovered/not resolved; fatal; or unknown (if follow-up is not possible). 
If the outcome of an SAE is reported as recovered/resolved with sequelae, the Investigator 
specifies the kind of sequelae on the SAE form. If the outcome of an SAE is reported as 
unknown, the Investigator specifies (on the SAE form) the rationale why unknown was 
selected. 
“Fatal” is to be recorded as an outcome when the AE results in death. Cause of death is 
required whenever known. If an autopsy was performed, an autopsy report will be provided. 
If an autopsy was not conducted, a Death Certificate will be provided if obtainable. Death 
will be reported as an outcome and not as an event. If more than one AE is possibly related 
to the subject's death, the outcome of death will be indicated for the AE that, in the opinion 
of the Investigator, is the most plausible cause of death. All other ongoing AE/SAEs will 
be recorded as not recovered/not resolved at the time of death. 


 
 
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10.5 Recording and Reporting 
10.5.1 Persistent or Recurrent Adverse Events 
AEs that extend continuously, without resolution, between trial assessments will only be 
recorded once in the eCRF. A new event will be documented each time the intensity of an 
event has changed. 
AEs that resolve and subsequently recur will have each recurrence recorded separately in 
the eCRF. 
10.5.2 Diagnosis Versus Signs and Symptoms 
Where possible, the Investigator reports a diagnosis rather than individual signs and 
symptoms or abnormal laboratory values. However, if a constellation of signs and/or 
symptoms cannot be medically characterized as a single diagnosis or syndrome at the time 
of reporting, each individual event should be recorded in the eCRF. If a diagnosis is 
subsequently established, all previously reported AEs based on signs and symptoms should 
be nullified and replaced by 1 AE report based on the single diagnosis, with a starting date 
that corresponds to the starting date of the first symptom of the eventual diagnosis. 
The Investigator should use standard medical terminology/concepts; avoid colloquialisms 
and abbreviations. Only 1 AE term should be recorded in each event field in the eCRF. 
10.5.3 Pre-existing Medical Conditions 
A pre-existing medical condition is one that is present at the Screening Visit for this study. 
Such conditions should be recorded on the medical history eCRF. A pre-existing medical 
condition should be recorded as an AE only if the frequency, severity, or character of the 
condition worsens during the study. When recording such events on the AE eCRF, it is 
important to convey the concept that the pre-existing condition has changed by including 
applicable descriptors (e.g., “more frequent headaches”). 
10.5.4 Clinical Laboratory Evaluations 
Not every out-of-range laboratory result qualifies as an AE. A laboratory investigation 
result must be reported as an AE if it meets any of the following criteria: 
• Is accompanied by clinical symptoms 
• Results in a change in study treatment (e.g., dosage modification, treatment interruption, 
or treatment discontinuation). For the purpose of this study, AEs should be reported if 
K+ <4.0 mEq/L or >5.0 mEq/L 
• Results in a medical intervention (e.g., K+ supplementation for hypokalemia) or a 
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• Presents shift of a parameter from a normal value to a pathological value or a further 
worsening of an already pathological value 
• Is clinically significant in the Investigator’s judgment 
It is the Investigator’s responsibility to review all laboratory findings. Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an AE. When evaluating such changes, the extent of 
deviation from the reference range, the duration until return to the reference range, either 
while continuing treatment or after the end of treatment with the investigational product, 
and the range of variation of the respective parameter within its reference range, must be 
taken into consideration. 
The Investigator has the responsibility to determine the clinical significance of each 
abnormality. 
If, at the end of the Treatment Phase, there are pathological laboratory values which were 
not present at Baseline, further clinical or laboratory investigations should be performed 
until the values return to within reference range or until a plausible explanation 
(e.g., concomitant disease) is found for the pathological laboratory values. 
The Investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a laboratory parameter is clinically significant and therefore 
represents an AE. If the Investigator considers such an AE as serious (e.g., medically 
significant event fulfilling criteria per Section 10.7.1), it must be reported as an SAE. 
If a laboratory abnormality meeting the above criteria is a sign of a disease or syndrome 
only the diagnosis should be recorded in the eCRF. 
If a laboratory abnormality meeting the above criteria is not a sign of a disease or syndrome, 
the abnormality itself should be recorded in the eCRF, along with a descriptor indicating if 
the test result is above or below the normal range (e.g., “elevated K+,” as opposed to 
“abnormal K+”). 
If the laboratory abnormality can be characterized by a precise clinical term per standard 
definitions, the clinical term should be recorded as the AE, for example, hypercalcemia or 
hypoglycemia. Observations of the same laboratory abnormality from visit to visit should 
not be repeatedly recorded in the eCRF unless the etiology changes. The initial severity of 
the event should be recorded, and the severity or seriousness should be updated any time 
the event worsens. 
All pathological laboratory findings/values diagnosed throughout the treatment period 
should be reviewed by the Investigator to provide a final clinical assessment in view of the 
dynamic of laboratory changes/abnormalities. 


 
 
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10.5.5 Abnormal Vital Signs and Other Abnormalities 
Out of range laboratory results, ECGs, vital signs, and other safety assessments will be 
considered AEs if they meet at least one of the following criteria: 
• Associated with symptoms or lead to a diagnosis (in such case the symptom or diagnosis 
will be recorded as an AE) 
• Lead to discontinuation of patiromer/placebo 
• Required treatment or subject referral for further testing outside the protocol (repeat 
testing or titration are within protocol procedures) 
It is the Investigator’s responsibility to review all vital sign, ECG, and other safety findings. 
Medical and scientific judgment should be exercised in deciding whether an isolated 
abnormality should be classified as an AE. 
If a clinically significant abnormality is a sign of a disease or syndrome (e.g., high blood 
pressure), only the diagnosis (i.e., hypertension) should be recorded in the eCRF. 
Observations of the same clinically significant abnormality from visit to visit should not be 
repeatedly recorded in the eCRF unless the etiology changes. The initial severity of the 
event should be recorded, and the severity or seriousness should be updated any time the 
event worsens. 
10.6 Adverse Drug Reaction and Reference Safety Information 
10.6.1 Adverse Drug Reaction 
An adverse drug reaction (ADR) is an untoward and unintended response to an IMP related 
to any dose administered. This definition implies a reasonable possibility of a causal 
relationship between the event and the IMP. This means that there are facts (evidence) or 
arguments to suggest a causal relationship. 
All AEs judged as having a reasonable causal relationship to a medicinal (investigational) 
product will be designated as ADRs. 
10.6.2 Reference Safety Information 
The Reference Safety Information (RSI) presents the basis for expectedness assessment of 
an ADR for expedited reporting and annual safety reporting, as well as surveillance of 
subject’s safety in a clinical trial by regulatory (and ethic) bodies. 
In the context of this study, the RSI for patiromer is integrated in Table 19 of the patiromer 
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10.7 Serious Adverse Event 
10.7.1 Definition of Serious Adverse Event 
An SAE is defined as any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening (the term life-threatening in the definition of serious refers to an event 
in which the subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe) 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
Hospitalization for elective surgery, i.e., a planned, non-emergency medical procedure, 
social hospitalizations and hospitalizations lasting less than 24 hours are not considered 
SAEs 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Is an important medical event (i.e., medically significant) 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require intervention to prevent one of the other outcomes listed in the 
definition above. These events should also be considered as serious. 
Any worsening of a pre-existing medical condition or any new medical condition that meets 
the above SAE criteria should be considered as an SAE. 
The Investigator is encouraged to discuss with the CRO or Sponsor any AEs for which the 
issue of seriousness is unclear or questionable. 
10.7.1.1 
Situations That Are Not Considered SAEs 
The following situations are not considered as SAEs: 
• Elective or pre-planned surgery for a pre-existing condition that has not worsened 
• Routine health assessments requiring admission not associated with any deterioration 
in condition 
• Social admission (lack of housing, family circumstances, etc.) 


 
 
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10.7.2 Serious Adverse Event Reporting 
The SAE reporting period begins at the time the ICF is signed by the subject. The SAE 
reporting period ends 2 weeks following the EoS or until 2 weeks after last study drug 
administration, whichever is longer. If the final Follow-up Visit is conducted as a telephone 
call rather than a formal visit, the Investigator must report any SAEs that occur during this 
period. 
The occurrence of an SAE must be immediately reported to the Sponsor (or its delegate, 
e.g., CRO) within 24 hours of awareness by facsimile, email, or telephone/via EDC system. 
This includes all SAEs (independent of relationship to study treatment). 
A death occurring during the study or which comes to the attention of the Investigator 
within 2 weeks after the EoS or until 2 weeks after the last study drug administration, 
whichever is longer, whether considered treatment-related or not, must be reported to the 
CRO/Sponsor. 
Any SAE considered to have a causal relationship (i.e., related) to the investigational 
product and discovered by the Investigator at any time after the study should be reported. 
A rationale for the assessment of a causal relationship must be provided by the Investigator. 
Any safety information that is obtained after database lock of the clinical database will be 
documented in the safety database and implications for handling the data in the clinical 
database assessed on an individual case basis. 
The onset date of the SAE is defined as the date the signs and symptoms/diagnosis became 
serious (i.e., met at least one of the criteria for seriousness; see Section 10.7.1). If the subject 
experiences an AE and it progresses into an SAE, a new SAE should be recorded. The 
original AE stop date should be the same as the start date of the SAE. However, when the 
SAE resolves and the pre-existing AE is still ongoing, this should be recorded as a new AE. 
The resolution date of an SAE is defined as when the symptoms resolve, or the event is 
considered chronic (e.g., sequelae) or stable, and/or if the seriousness criteria are no longer 
applicable. 
The Investigator must complete the SAE report form and verify the accuracy of the 
information recorded on the SAE pages with the source documents. The Sponsor SAE 
report form will be completed in capital letters, in medical terms, in English and to the best 
extent possible given the time constraints. Any supporting documentation (e.g., hospital 
discharge summary, autopsy report/death certificate, etc.) should be sent/transmitted along 
with the (follow-up) SAE report form. The supporting information provided should not 
reveal a subject’s identity beyond the agreed study identifier. The Investigator should 
ensure that the information reported is accurate and consistent. 
At a minimum, the following should be provided at the time of the initial SAE report: 
• Study name and/or number 


 
 
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• Subject number, age, and gender/sex 
• Event description/verbatim (including onset date of the SAE, outcome, and reason for 
it being considered serious) 
• Relationship to patiromer/placebo (i.e., causality) 
• Patiromer/placebo dose (number of packets) and administration dates 
• Action taken with patiromer/placebo 
• Severity of the event 
• Investigator name and address 
• Name of the reporter (including site name or number and country), and, 
• Dated signature of the Investigator or Sub-/Co-Investigator 
When using electronic methods of reporting SAEs, some of the information in the above 
list may be generated by the electronic system. 
Since SAEs are also AEs, the information for the AE eCRF and SAE form should be 
consistent. 
Follow-up information must be handled in the same way and reported within the same time 
frame as the initial SAE report. A safety contact sheet will be provided by the Sponsor to 
the Investigator (prior to first subject providing informed consent) detailing all applicable 
contact information for safety reporting. This contact sheet will be kept up to date with any 
changes being provided to the Investigator immediately. 
Where possible, the Investigator should report a diagnosis rather than signs and symptoms. 
Death should be considered an outcome and not a distinct event. In case of a fatal outcome, 
the Investigator should provide a working diagnosis (event which caused outcome, e.g., 
death due to fatal myocardial infarction) instead of reporting only death; and an autopsy 
report should be provided where possible. If the cause of death later becomes available (e.g., 
after autopsy), this working diagnosis should be replaced by the established cause of death. 
All recorded SAEs, regardless of relationship to investigational product, will be followed 
up until resolution, stabilization, or the subject is lost to follow-up and cannot be contacted. 
After the completion of the 2 weeks follow-up after the EoS, updates should be submitted 
to the Sponsor (or its delegate, CRO) using the Sponsor SAE report form. In circumstances 
where the Investigator is unable to make contact with the subject (or his/her relatives), the 
Investigator must provide a written statement (recorded in the subject’s source documents) 
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SAE information that is obtained after the EoS should be reported to: 
Sponsor-Vifor Pharma: 
Email address: 
 
FAX: 
 or 
 
Please reference further guidance provided along with the EDC system entry. 
10.7.2.1 
Study Endpoints 
All events potentially related to the endpoint of CV death or CV hospitalizations or urgent 
HF visits will be collected starting from the date of randomization. For the purposes of this 
protocol, the following events are considered SAEs and must be reported as described in 
Section 10.7.2. 
• Death from any cause 
• Any CV event leading to hospitalization (e.g., HF, myocardial infarction, stroke, 
unstable angina, arrhythmia) 
The following CV hospitalization events will be counted towards the endpoint: 
• HF hospitalization or equivalent urgent HF visit (e.g., emergency room or outpatient 
visit for worsening HF during which the subject received intravenous medications for 
the treatment of HF) 
• Type I acute myocardial infarction (including both ST segment elevation myocardial 
infarction and non-ST segment elevation myocardial infarction) leading to 
hospitalization 
• All types of arrhythmia including atrial fibrillation requiring leading to hospitalization 
• Hypertension emergency; systolic blood pressure ≥180 mmHg leading to 
hospitalization 
• Stroke leading to hospitalization 
Based on the specific study design and the advanced underlying disease state of the 
recruited subject population, events suggestive of the study outcomes would automatically 
qualify to meet the criteria of seriousness in this study. These events include known 
consequences of the underlying disease and are anticipated to occur in the study population 
independent of drug exposure (see above bullet points). These events would be reported, 
collected and monitored during the course of the study like all other SAEs, but would not 
be reported individually in an expedited manner, unless the Investigator and/or Sponsor has 


 
 
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deemed it to have reasonable possibility that the study drug caused the event and would 
follow the reporting process of a SUSAR. 
The DSMB will monitor the identified events during the conduct of the study and alert if 
there is evidence of causal relationship between patiromer/placebo and the event following 
their analysis. 
10.7.3 SUSARs 
The definition of a SUSAR is any ADR (see Section 10.6.1) that is both serious (see Section 
10.7.1) and unexpected (per the RSI; see Section 10.6.2) that is felt to have a reasonable 
suspected causal relationship to a medicinal product. 
10.7.3.1 
SUSAR Reporting 
The Investigator is responsible for notifying the IRB in accordance with local regulations 
of all SUSARs that occur. The Investigator must review and file the associated safety report 
with the IB. 
10.8 Special Situations 
10.8.1 Definition of Special Situations 
The following are defined as special situations: 
• Use of an IMP during pregnancy or breastfeeding 
• Medication abuse: the persistent or sporadic, intentional excessive use of study 
medication by the subject (not for therapeutic purpose) 
• Medication error: any unintentional error in the prescribing, dispensing or 
administration of an IMP during the study. (Medication errors are any preventable event 
that may cause or lead to inappropriate medication use or patient harm while the 
medication is in the control of the health care professional or subject) 
• Medication misuse: an intentional and inappropriate use of an IMP by the subject for a 
therapeutic purpose not in accordance with the protocol dose, route of administration, 
and/or the indication(s) (e.g.: Subject deliberately took the medication twice daily 
instead of once daily) 
• Medication overdose: the administration of a quantity of study medication given per 
administration or per day which is 3 times above the protocol maximum permitted dose 
• Drug interaction involving study medication 
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Suspected AEs associated with medication errors of the IMP or use outside that foreseen 
in the protocol (e.g., overdose) are also considered as ADRs. Any special situation 
occurring with/without ADR/AE shall be recorded in the study-specific documentation by 
the Investigator. 
10.8.2  Special Situation Recording and Reporting 
All special situations have to be documented in the subject’s eCRF and source documents. 
If any special situation leads to an SAE (see Section 10.7.1), then the event has to be 
immediately reported to the Sponsor (or its delegate; e.g., CRO) within 24 hours of 
awareness by facsimile, email or telephone/via EDC system. 
Medication error due to product dose omission (subject forgetting to take a dose), does not 
need to be documented in the eCRF if the product dose omission did not occur 
consecutively, and compliance is not <80%. 
10.8.3 Pregnancy Exposure and Birth Events 
10.8.3.1 
Definition of Pregnancy Exposure and Birth Events 
When a female subject becomes pregnant during the study and study treatment has been 
administered to the subject, the outcome of the pregnancy needs to be monitored and the 
safety of the mother and unborn child need to be safeguarded (as per protocol, pregnancy 
is an exclusion criteria). Therefore, the outcome of all such pregnancies (including normal 
births) must be followed up and documented, even if the subject was withdrawn from the 
study or the study has been completed. 
Women of child-bearing potential, defined as a premenopausal female capable of becoming 
pregnant, should have a negative pregnancy test prior to randomization. Study medication 
must not be initiated by the Investigator until a report of a negative pregnancy test has been 
obtained. 
Effective birth control must be used (in female subjects) before beginning study medication, 
during study dosing, and for 4 weeks following discontinuation of study medication; see 
Section 9.8. 
A female subject must immediately inform the Investigator if she becomes pregnant during 
the study, and she will be instructed by the Investigator to stop taking study medication. 
The Medical Monitor must be contacted immediately. The Investigator should counsel the 
subject and discuss the risks of continuing with the pregnancy and the possible effects on 
the fetus. 
The Investigator is responsible for monitoring the subject and pregnancy outcome and 
reporting this information to the Sponsor. Every effort should be made to gather 
information regarding the pregnancy outcome until 90 days postpartum (or otherwise as 
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10.8.3.2 
Pregnancy Exposure and Birth Events Recording and Reporting 
If a female subject becomes pregnant or is suspected of being pregnant while participating 
in this study, the investigational product will be permanently discontinued, and the event 
must be reported to Drug Safety upon receipt of information by the study staff. Pregnancies 
must be reported throughout the conduct of the study including 4 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 Drug 
Safety within 24 hours of becoming aware on the Sponsor Report on Exposure to Medicines 
During Pregnancy 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 an SAE before, 
during, or after delivery (including lactation by the maternal subject) will be followed until 
resolution of the event (or for a minimum of 1 year). 


 
 
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11. STUDY COMMITTEES 
11.1 DSMB 
The independent DSMB will act in an advisory capacity to the Sponsor to monitor the 
safety of subjects who participate in this study. The DSMB is governed by a charter which 
explains the working procedures and responsibilities of the DSMB [38]. 
11.2 Event Adjudication Committee 
The independent Event Adjudication Committee (EAC) will adjudicate all events relating 
to the study endpoints based on prospectively defined criteria detailed in the EAC charter. 
EAC members must not be employees of the study Sponsor and consists of, at minimum, 
3 qualified members (at least one cardiologist specializing in HF); see EAC charter for 
further details [39]. The EAC will be blinded to study treatment allocations while 
adjudicating the events. Endpoint adjudication will occur on an ongoing basis throughout 
the Blinded Treatment Phase of the study. 
11.3 Steering Committee 
The independent Steering Committee will advise the Sponsor scientifically as well as 
monitor trial progress and conduct. The specific areas of focus for the Steering Committee 
are protocol design, execution, analysis, interpretation, and publication of the DIAMOND 
study, and any proposed sub-studies. 


 
 
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12. STATISTICAL ANALYSIS 
12.1 Statistical Methods 
Detailed methodology for summary and statistical analyses of the data collected in this trial 
will be documented in an SAP. A general description of the planned methods is provided 
below. Any deviation from the SAP will be noted and explained in the final study report. 
12.2 Sample Size and Power Calculations 
The sample size of 410 subjects per treatment arm (total of 820 subjects) has been 
calculated to provide 90% power to detect a difference between the control group (placebo) 
and the active group (patiromer) on the mean change in K+ levels from Baseline. This 
sample size calculation was based upon the following assumptions: alpha level of 5% 
(2-sided), a difference between group means of 0.116, an SD of 0.5, and a 5% annual rate 
of loss to follow-up. 
12.3 Randomization 
Subjects will be randomized to the treatment arms (1:1 assignment) using permuted block 
randomization stratified by geographic region. Randomization will take place using a 
centralized list accessed electronically via IWRS on the day of randomization, after 
randomization eligibility is determined. 
12.4 Analysis Sets 
12.4.1 Randomized Set 
All subjects randomized to study treatment. 
12.4.2 Full Analysis Set 
The full analysis set consist of all subjects who satisfy the following criteria: 
• Randomized to treatment 
• Received at least 1 dose of randomized treatment 
This set will be used for the evaluation of efficacy. 
12.4.3 Safety Set 
The safety set (SS) consists of all subjects who have taken at least 1 dose of randomized 
study medication. The subjects in this group will be analyzed based on the treatment they 
received with data summarized separately for the Run-in and Blinded Treatment Phases of 
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12.4.4 Run-in Phase Set 
The Run-in Phase Set will consist of subjects that signed informed consent, entered the 
Run-in Phase, and received patiromer, but were not randomized. This set will be used to 
summarize safety related events that may be related to patiromer treatment. 
12.5 Background and Demographic Characteristics 
Demographic and Baseline characteristics will be summarized for the Randomized Set and 
the Run-in Phase Set. 
Summaries of continuous variables will include the mean, SD, SE, median, 25th and 75th 
percentiles, and the maximum and minimum. Summaries of categorical variables will 
include counts and percentages. 
Listings for demographics and baseline characteristics will be provided. 
12.6 Study Medication 
The total amount of drug given will be calculated for each subject and will be compared to 
the amount expected to be given for each subject. Treatment compliance will be calculated 
for each subject and summarized by treatment group. 
12.7 Concomitant Therapy 
Concomitant medications (as defined in Section 6.8.4) will be categorized according to a 
standard dictionary (World Health Organization Drug Dictionary). Counts and percentages 
of subject use for each medication will be computed and summarized by treatment group. 
Summaries will be provided for the periods before and after randomized treatment was 
received. 
12.8 Efficacy Evaluations 
12.8.1 Primary 
The primary analysis will be based upon the mean change in serum K+ levels from Baseline 
and is analyzed by means of an MMRM approach including all available post Baseline data. 
All analyses will be restricted to serum K+ assessments and not substituted by plasma values 
as they are known to be systematically lower. Central laboratory values and/or local 
laboratory will be used at all visits, and if both values are present at one visit, then central 
laboratory values will be used. A Gaussian linear model for repeated measures with 
treatment, geographic region, sex, baseline T2DM status, and visit as factors, and baseline 
K+ level, baseline eGFR as covariates. The error terms are assumed to follow a multivariate 
normal distribution with unstructured covariance. Least squares mean changes from 
Baseline will be reported for both treatment groups with 95% CIs as well as the difference 
between the least squares group means with 95% CI and p-value testing the null hypothesis 
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Sensitivity analyses for the primary endpoint will be based upon the use of all CV deaths 
and hospitalizations (i.e., recurrent event analysis) recorded during follow-up using the 
following methods: will explore changes in treatment effect over follow-up time by 
including treatment by visit interactions in the above-mentioned model. In addition, 
sensitivity analyses for the primary endpoint will explore changes in treatment effect over 
follow-up time by including treatment by visit interactions in the above-mentioned model. 
In addition, sensitivity analyses accounting for potentially informative missingness will be 
based upon a Win Ratio approach [4,40].  
12.8.2 Key Secondary Endpoints (Hierarchically Ordered) 
Secondary efficacy endpoints will be tested sequentially in the order listed below 
(i.e., fixed-sequence method to preserve the family-wise error rate) and summarized 
descriptively through the calculation of point estimates by treatment group along with 95% 
CIs for the treatment differences. The following lists the secondary endpoints and the 
analysis method to be used: 
• Hyperkalemia events: The time to the first event of hyperkalemia with a serum K+ 
value >5.5 mEq/L as per the measured values from the central or local laboratories is 
analyzed using a Cox proportional hazards regression model. The event probabilities 
will be estimated using the Aalen-Johansen estimator of the cumulative incidence 
function accounting for competing events such as death. 
• Durable enablement to stay on the MRA target dose (of 50 mg spironolactone or 
eplerenone): The time to the event of reduction of the MRA dose below target is 
analyzed using a Cox proportional hazards regression model. The event probabilities 
will be estimated using Aalen-Johansen estimator of the cumulative incidence function 
accounting for competing events such as death. 
Note: Discontinuation of the target dose for at least 14 days (or less if at the EoS) is 
required to confirm this endpoint.  
• Investigator reported AEs of hyperkalemia (first and recurrent) are analyzed using a 
negative binomial regression with the logarithm of the individual follow-up time as 
offset. A joint frailty model of the total (first and recurrent) hyperkalemia events and 
time to death as terminating event. If all-cause mortality is substantial in number and 
differential between the treatment groups, then the joint frailty model would become 
the main analysis approach. Note: For analyses based upon the negative binomial 
distribution, the subject level count data will be modeled as function of treatment with 
the natural log of the subject level follow-up time taken into account in the estimation 
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• Hyperkalemia-related hard outcomes are analyzed using the Win Ratio approach with 
the following hierarchical components (all assessed during comparable follow-up 
times): 
1. Time to CV death 
2. Total number of CV hospitalizations 
3. Total number of hyperkalemia toxicity events with serum K+ >6.5 mEq/L 
4. Total number of hyperkalemia toxicity events with serum K+ >6.0-6.5 mEq/L 
5. Total number of hyperkalemia toxicity events with serum K+ >5.0-6.0 mEq/L 
• RAASi Use Score which will be analyzed using the Win Ratio approach for each pair 
of patients at the end of the comparable follow-up period that is appropriate for that pair 
of patients with the following additive components. Points are accumulated from two 
components at the respective time for each patient in each comparison: 
Component A: 
− 
If during the follow-up (to the respective end of follow-up in the comparison) there 
was a death, the subject is assigned 0 points 
− 
If during the follow-up (to the respective end of follow-up in the comparison) there 
was a CV hospitalization, but the subject is alive at the end of that follow-up, the 
subject is assigned 1 point 
− 
If during the follow-up (to the respective end of follow-up in the comparison) there 
was no CV hospitalization and the subject is alive at the end of that follow-up, the 
subject is assigned 2 points 
Component B: 
Further points are collected for the treatment status at the respective end of follow-up 
in the comparison: 
− 
For ACEi/ARB/ARNi use: >50% of the target dose = 2 points 
− 
For ACEi/ARB/ARNi use: >0 and up to 50% of the target dose = 1 point 
− 
For MRA use: >50% of the target dose = 2 points 
− 
For MRA use: >0 and up to 50% of the target dose = 1 point 
− 
For beta-blocker use: >50% of the target dose = 2 points 


 
 
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− 
For beta-blocker use: >0 and up to 50% of the target dose = 1 point 
In summary, each subject in each comparison can have 0-8 points (sum of Components 
A and B) and all subjects are compared using this score at the respective appropriate 
follow-up time point. 
The regression analyses will be adjusted for geographic region as the stratification 
factor of the randomization and relevant baseline characteristics of the subjects. 
12.8.3 Other Secondary Endpoints 
The additional endpoints listed below (Other Secondary Endpoints), will also be 
summarized descriptively by treatment arm in the full analysis set: 
• Durable enablement to stay on the target dose of ACE/ARB/ARNi 
Note: Discontinuation of the target dose for at least 14 days (or less if at the EoS) is 
required to confirm this endpoint 
• Durable hyperkalemia-free enablement to stay on the MRA target dose (days on 50 mg 
MRA without presence of hyperkalemia) 
• Hyperkalemia toxicity events with serum K+ >6.5 mEq/L 
• Hyperkalemia toxicity events with serum K+ >6.0-6.5 mEq/L 
• Emergency treatment for hyperkalemia (hospitalization or emergency room) 
• Total number of hyperkalemia toxicity events with serum K+ >5.0-6.0 mEq/L 
• KCCQ questionnaire - OSS, CSS and TSS  
• Investigator reported events of hyperkalemia (recurrent events) 
• Proportion of subjects on ≥50% of target dose of ACEi, ARB, or ARNi and ≥50% of 
target dose of MRA at the EoS Visit 
• Time to first occurrence of CV death or CV hospitalization 
12.8.4 Other Endpoints 
• CV death 
• First and recurrent CV hospitalizations 
• First and recurrent HF hospitalizations (or equivalent in outpatient clinic) 
• Patient-reported outcome: EQ-5D-5L questionnaire 


 
 
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• Proportion of subjects on any dose of MRA at the EoS Visit 
• Proportion of subjects on any dose of ACEi, ARB, or ARNi at the EoS Visit 
• Change in proteinuria from Screening 
• Change in NT-proBNP from Screening 
• Change in high sensitivity troponin from Baseline 
• Functional status by NYHA class 
• 30-day HF re-hospitalization after a prior HF hospitalization 
• HEOR analyses 
• Changes in serum K+ from Baseline to individual visits 
12.8.5 Subgroups of Interest 
Descriptive analyses (including the presentation of 95% CIs) will be produced for the 
subgroups specified below. These descriptive analyses will be summarized graphically 
through the use of forest plots. 
Subgroups to be analyzed include: 
• At Screening, hyperkalemic versus normokalemic with a history of hyperkalemia 
• Screening use of ARNi (Yes or No) 
• Screening use of eplerenone or spironolactone (Yes or No) 
• Screening comorbidity: 
− 
Diabetes mellitus (Yes or No) 
− 
CKD stage (Stage 3b versus Stages 1–3a, Stage ≤3a versus Stage ≥3b, Stage 4 
versus Stage <4) 
− 
NYHA Class (II versus III–IV) 
• Region (US versus Non-US) 
Note: Depending on actual subject recruitment, additional comparisons between other 
regions, e.g., Latin America, Western Europe, Eastern Europe, will be defined in the 
SAP 
• Gender (male or female) 


 
 
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• Age (age group categories will be defined prior to unblinding) 
• Race/ethnicity (limited to racial/ethnic subgroups that comprise 20% or more of the 
study population) 
• Median NT-proBNP at Screening 
12.9 Safety Evaluations 
The following safety variables will be summarized using the safety set: 
• AEs and SAEs (coded using Medical Dictionary for Regulatory Activities (MedDRA); 
see Study Manual for MedDRA version), including all-cause mortality 
• Slope of eGFR change during the study will be estimated and compared between 
treatment groups using a repeated measures analysis with time treated as a continuous 
variable 
• Decline in eGFR >50% or ESRD, renal death, or need for dialysis 
• Laboratory parameters other than those defined as efficacy endpoints 
AE summaries will be provided separately for: (1) AEs with start date on or after first dose 
date during the Run-in Phase and on or before the date of randomization; and (2) AEs with 
start date on the day after randomization. Summaries will consist of counts (%) by system 
organ class (SOC), preferred term (PT) and severity in the Run-in Phase, and by SOC, PT, 
severity, and treatment in the blinded withdrawal phase. The following types of AEs will 
be summarized: 
• All treatment-emergent adverse events (TEAEs) 
• TEAEs related to study medication (patiromer/placebo) and to RAASi 
• TEAEs leading to study medication discontinuation (patiromer/placebo) and to RAASi 
discontinuation 
• SAEs 
A listing of AEs will be provided, to include verbatim term, PT, SOC, intensity/severity, 
relationship to patiromer/placebo, and to RAASi, whether serious, onset/end date, action 
taken and outcome of event. 
12.10 Interim Analyses 
No interim analysis is planned. 


 
 
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13. STUDY ETHICAL CONSIDERATIONS 
13.1 Ethical Conduct of the Study 
The study will be conducted according to the principles of the World Medical Association’s 
Declaration of Helsinki [41], and the International Council for Harmonisation (ICH) 
guidelines for GCP [42] as amended. The Sponsor will ensure that the study complies with 
all local, federal, or country regulatory requirements. 
The Investigator must ensure the anonymity of all subjects participating in the study. Each 
subject will be assigned a unique subject number, and this should be used on all forms 
associated with the subject’s documents or samples that will be supplied to the Sponsor or 
any party completing testing on behalf of the Sponsor (e.g., blood for central laboratory 
assessments). 
All anonymous data remains the property of the Sponsor. 
13.2 Informed Consent 
Individual subject’s medical information obtained as a result of this study is considered 
confidential and disclosure to unauthorized parties is prohibited. Subject’s confidentiality 
will be assured by utilizing unique subject numbers, instead of names. If results of this 
study are reported in medical journals or at meetings or may be submitted to competent 
regulatory authorities in connection with regulatory procedures such as applications to 
authorize the marketing of pharmaceutical products, the subject’s identity will not be 
disclosed. 
With the subject’s authorization, medical information may be provided to the subject’s 
personal physician or to other appropriate medical personnel responsible for the subject’s 
welfare. 
In compliance with GCP guidelines, all subjects will be informed of the purpose of the 
research, the possible risks, and their right to withdraw at any time from the study without 
prejudice and without jeopardy to their future medical care at the center. Each subject must 
agree to cooperate in all aspects of the study and must give informed written 
acknowledgment (signed ICF) to the Investigator prior to participation in the study. If the 
ICF is revised during the study, active subjects must sign the new version in order to 
continue participating in the study. For any updated or revised ICF, if applicable, the subject 
record should state that written informed consent was obtained for the updated/revised 
consent form for continued participation in the trial. The ICF should be revised whenever 
there are changes to procedures in the amended protocol associated with procedures in the 
ICF or when new information becomes available that may affect the willingness of the 
subject to participate. Every subject will be given a copy of each version of the form that 
he/she signs before and during the study. 


 
 
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In the US, each ICF may also include authorization allowing the institution, Investigator, 
and the Sponsor to use and disclose personal health information in compliance with the 
Health Insurance Portability and Accountability Act of 1996 (HIPAA). 
No subject is to participate in study activities until informed consent has been obtained. 
Documentation of the informed consent process and subject information discussion must 
appear in the subject’s medical record and include a statement that informed consent was 
obtained prior to participation in the study. Signed acknowledgments (ICFs) must remain 
in the subjects’ files and be available for verification by monitors, auditors, and/or 
regulatory agency inspectors at any time. All Independent Ethics Committee 
(IEC)/IRB-approved ICF versions must be provided to the Sponsor for regulatory purposes. 
13.3 IRB or EC/IEC 
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 IB, 
and any information to be given to the subject before a site can begin conducting any study-
related activities. A copy of the IRB/IEC approval letter for the protocol and the ICF must 
be provided to the Sponsor 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 the Sponsor. The Investigator must also inform the IRB/IEC of any 
protocol changes or amendments, changes to the IB, 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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14. 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. 
Sponsor employees or designee will conduct site monitoring visits at regular intervals in 
accordance with FDA and ICH guidelines. The Investigator will permit Sponsor or 
designee monitors to review and inspect facilities, and all records relevant to this study. 
The Investigator will also permit the Sponsor or designee auditors, the IRB/IEC, FDA, or 
other Regulatory Authority inspectors to review and inspect facilities, procedures, and all 
records relevant to this study. These records include, but are not limited to subject signed 
ICFs, source documentation, regulatory and essential documents, eCRFs, and drug 
accountability records. If the FDA or other regulatory agency should schedule an inspection, 
the Investigator should notify the Sponsor and/or designee 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 
14.1 Quality Management: Critical Processes and Data 
The following processes and data have been identified during the risk management 
activities for this trial as critical to ensure human subject protection and the reliability of 
trial results. 
14.1.1 Critical Processes 
Throughout the study, the clinical study team will work to ensure that the trial is 
operationally feasible and focuses on study activities essential to human subject protection 
and the reliability of trial results, including, but not limited to: 
• Study protocol design and implementation 


 
 
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• Tools and procedures supporting data collection and processing 
• Tools and procedures safeguarding the rights and protection of human subjects 
• Activities essential to trial decision-making and compliance 


 
 
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15. REPORTING AND RECORDING OF DATA 
Source documents are original documents, data, and records (e.g., case histories, progress 
notes of the physician, nurses’ notes, medical records, hospital records, clinical and office 
charts, laboratory notes, memoranda, or evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, copies or transcriptions certified after 
verification as being accurate and complete, records kept at the pharmacy or laboratories, 
and subject logs). Source data are contained in source documents and must be adequate to 
reconstruct all data transcribed onto the eCRFs and to evaluate the study. Examples of 
source data include clinical findings, observations, enrollment summary information and 
ICF procedures, assessment of clinical significance for laboratory results, AE severity and 
seriousness, and Investigator’s opinion of AE relatedness to patiromer/placebo. 
The Investigator is required to prepare and maintain adequate and accurate case histories 
that record all observations and other data pertinent to the investigation for all subjects. 
Source documentation should be available at monitoring visits to verify entries made on 
eCRFs, as needed. Source documentation should also be available for verification by 
auditors and/or inspectors, as needed. 
15.1 Source Documentation 
The Investigator must maintain adequate and accurate source documents upon which case 
reports for each subject are based. They are to be separate and distinct from eCRFs. These 
records should include detailed notes on: 
• The medical history prior to participation in the study 
• The basic identifying information, such as demographics, that link the subject’s source 
documents with the eCRFs 
• The results of all diagnostic tests performed, diagnoses made, therapy provided, and 
any other data on the condition of the subject 
• The subject’s exposure to study treatment 
• All AEs and pregnancies 
• All special situations as defined in Section 10.8 
• The subject’s exposure to any concomitant therapy 
• All relevant observations and data on the condition of the subject throughout the study 
• The oral and written communication with the subject regarding the study treatment 
(including the risks and benefits of the study); the date of informed consent must be 
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All data for the study must be available in source documentation. 
15.2 Case Report Forms/Electronic Data Record 
An eCRF is designed to record all of the protocol required information to be reported to the 
Sponsor 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. Site staff will have proper training prior to accessing the 
EDC system. 
Any change or correction to an eCRF will be tracked via an audit trail within the EDC 
system. The audit trail will contain the original data value, new data value, date changed, 
the user who made the change, and the reason(s) for the change. 
eCRFs should be completed in a timely manner to the respective visit (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 the Sponsor 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., MedDRA and World Health Organization Drug 
Dictionary). 
The Investigator is responsible for reviewing, verifying, and approving all subject data (i.e., 
eCRFs and resolved queries). 
15.3 Records Retention 
The Investigator must maintain adequate records for the study including completed eCRFs, 
medical records, laboratory reports, signed ICFs, drug disposition records, adverse 
experience reports, information regarding subjects who discontinued, all correspondence 
with the IRB/IEC and the Sponsor, and other pertinent data. 
The Investigator is to retain all records until notified by the Sponsor. The Investigator will 
notify the Sponsor in writing of the relocation of any study records away from the research 
facility after study closure. The Investigator must contact the Sponsor in writing prior to 
the destruction of any study records, or in the event of loss of any study records. 


 
 
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15.4 Site Documentation 
The Investigator must maintain adequate and accurate records to enable the conduct of the 
study to be fully documented and the study data to be subsequently verified. 


 
 
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16. PROCEDURE FOR MODIFICATION OF PROTOCOL OR 
PREMATURE TERMINATION OF THE STUDY 
16.1 Protocol Deviations 
The Investigator will not deviate from the protocol without prior written approval from the 
Sponsor, 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 (see Section 16.2). The 
criteria describing protocol deviation(s) and how they will be handled will be documented 
in the Study Manual. 
16.2 Protocol Amendments 
Protocol amendments, except where necessary to eliminate an immediate hazard to subjects, 
must be made only with the prior approval of the Sponsor. Each applicable Regulatory 
Authority/IRB/EC/IEC will review and approve amendments prior to their implementation. 
Regulatory Authority/IRB/EC/IEC approval need not be obtained prior to removal of an 
immediate hazard to subjects. 
16.3 Study Termination 
The Sponsor reserves the right to terminate the study in its entirety or at a site at any time. 
Reasons for termination may include (but are not limited to) unsatisfactory subject 
enrollment with respect to quality and/or quantity, site is unable to comply with the 
requirements of the protocol or GCP, or data recording is inaccurate and/or incomplete. 
In terminating the study, the Sponsor and the Investigator will assure that adequate 
consideration is given to the protection of the subject’s interests. Both parties will arrange 
the procedures on an individual basis after review and consultation and in accordance with 
the study contract. 
Based on their data review, the DSMB may provide recommendations to stop the study as 
per guidance within the DSMB Charter. The Sponsor will determine whether the study 
should be stopped early. 
The study may be terminated or suspended upon request of regulatory authorities. 


 
 
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17. POLICY FOR PUBLICATION AND PRESENTATION OF DATA 
The Clinical Trial Agreement describes the Sponsor’s publication terms. 
In accordance with applicable laws and regulations, the Sponsor will publicly register and 
provide all mandatory information regarding this trial including, to the extent and within 
the timelines required, a summary of the trial data and results. 


 
 
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18. REFERENCES 
1. 
PAT-CR-302 Study Manual. A multicenter, double-blind, placebo-controlled, 
randomized withdrawal, parallel group study of patiromer for the management of 
hyperkalemia in subjects receiving renin-angiotensin-aldosterone system inhibitor 
(RAASi) medications for the treatment of heart failure (DIAMOND). Version 5.0 
PAT-CR-302 Study Manual for Protocol Amendment v4.0. Redwood City (CA): 
Vifor Pharma Inc.; 2021 June 23. 
2. 
Lin DY, Wei LJ, Yang I, Ying Z. Semiparametric regression for the mean and rate 
functions of recurrent events. J R Statist Soc B. 2000;62(Part4):711-30. 
3. 
Ariti CA, Cleland JGF, Pocock SJ, Pfeffer MA, Swedberg K, Granger CB, et al. 
Days alive and out of hospital and the patient journey in patients with heart failure: 
Insights from the Candesartan in Heart failure: Assessment of Reduction in 
Mortality and morbidity (CHARM) program. Am Heart J. 2011 Nov;162(5):900-6. 
4. 
Finkelstein DM, Schoenfeld DA. Combining mortality and longitudinal measures 
in clinical trials. Statist Med. 1999;18:1341-54. 
5. 
Ponikowski P, Anker SD, AlHabib KF, Cowie MR, Force TL, Hu S, et al. Heart 
failure: preventing disease and death worldwide. ESC Heart Failure. 2014;1:4-25. 
Epub 2014 Aug 29. 
6. 
Dev S, Hoffman TK, Kavalieratos D, Heidenreich P, Wu W-C, Schwenke DC, et 
al. Barriers to adoption of mineralocorticoid receptor antagonists in patients with 
heart failure: a mixed-methods study. J Am Heart Assoc. 2016;5:e002493. p. 1-11. 
7. 
Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, et al. Heart 
disease and stroke statistics—2017 update: a report from the American Heart 
Association. Circulation. 2017 Mar 7;135(10):e146-603. 
8. 
Collins AJ, Pitt B, Reaven N, Funk S, McGaughey K, Wilson D, et al. Association 
of serum potassium with all-cause mortality in patients with and without heart 
failure, chronic kidney disease, and/or diabetes. Am J Nephrol. 2017;46:213-21. 
Epub 2017 Sep 2. 
9. 
Damman K, Tang WH, Felker GM, Lassus J, Zannad F, Krum H, McMurray JJ. 
Current evidence on treatment of patients with chronic systolic heart failure and 
renal insufficiency: practical considerations from published data. J Am Coll Cardiol 
2014; 63:853–71. 
10. 
Rossignol P, Agarwal R, Canaud B, Charney A, Chatellier G, Craig JC, et al. 
Cardiovascular outcome trials in patients with chronic kidney disease: challenges 
associated with selection of patients and endpoints. Eur Heart J. 2017;1-8. 
11. 
Allen LA, Fonarow GC, Liang L, Schulte PJ, Masoudi FA, Rumsfeld JS, et al. 
Medication initiation burden required to comply with heart failure guideline 
recommendations and hospital quality measures. Circulation. 2015 Oct 
6;132:1347-53. 


 
 
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12. 
Yancy CW, Jessup M, Bozkurt B, Butler J, Casey Jr DE, Colvin MM, et al. 2016 
ACC/AHA/HFSA Focused update on new pharmacological therapy for heart 
failure: an update of the 2013 ACCF/AHA guideline for the management of heart 
failure. J Am Coll Cardiol. 2016 Sep 27;68(13):1476-88. 
13. 
Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, et al. 2016 
ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. 
The Task Force for the diagnosis and treatment of acute and chronic heart failure of 
the European Society of Cardiology (ESC). Eur Heart J. 2016;37:2129-200m. 
14. 
Maggioni AP, Anker SD, Dahlström U, Filippatos G, Ponikowski P, Zannad F, et 
al. Are hospitalized or ambulatory patients with heart failure treated in accordance 
with European Society of Cardiology guidelines? Evidence from 12,440 patients of 
the ESC Heart Failure Long-Term Registry. Eur J Heart Fail. 2013;15:1173-84. 
Epub 2013 Aug 26. 
15. 
Desai AS, Swedberg K, McMurray JJV, Granger CB, Yusuf S, Young JB, et al. 
Incidence and predictors of hyperkalemia in patients with heart failure: an analysis 
of the CHARM Program. J Am Coll Cardiol. 2007 Nov 13;50(20):1959-66. 
16. 
Rossignol P, Pitt B, Thompson A, Zannad F. Roadmap for cardiovascular 
prevention trials in chronic kidney disease. Lancet. 2016 Oct 22;388:1964-6. 
17. 
Edner M, Benson L, Dahlström U, Lund LH. Association between renin-
angiotensin system antagonist use and mortality in heart failure with severe renal 
insufficiency: a prospective propensity score-matched cohort study. Eur Heart J. 
2015;36:2318-26. Epub 2015 Jun 11. 
18. 
Zannad F, Rossignol P, Stough WG, Epstein M, Alonso Garcia MdlA, Bakris GL, 
et al. New approaches to hyperkalemia in patients with indications for renin 
angiotensin aldosterone inhibitors: considerations for trial design and regulatory 
approval. Int J Cardiol. 2016;216:46-51. Epub 2016 Apr 19.  
19. 
Ferreira JP, Butler J, Rossignol P, Pitt B, Anker SD, Kosiborod M, et al. 
Abnormalities of potassium in heart failure: JACC State-of-the-Art review. J Am 
Coll Cardiol. 2020 Jun 9;75(22):2836–50. 
20. 
Epstein M, Reaven NL, Funk SE, McGaughey KJ, Oestreicher N, Knispel J. 
Evaluation of the treatment gap between clinical guidelines and the utilization of 
renin-angiotensin-aldosterone system inhibitors. Am J Manag Care. 2015 
Sep;21(11):S212-20. 
21. 
Ouwerkerk W, Voors AA, Anker SD, Cleland JG, Dickstein K, Filippatos G, et al. 
Determinants and clinical outcome of uptitration of ACE-inhibitors and 
beta-blockers in patients with heart failure: a prospective European study. Eur Heart 
J. 2017;38:1883-90. Epub 2017 Mar 11. 


 
 
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22. 
Bandak G, Sang Y, Gasaparini A, Chang AR, Ballew SH, Evans M, et al. 
Hyperkalemia after initiating renin-angiotensin system blockade: The Stockholm 
Creatinine Measurements (SCREAM) Project. J Am Heart Assoc. 2017;6:e005428. 
13 p. 
23. 
Trevisan M, de Deco P, Xu H, Evans M, Lindholm B, Belloco R, et al. Incidence, 
predictors and clinical management of hyperkalaemia in new users of 
mineralocorticoid receptor antagonists. Eur J Heart Fail. 2018;20(8):1217-26. Epub 
2018 Apr 18. 
24. 
Veltassa (patiromer) for oral suspension Prescribing Information. Version 5. 
Redwood City, CA, Relypsa, Inc. 2018 May. 
25. 
Pitt B, Bakris GL, Bushinsky DA, Garza D, Mayo MR, Stasiv Y, et al. Effect of 
patiromer on reducing serum potassium and preventing recurrent hyperkalaemia in 
patients with heart failure and chronic kidney disease on RAAS inhibitors. Eur J 
Heart Fail. 2015;17:1057-65. Epub 2015 Oct 12. 
26. 
Bakris GL, Pitt B, Weir MR, Freeman MW, Mayo MR, Garza D, et al. Effect of 
patiromer on serum potassium level in patients with hyperkalemia and diabetic 
kidney disease. The AMETHYST-DN randomized clinical trial. JAMA. 2015 Jul 
14;314(2):151-61. 
27. 
Rossignol P, Dobre D, McMurray JJV, Swedberg K, Krum H, van Veldhuisen DJ, 
et al. Incidence, determinants, and prognostic significance of hyperkalemia and 
worsening renal function in patients with heart failure receiving the 
mineralocorticoid receptor antagonist eplerenone or placebo in addition to optimal 
medical therapy: results from the Eplerenone in Mild Patients Hospitalization and 
Survival Study in Heart Failure (EMPHASIS-HF). Circ Heart Fail. 2014 Jan;7:51-8. 
28. 
Aldahl M, Jensen A-SC, Davidsen L, Eriksen MA, Hansen SM, Nielsen BJ, et al. 
Associations of serum potassium levels with mortality in chronic heart failure 
patients. Eur Heart J. 2017;38:2890-6. Epub 2017 Aug 14. 
29. 
Krogager ML, Torp-Pedersen C, Mortensen RN, Køber L, Gislason G, Søgaard P, 
et al. Short-term mortality risk of serum potassium levels in hypertension: a 
retrospective analysis of nationwide registry data. Eur Heart J. 2017;38:104-12. 
Epub 2016 Apr 20. 
30. 
Investigator’s Brochure Patiromer for Oral Suspension. (Veltassa®). Version 13.0. 
Final report. Redwood City (CA): Relypsa, Inc.; 2020 Jul 13. 
31. 
Bianchi S, Batini V, Bigazzi R. The renal effects of mineralocorticoid receptor 
antagonists. Int J Cardiol. 2015;200:20-4. Epub 2015 May 22. 
32. 
KDIGO. KDIGO Clinical practice guideline for the management of blood pressure 
in chronic kidney disease. Kidney Int Suppl. 2012 Dec;2(5):337-414. 


 
 
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33. 
National Kidney Foundation. KDOQI Clinical practice guidelines on hypertension 
and antihypertensive agents in chronic kidney disease. Guideline 11: Use of 
angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in 
CKD. Am J Kidney Dis. 2004 May;43(5 Suppl 1):S183-205. [Accessed on 2016 
Jun 29]. Available from: https://kidneyfoundation.cachefly.net/professionals/ 
KDOQI/guidelines_bp/guide_11.htm. 
34. 
Aldactone® spironolactone tablets, USP Prescribing Information. New York, G.D. 
Searle LLC Division of Pfizer Inc. 2014 Oct. 
35. 
Bushinsky DA, Spiegel DM, Gross C, Benton WW, Fogli J, Gallant KMH, et al. 
Effect of patiromer on urinary ion excretion in healthy adults. Clin J Am Soc 
Nephrol. 2016 Oct;11:1769-76. 
36. 
Rosano GMC, Tamargo J, Kjeldsen KP, Lainscak M, Agewall S, Anker SD, et al. 
Expert consensus document on the management of hyperkalaemia in patients with 
cardiovascular disease treated with renin angiotensin aldosterone system inhibitors: 
coordinated by the Working Group on Cardiovascular Pharmacotherapy of the 
European Society of Cardiology. Eur Heart J Cardiovasc Pharmacother. 
2018;4:180-8. Epub 2018 May 3. 
37. 
European Medicines Agency. ICH Topic E2A: Note for guidance on clinical safety 
data 
management: 
definitions 
and 
standards 
for 
expedited 
reporting. 
CPMP/ICH/377/95. 1995 Jun. 
38. 
Chebotareva J. A multicenter, double-blind, placebo-controlled, randomized 
withdrawal, parallel group study of patiromer for the management of hyperkalemia 
in subjects receiving renin-angiotensin-aldosterone system inhibitor (RAASi) 
medications for the treatment of heart failure (DIAMOND). Data and Safety 
Monitoring Board. Final report. Redwood City (CA): Relypsa Inc.; 2019 Apr 18. 
Protocol No.: PAT-CR-302. Syneos Health Project Code: 7000009A. 
39. 
Catapane EK. A multicenter, double-blind, placebo-controlled, randomized 
withdrawal, parallel group study of patiromer for the management of hyperkalemia 
in subjects receiving renin-angiotensin-aldosterone system inhibitor (RAASi) 
medications for the treatment of heart failure (DIAMOND). Version 1.0. 
DIAMOND Endpoint Adjudication Committee Charter. Final report. Redwood 
City (CA): Relypsa Inc.; 2019 Dec 11. 
40. 
Pocock SJ, Ariti CA, Collier TJ, Wang D. The win ratio: a new approach to the 
analysis of composite endpoints in clinical trials based on clinical priorities. Eur 
Heart J. 2012;33:176-82. Epub 2011 Sep 6. 
41. 
World Medical Association Declaration of Helsinki. Ethical principles for medical 
research involving human subjects. 2013 Oct. p. 1-8. 
42. 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH). ICH Harmonised Guideline E6(R2): 
Integrated addendum to ICH E6(R1): guideline for good clinical practice. 
2016 Nov 9. 


 
 
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19. SUMMARY OF CHANGES: PROTOCOL AMENDMENT VERSION 3.0 TO 4.0 
Note: New text is in bold font, deleted text is presented with strikethrough, and other modified (moved) text is in italic. 
No 
Section 
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Revised and/or New Text 
1 
Title Page 
Updated to reflect 
amendment 
9 April 2021 
23 June 2021 
2 
Synopsis 
 
 
 
3 
Synopsis 
Section 3 
 
To determine if patiromer treatment of subjects who developed 
hyperkalemia while receiving RAASi medications will result 
in continued use of RAASi medications in accordance with 
heart failure (HF) treatment guidelines and thereby decrease 
the occurrence of the combined endpoint of cardiovascular 
(CV) death and CV hospitalization events compared with 
placebo treatment. 
To assess the effects of patiromer compared with 
placebo serum K+ in HF patients. 
4 
Synopsis 
 
Study Population: 
Subjects with HF with reduced ejection fraction (HFrEF) who 
are hyperkalemic (serum K+ >5.0 mEq/L) while receiving 
treatment with RAASi medications or who are normokalemic 
(serum K+ ≥4.0–≤5.0 mEq/L) but have a history of 
hyperkalemia in the 12 months prior to Screening with 
subsequent reduction or discontinuation of a RAASi 
medication. 
Study Population: 
Subjects with HF with reduced ejection fraction 
(HFrEF) who are hyperkalemic (serum 
K+ >5.0 mEq/L) while receiving treatment with 
RAASi medications or who are normokalemic (serum 
K+ ≥4.0–≤5.0 mEq/L) but have a history of 
hyperkalemia prior to Screening with subsequent 
reduction or discontinuation of a RAASi medication. 
5 
Synopsis 
Section 4.2 
 
Duration: 
Each subject’s participation includes a Run-in Phase (single-
blinded, up to 12 weeks) followed by the Treatment Phase 
(double-blinded, anticipated to be at least 6 months per 
subject). The study will continue until the required number of 
composite endpoint events have occurred. Study duration for 
Duration: 
Each subject’s participation includes a Run-in Phase 
(single-blinded, up to 12 weeks) followed by the 
Treatment Phase (double-blinded, anticipated to be 
reaching at least 6 weeks per subject). Study 
duration for individual subjects will vary, depending 


 
 
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individual subjects will vary, depending on the rate of 
occurrence of composite endpoint events. Given the 
assumptions underlying the study design, accumulation of the 
requisite number of composite endpoint events is expected to 
occur over approximately 2.5 years. Subjects who prematurely 
discontinue patiromer/placebo will remain in the study for the 
collection of composite endpoint event data up to and 
including the common end of study (EoS) and will receive 
usual care during the study phase. 
on their individual enrollment date. Subjects who 
prematurely discontinue patiromer/placebo will 
remain in the study for the collection of clinical 
events data up to and including the common end of 
study (EoS) and will receive usual care during the 
study phase.  
6 
Synopsis 
Section 5.2 
 
7. Hyperkalemia at Screening (defined by 2 local serum K+ 
values of >5.0 mEq/L, each obtained from a separate 
venipuncture, e.g., one in each arm or 2 separate 
venipunctures in the same arm) 
• While receiving ACEi/ARB/ARNi, and/or MRA 
OR 
Normokalemia at Screening (defined by 2 local serum K+ 
≥4.0-≤5.0 mEq/L, each obtained from a separate venipuncture, 
e.g., one in each arm or 2 separate venipunctures in the same 
arm) 
• With a history of hyperkalemia documented by a usual care 
serum K+ measurement >5.0 mEq/L 
• While on MRA 
• Leading to a subsequent and permanent discontinuation of 
the MRA medication 
7. Hyperkalemia at Screening (defined by 2 local 
serum K+ values of >5.0 mEq/L, each obtained 
from a separate venipuncture, e.g., one in each arm 
or 2 separate venipunctures in the same arm) while 
receiving ACEi/ARB/ARNi, and/or MRA 
OR 
Normokalemia at Screening (defined by 2 local 
serum K+ ≥4.0–≤5.0 mEq/L each obtained from a 
separate venipuncture, e.g., one in each arm or two 
separate venipunctures in the same arm) with a 
history of hyperkalemia documented by a usual 
care serum K+ measurement >5.0 mEq/L, while on 
RAASi treatment in the 12 months prior to 
Screening leading to a subsequent and permanent 
dose decrease or discontinuation of one or more 
RAASi medications 


 
 
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• 
MRA discontinuation occurred >2 weeks prior to 
Screening 
OR 
For MRA naive subjects with normokalemia at Screening 
(defined by 2 local serum K+ values ≥4.0-≤5.0 mEq/L, each 
obtained from a separate venipuncture, e.g., one in each arm 
or 2 separate venipunctures in the same arm) 
• 
With a history of hyperkalemia documented by a usual 
care serum K+ measurement >5.0 mEq/L 
• 
While on an ACEi/ARB/ARNi 
• 
Leading to a subsequent, permanent dose decrease or 
discontinuation of one of the ACEi/ARB/ARNi 
medication 
• 
ACEi/ARB/ARNi dose decrease or discontinuation 
occurred >2 weeks prior to Screening 
7 
Synopsis 
Section 5.3 
 
20. Planned or scheduled dialysis within 3 months from 
Screening 
 
8 
Synopsis 
Section 5.4 
 
1. Current MRA dose is at least 50% of the target dose* (e.g., 
spironolactone 25 mg/day, eplerenone 25 mg/day) and has been 
stable for at least 1 week 
1. Current MRA dose is at least the target dose* 
(e.g., spironolactone 50 mg/day, eplerenone 50 
mg/day) and has been stable for at least 1 week 
9 
Synopsis 
Section 3 
 
Primary Endpoint: 
• 
Time to first occurrence of CV death or CV hospitalization 
Primary Endpoint: 
• 
Changes in serum K+ levels from Baseline. 


 
 
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Note: All analyses will be restricted to serum K+ 
levels and not substituted by plasma values as they 
are known to be systematically lower. Both central 
laboratory and local laboratory values will be used 
at all visits; however, if both values are available at 
one visit, then central laboratory values will be used. 
10 
Synopsis 
Section 3 
 
Secondary Endpoints: 
• 
Proportion of subjects on ≥50% of target dose of ACEi, 
ARB, or ARNi and ≥50% of target dose of MRA at the EoS 
Visit 
• 
Total HF hospitalizations (or equivalent in outpatient 
clinic) 
• 
Change from randomization in the clinical summary score 
of Kansas City Cardiomyopathy Questionnaire (KCCQ) 
at 8 months 
Key Secondary Endpoints (Hierarchically Ordered) 
1. Hyperkalemia events with a serum K+ 
value >5.5 mEq/L. 
2. Durable enablement to stay on the MRA target 
dose (of 50 mg daily spironolactone or 
eplerenone), as assessed by the between treatment 
groups difference of the cumulative frequency of 
patients not staying on the target dose. 
 Note: Discontinuation of the target dose for at least 
14 days (or less if at the EoS) is required to confirm 
this endpoint. 
3. Investigator reported events of hyperkalemia 
(first and recurrent events). 
4. Hyperkalemia-related hard outcomes endpoints 
(Win Ratio) 
a. Time to CV death 
b. Total number of CV hospitalizations 
c. 
Total number of hyperkalemia toxicity 
events with serum K+ >6.5 mEq/L 
d. Total number of hyperkalemia events 
with serum K+ >6.0-6.5 mEq/L 


 
 
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e. 
Total number of hyperkalemia events 
with serum K+ >5.0 mEq/L 
5. RAASi Use Score (Win Ratio). Note: This score 
(of 0–8 points) will be analyzed at the respective 
time points for each patient in each comparison, 
and it consists of the following components:  
a. All-cause death 
b.  Occurrence of a CV hospitalization 
b. HF medication use and dose for i) an 
ACEi/ARB/ARNi, ii) an MRA, and iii) a beta-
blocker 
11 
Synopsis 
Section 3 
 
- 
Other Secondary Endpoints 
• 
Durable enablement to stay on the target dose 
of ACE/ARB/ARNi. Note: Discontinuation of the 
target dose for at least 14 days (or less if at the EoS) 
is required to confirm this endpoint 
• 
Durable hyperkalemia-free enablement to 
stay on the MRA target dose (days on 50mg MRA 
without presence of hyperkalemia) 
• 
Total number of hyperkalemia toxicity events 
with serum K+ >6.5 mEq/L 
• 
Total number of hyperkalemia events with 
serum K+ >6.0-6.5 mEq/L 
• 
Emergency treatment for hyperkalemia 
(hospitalization or emergency room) 
• 
Total number of hyperkalemia events with 
serum K+ >5.0 mEq/L 


 
 
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• 
KCCQ questionnaire, changes in OSS, CSS 
and TSS 
• 
Investigator reported events of hyperkalemia 
(first events) 
• 
Proportion of subjects on ≥50% of target dose of 
ACEi, ARB, or ARNi and ≥50% of target dose of 
MRA at the EoS Visit 
• 
Time to first occurrence of CV death or CV 
hospitalization 
12 
Synopsis 
Section 3 
 
Other Endpoints: 
• 
Emergency treatment for hyperkalemia (hospitalization or 
emergency room) 
• 
Patient-reported outcome: EQ-5D-5L questionnaire 
• 
Proportion of subjects with change in the patient-reported 
outcome, KCCQ, greater than 5 points at 8 months after 
randomization 
• 
Time to first occurrence of HF hospitalization (or 
equivalent in outpatient clinic) 
• 
Total CV hospitalizations 
• 
Proportion of subjects on any dose of MRA at the EoS 
Visit 
• 
Proportion of subjects on any dose of ACEi, ARB, or 
ARNi at the EoS Visit 
• 
Change in proteinuria from Screening 
• 
Change in NT-proBNP from Screening 
• 
Change in high sensitivity troponin from Baseline 
• 
Functional status by NYHA class 
Other Endpoints: 
• 
CV death 
• 
First and recurrent CV hospitalizations 
• 
First and recurrent HF hospitalizations (or 
equivalent in outpatient clinic) 
• 
Patient-reported outcome: EQ-5D-5L 
questionnaire 
• 
Proportion of subjects on any dose of MRA at 
the EoS Visit 
• 
Proportion of subjects on any dose of ACEi, 
ARB, or ARNi at the EoS Visit 
• 
Change in proteinuria from Screening 
• 
Change in NT-proBNP from Screening 
• 
Change in high sensitivity troponin from 
Baseline 


 
 
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• 
30-day HF re-hospitalization after a prior HF 
hospitalization 
• 
Health Economics and Outcomes Research (HEOR) 
analyses 
• 
Functional status by NYHA class 
• 
30-day HF re-hospitalization after a prior HF 
hospitalization 
• 
Health Economics and Outcomes Research 
(HEOR) analyses 
• 
Changes in serum K+ from Baseline to 
individual visits 
13 
Synopsis 
Section 3 
 
Safety Evaluations: 
• 
- 
Safety Evaluations: 
• 
All-cause mortality 
14 
Synopsis 
Section 3 
 
Safety Evaluations: 
• 
Laboratory parameters including serum K+ 
Safety Evaluations: 
• 
Laboratory parameters other than those defined 
as efficacy endpoints 
15 
Synopsis 
 
EoS Visit (Event-Driven) 
EoS Visit 
16 
Synopsis 
 
This design will also accelerate the collection of endpoints 
required for the objective of the study. 
 
17 
Synopsis 
Section 12.2 
 
Sample Size: 
The sample size of 1,194 subjects per treatment arm (total of 
2,388 subjects) has been calculated to provide 90% power to 
detect a difference between the control group (placebo) and the 
active group (patiromer) on the time until the first occurrence 
of CV death or CV hospitalization (total of 844 events). This 
sample size calculation was based upon the following 
assumptions: alpha level of 5% (2 sided), 24 months to accrue 
the subjects (uniform accrual), a minimum of 6 months of 
follow-up, a 30% annual rate for the control arm, a treatment 
effect associated with a hazard ratio (control/active) of 0.8, a 
Sample Size: 
The sample size of 410 subjects per treatment arm 
(total of 820 subjects) has been calculated to provide 
90% power to detect a difference between the control 
group (placebo) and the active group (patiromer) on 
the mean change in K+ levels from Baseline. This 
sample size calculation was based upon the following 
assumptions: alpha level of 5% (2 sided), a 
difference between group means of 0.116 a 
standard deviation (SD) of 0.5 and a 5% rate of loss 
to follow-up. 


 
 
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5% annual rate of loss to follow-up due to non-CV deaths and 
the time to event follows an exponential distribution. The 
power will be approximately 80% if a gamma frailty is 
assumed with a variance of 4.0. 
18 
Synopsis 
 
Study Sites: 460 
Study Sites: 375 
19 
Synopsis 
Section 12.8.1 
 
Statistical Methods: 
The primary analysis will be based upon the time to the first 
occurrence of the primary endpoint consisting of a CV death or 
CV hospitalization (or equivalent in outpatient clinic). The test 
of significance will be based upon a stratified (randomization 
strata) log-rank test. The treatment effect will be summarized 
using the hazard ratio (HR) and 95% confidence interval (CI) 
calculated using a stratified (randomization strata) Cox 
regression model with treatment as the model parameter. In 
these analyses, subjects will be censored as of their last 
assessment for the primary endpoint as well as for deaths for 
non-CV causes. Sensitivity analyses for the primary endpoint 
will be based upon the use of all CV deaths and 
hospitalizations (i.e., recurrent event analysis) recorded during 
follow-up using the following methods: 
• 
Extended Cox model [2] 
• 
Days alive outside of the hospital [3] 
• 
Rank based analysis [4] 
Additional descriptive statistics will be calculated to better 
understand the recurrent events pattern. In particular, the HR 
will be estimated within event count using a conditional model 
(gap-time method) that allows both the underlying hazard and 
HR to vary (Prentice, Williams and Peterson, 1981) with a 
robust variance estimator. In this approach, subjects 
Statistical Methods: 
The mean change in serum K+ levels from Baseline 
is analyzed by means of a mixed model for 
repeated measures (MMRM) approach including 
all available follow-up data. A Gaussian linear 
model for repeated measures with treatment, 
geographic region, sex, baseline Type 2 diabetes 
mellitus (T2DM) status and visit as factors, and 
baseline K+ level, baseline eGFR as covariates. The 
error terms are assumed to follow a multivariate 
normal distribution with unstructured covariance.  
Sensitivity analyses for the primary endpoint will 
explore changes in treatment effect over follow-up 
time by including treatment by visit interactions in 
the above-mentioned model. In addition, 
sensitivity analyses accounting for potentially 
informative missingness will be based upon a Win 
Ratio approach.  
Secondary efficacy endpoints will be tested in the 
order listed (i.e., fixed-sequence method to preserve 
the family-wise error rate) and summarized 
descriptively through the calculation of point 
estimates by treatment group along with 95% CIs for 
the treatment differences. Other endpoints will be 


 
 
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experiencing a death are removed from the risk sets for 
subsequent events. Additional estimates will be calculated 
treating CV death as a competing risk for the occurrence of 
CV hospitalizations. 
Secondary efficacy endpoints will be tested in the order listed 
(i.e., fixed-sequence method to preserve the family-wise error 
rate) and summarized descriptively through the calculation of 
point estimates by treatment group along with 95% CIs for the 
treatment differences. Other endpoints will be summarized 
using descriptive methods. 
Safety evaluations include AEs and serious adverse events 
(SAEs) (including all-cause mortality); slope of eGFR change 
during the study; decline in eGFR >50% or ESRD, renal death, 
or need for dialysis; and serum K+ level. Safety variables will 
be summarized using the safety set. 
An interim analysis is planned when 50% of the planned 
primary endpoint events are recorded. 
summarized using the calculation of point estimates 
by treatment group along with 95% CIs for the 
treatment differences and descriptive methods as 
appropriate. 
Safety evaluations include AEs and serious adverse 
events (SAEs) (including all-cause mortality); slope of 
eGFR change during the study; decline in eGFR >50% 
or ESRD, renal death, or need for dialysis; and serum 
K+ level. Safety variables will be summarized using 
the safety set. 
No interim analysis is planned. 
 
20 
Study Schema 
 
− EoS Visit Event driven 
− 
EoS Visit 
21 
Section 2 
 
- 
Patients with HF and CKD are among those at the 
highest risk of severe outcomes of COVID-19 
infection. Treatment practices for this patient 
population have been adapted to reduce risks of 
exposure to infection during hospital visits, 
disrupting clinical care and impacting the conduct 
of randomized clinical trials such as the 
DIAMOND study. The first priority has been to 
protect the safety of the patients in the trial and to 
respect the need of the healthcare system to 
prioritize efforts to contain the pandemic. This has 


 
 
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led to a fewer patients enrolled in the trial than 
anticipated. 
Due to the changing treatment landscape in 
HFrEF, the lower-than-expected recruitment rate 
due to the COVID-19 pandemic and the lower-
than-expected event rates, the Sponsor with 
recommendations from the Executive Steering 
Committee of the study decided to change the 
study objectives and the primary and secondary 
endpoints. The decision was made to maximize the 
scientific value of the data already collected in 
DIAMOND, while at the same time ensuring the 
safety and wellbeing of patients. It will also take 
into account the way the unprecedented demands 
of the COVID-19 pandemic altered clinical care 
during this period. 
It is therefore hypothesized that patiromer can be 
used to treat hyperkalemia that develops in high 
risk HFrEF patients while receiving treatment 
with RAASi. This is expected to result in improved 
adherence to guideline RAASi treatment, and less 
hyperkalemic events compared with the current 
standard of care in these patients, which includes 
RAASi dose reduction or discontinuation. 
22 
Section 2 
 
Therefore, the present multinational, multicenter, double-blind, 
placebo-controlled, randomized withdrawal, parallel group 
study of subjects with HFrEF who have developed 
hyperkalemia (serum K+ >5.0 mEq/L) while being treated 
with RAASi medications is designed to determine if patiromer 
Therefore, the present multinational, multicenter, 
double-blind, placebo-controlled, randomized 
withdrawal, parallel group study of subjects with 
HFrEF who have developed hyperkalemia (serum 
K+ >5.0 mEq/L) while being treated with RAASi 


 
 
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treatment will result in greater adherence to HF treatment 
guidelines and thereby decrease the occurrence of CV 
hospitalization and CV death compared with placebo 
treatment. 
medications is re-designed to determine if patiromer 
treatment will result in better K+ control compared 
with placebo treatment. 
23 
Section 4.2 
 
Each eligible subject’s participation includes a Screening Phase 
(within a maximum of 10 calendar days), Run-in Phase (single-
blinded, up to 12 weeks) followed by the Treatment Phase 
(double-blinded, anticipated to be at least 6 months per subject). 
The study will continue until the required number of composite 
endpoint events, i.e., time to first occurrence of CV death or CV 
hospitalization have occurred. Study duration for individual 
subjects will vary, depending on the rate of occurrence of 
composite endpoint events. Given the assumptions underlying 
the study design, accumulation of the requisite number of 
composite endpoint events is expected to occur over 
approximately 2.5 years. The common EoS date will be 
determined using the accrual rate of composite safety endpoint 
events to project the date when there should be sufficient data 
to provide adequate power for the composite primary endpoint 
analysis.  
Each eligible subject’s participation includes a 
Screening Phase (within a maximum of 10 calendar 
days), Run-in Phase (single-blinded, up to 12 weeks) 
followed by the Treatment Phase (double-blinded, 
variable per subject). Study duration for individual 
subjects will vary, depending on their individual 
enrollment date. The common EoS will occur when 
820 subjects have completed the Week 6 visit. 
Recruitment will be stopped when it is projected 
that a sufficient number of subjects have been enrolled 
in order for 820 subjects to reach the Week 6 visit.  
24 
Section 5.2 
 
6. eGFR ≥20 mL/min/1.73 m2 at Screening (based on a single 
local laboratory analysis of serum creatinine and calculation 
using the CKD-EPI equation; see Section 9.2) 
6 
eGFR ≥30 mL/min/1.73 m2 at Screening (based 
on a single local laboratory analysis of serum 
creatinine and calculation using the CKD-EPI 
equation; see Section 9.2) 


 
 
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25 
Section 5.2 
 
7. Hyperkalemia at Screening (defined by 2 local serum K+ 
values of >5.0 mEq/L, each obtained from a separate 
venipuncture, e.g., one in each arm or 2 separate venipunctures 
in the same arm) 
• 
While receiving an ACEi/ARB/ARNi, and/or an MRA 
OR 
Normokalemia at Screening (defined by 2 local serum K+ 
≥4.0–≤5.0 mEq/L, each obtained from a separate 
venipuncture, e.g., one in each arm or 2 separate 
venipunctures in the same arm) 
• 
With a history of hyperkalemia documented by a usual care 
serum K+ measurement >5.0 mEq/L 
• 
While on an MRA 
• 
Leading to a subsequent and permanent discontinuation of 
the MRA medication 
• 
MRA discontinuation occurred >2 weeks prior to 
Screening 
OR 
7. Hyperkalemia at Screening (defined by 2 local 
serum K+ values of >5.0 mEq/L, each obtained from a 
separate venipuncture, e.g., one in each arm or two 
separate venipunctures in the same arm) while 
receiving an ACEi/ARB/ARNi, and/or an MRA 
OR 
Normokalemia at Screening (defined by 2 local serum 
K+ ≥4.0–≤5.0 mEq/L, each obtained from a separate 
venipuncture, e.g., one in each arm or two separate 
venipunctures in the same arm) with a history of 
hyperkalemia documented by a usual care serum K+ 
measurement >5.0 mEq/L while on RAASi treatment 
in the 12 months prior to Screening leading to a 
subsequent and permanent dose decrease or 
discontinuation of one or more RAASi medications 


 
 
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For MRA naive subjects and normokalemia at Screening 
(defined by 2 local serum K+ values ≥4.0-≤5.0 mEq/L) each 
obtained from a separate venipuncture, e.g., one in each arm 
or 2 separate venipunctures in the same arm) 
• 
With a history of hyperkalemia documented by a 
usual care serum K+ measurement >5.0 mEq/L 
• 
While on an ACEi/ARB/ARNi 
• 
Leading to a subsequent, permanent dose decrease 
or discontinuation of one of the ACEi/ARB/ARNi 
medication 
• 
ACEi/ARB/ARNi 
dose 
decrease 
or 
discontinuation occurred >2 weeks prior to 
Screening 
26 
Section 5.3 
 
20. Planned or scheduled dialysis within 3 months from 
Screening 
20. - 
27 
Section 6.7.2 
 
Note: The aim for all subjects for the MRA dose should be 50 
mg/day, but randomization can occur at 25 mg/day. 
- 
28 
Section 6.7.3 
 
Note: The aim for all subjects for the MRA dose should be 50 
mg/day. However, the MRA dose must be at least 25 mg/day 
for at least 1 week for subjects to meet the randomization 
criteria. 
For subjects who are on <50 mg/day of MRA, double 
their current dose up to 50 mg/day. Assess tolerance 
to the 50 mg target dose. 
MRA dose is at least 50 mg/day and has been stable 
for at least 1 week 


 
 
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• 
MRA dose is at least 25 mg/day and has been stable for at 
least 1 week 
29 
Section 8.2 
 
If a subject cannot be randomized on the same day the 
randomization criteria were met, then the subject must be 
randomized within 1 week and all assessments described in 
Section 8.2.1 will be performed. 
If a subject cannot be randomized on the same day 
the randomization criteria were met, then the subject 
should be randomized within 1 week and all 
assessments described in Section 8.2.1 will be 
repeated on the day of randomization. 
30 
Section 8.4 
 
Event-Driven EoS Visit Procedures 
The common end of the study date will be set by the Sponsor 
based on when the study is projected to accrue the required 
number of events of CV mortality or CV hospitalization. 
Investigational sites will be notified of the study termination 
date approximately 3 months prior to study closure and should 
advise ongoing study subjects of the study termination date 
thereafter 
EoS Visit Procedures 
The common end of the study date will be set by the 
Sponsor. The common EoS will occur when 820 
subjects have completed the Week 6 visit. 
Recruitment will be stopped, and subjects called in 
by the sites for the EoS visit when it is projected 
that a sufficient number of subjects have been 
enrolled in order for 820 subjects to reach the 
Week 6 visit. All randomized subjects, including 
those who prematurely discontinued 
patiromer/placebo, will complete the EoS Visit within 
the timeline provided by the Sponsor around the 
common EoS date. 
Investigational sites will be notified of the study 
termination date as soon as possible after the 
decision is taken and should advise ongoing study 
subjects of the study termination date thereafter 
31 
Section 9.1 
 
- 
The definition of hyperkalemia follows the European 
Society of Cardiology expert consensus document on 
the management of hyperkalemia in patients with 
cardiovascular 
disease 
[37]. 
Hyperkalemia 
is 


 
 
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considered for all serum K+ values >5.0 mEq/l with the 
gradings of mild hyperkalemia (serum K+ >5.0 mEq 
≤5.5 mEq/l), moderate hyperkalemia (serum K+ >5.5 
mEq ≤6.0 mEq/l) and severe hyperkalemia (serum K+ 
>6.0 mEq). 
32 
Section 10.7.2.1  
Composite Study Endpoints: 
All events potentially related to the composite primary 
endpoint of CV death or CV hospitalizations or urgent HF 
visits will be collected starting from the date of randomization. 
For the purposes of this protocol, the following events are 
considered SAEs and must be reported as described in Section 
10.7.2. 
Study Endpoints: 
All events potentially related to the endpoint of CV 
death or CV hospitalizations or urgent HF visits will 
be collected starting from the date of randomization. 
For the purposes of this protocol, the following events 
are considered SAEs and must be reported as described 
in Section 10.7.2. 
33 
Section 10.7.2.1  
The following CV hospitalization events will be counted 
towards the primary endpoint: 
The following CV hospitalization events will be 
counted towards the endpoint: 
34 
Section 12.2 
 
Following Claggett (2018), simulations were conducted to 
investigate the effect of heterogeneity of the subject level 
exponential risk on the power of the proposed sample size for 
the primary analysis (log-rank test for the time to first 
occurrence of CV death or CV hospitalization) [39]. Based 
upon an assumed heterogeneity factor of 4.0 (i.e., gamma 
frailty with variance of 4.0), the proposed sample will have 
approximately 80% power. A recurrent event analysis (LWYY 
test) would have approximately 78% power assuming 30% of 
events result in death and 20% treatment effect attenuation 
after each event. 
- 


 
 
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35 
Section 12.8.1 
 
The primary analysis will be based upon the time to the first 
occurrence of the primary endpoint consisting of a CV death or 
CV hospitalization (or equivalent in outpatient clinic). The test 
of significance will be based upon a stratified (randomization 
strata) log-rank test. The treatment effect will be summarized 
using the HR and 95% CI calculated using a stratified 
(randomization strata) Cox regression model with treatment as 
the only model parameter. In these analyses, subjects will be 
censored as of their last assessment for the primary endpoint as 
well as for deaths for non-CV causes. 
Sensitivity analyses for the primary endpoint will be based 
upon the use of all CV deaths and hospitalizations (i.e., 
recurrent event analysis) recorded during follow-up using the 
following methods: 
• 
Extended Cox model [2] 
• 
Days alive outside of the hospital [3] 
• 
Rank based analysis [4] 
Additional descriptive statistics will be calculated to better 
understand the recurrent events pattern. In particular, the HR 
will be estimated within event count using a conditional model 
(gap-time method) that allows both the underlying hazard and 
HR to vary [40] with a robust variance estimator. In this 
approach, subjects experiencing a death are removed from the 
risk sets for subsequent events. Additional estimates will be 
calculated treating CV death as a competing risk for the 
occurrence of CV hospitalizations 
The primary analysis will be based upon the mean 
change in serum potassium levels from Baseline 
and is analyzed by means of an MMRM approach 
including all available post baseline data. All 
analyses will be restricted to serum K+ assessments 
and not substituted by plasma values as they are 
known to be systematically lower. Central 
laboratory values and/or local laboratory will be 
used at all visits, and if both values are present at 
one visit, then central laboratory values will be 
used. A Gaussian linear model for repeated 
measures with treatment, geographic region, sex, 
baseline T2DM status and visit as factors, and 
baseline potassium level, baseline eGFR as 
covariates. The error terms are assumed to follow 
a multivariate normal distribution with 
unstructured covariance. Least squares mean 
changes from Baseline will be reported for both 
treatment groups with 95% CIs as well as the 
difference between the least squares group means 
with 95% CI and p-value testing the null 
hypothesis of no treatment effect. 
Sensitivity analyses for the primary endpoint will 
be based upon the use of all CV deaths and 
hospitalizations (i.e., recurrent event analysis) 
recorded during follow-up using the following 
methods: will explore changes in treatment effect 
over follow-up time by including treatment by 
visit interactions in the above-mentioned model. 


 
 
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In addition, sensitivity analyses for the primary 
endpoint will explore changes in treatment effect 
over follow-up time by including treatment by 
visit interactions in the above-mentioned model. In 
addition, sensitivity analyses accounting for 
potentially informative missingness will be based 
upon a Win Ratio approach [4,31]. 
36 
Section12.8.2 
 
- 
Key Secondary Endpoints (Hierarchically 
Ordered) 
• 
Hyperkalemia events: The time to the first 
event of hyperkalemia with a serum K+ value >5.5 
mEq/L as per the measured values from the 
central or local laboratories is analyzed using a 
Cox proportional hazards regression model. The 
event probabilities will be estimated using the 
Aalen-Johansen estimator of the cumulative 
incidence function accounting for competing 
events such as death. 
• 
Durable enablement to stay on the MRA 
target dose (of 50 mg spironolactone or 
eplerenone): The time to reduction of the MRA 
dose below target is analyzed using a Cox 
proportional hazards regression model. The event 
probabilities will be estimated using Aalen-
Johansen estimator of the cumulative incidence 
function accounting for competing events such as 
death. 


 
 
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Note: Discontinuation of the target dose for at 
least 14 days (or less if at the EoS) is required to 
confirm this endpoint.  
• 
Investigator reported AEs of hyperkalemia 
(first and recurrent) are analyzed using a negative 
binomial regression with the logarithm of the 
individual follow-up time as offset.  
A joint frailty model of the total (first and 
recurrent) hyperkalemia events and time to death 
as terminating event. If all-cause mortality is 
substantial in number and differential between the 
treatment groups, then the joint frailty model 
would become the main analysis approach. 
Note: For analyses based upon the negative 
binomial distribution, the subject level count data 
will be modeled as function of treatment with the 
natural log of the subject level follow-up time 
taken into account in the estimation of the event 
rate. 
• 
Hyperkalemia-related hard outcomes are 
analyzed using the Win Ratio approach with the 
following hierarchical components (all assessed 
during comparable follow-up times) 
1. Time to CV death 
2 
Total number of CV hospitalizations 
3 
Total number of hyperkalemia toxicity events 
with serum K+ >6.5 mEq/L 
4 
Total number of hyperkalemia toxicity events 
with serum K+ >6.0-6.5 mEq/L 


 
 
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5 
Total number of hyperkalemia toxicity events 
with serum K+ >5.0-6.0 mEq/L 
• 
RAASi Use Score which will be analyzed using 
the Win Ratio approach for each pair of patients 
at the end of the comparable follow-up period that 
is appropriate for that pair of patients with the 
following hierarchical components. Points are 
accumulated from two components at the 
respective time for each patient in each 
comparison: 
Component A: 
• 
If during the follow-up (to the respective end 
of follow-up in the comparison) there was a death, 
the subject is assigned 0 points 
• 
If during the follow-up (to the respective end 
of follow-up in the comparison) there was a CV 
hospitalization, but the subject is alive at the end 
of that follow-up, the subject assigned 1 point 
• 
If during the follow-up (to the respective end 
of follow-up in the comparison) there was no CV 
hospitalization and the subject is alive at the end 
of that follow-up, the subject is assigned 2 points 
Component B: 
Further points are collected for the treatment 
status at the respective end of follow-up in the 
comparison 
• 
For ACEi/ARB/ARNi use: >50% of the target 
dose = 2 points 


 
 
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• 
For ACEi/ARB/ARNi use: >0 and up to 50% 
of the target dose = 1 point 
• 
For MRA use: >50% of the target dose = 2 
points 
• 
For MRA use: >0 and up to 50% of the target 
dose = 1 point 
• 
For beta-blocker use: >50% of the target dose 
= 2 points 
• 
For beta-blocker use: >0 and up to 50% of the 
target dose = 1 point 
In summary, each subject in each comparison can 
have 0-8 points (sum of Components A and B) and 
all subjects are compared using this score at the 
respective appropriate follow-up time point. 
The regression analyses will be adjusted for 
geographic region as the stratification factor of the 
randomization and relevant baseline 
characteristics of the subjects. 
37 
Section 12. 8. 3  
Secondary 
• 
Proportion of subjects on ≥50% of target dose of ACEi, 
ARB, or ARNi and ≥50% of target dose of MRA at the EoS 
Visit with analysis using Fisher’s Exact Test 
• 
Total HF hospitalizations (or equivalent in outpatient 
clinic) analyzed using the negative binomial distribution 
• 
Change from randomization in the clinical summary score 
of KCCQ at 8 months 
For analyses based upon the negative binomial distribution, the 
subject level count data will be modeled as function of 
Other Secondary Endpoints 
The additional endpoints listed below (Other 
Secondary Endpoints), will also be summarized 
descriptively by treatment arm in the full analysis set: 
• 
Durable enablement to stay on the target dose 
of ACE/ARB/ARNi 
Note: Discontinuation of the target dose for at least 
14 days (or less if at the EoS) is required to confirm 
this endpoint 


 
 
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treatment with the natural log of the subject level follow-up 
time taken into account in the estimation of the event rate. 
The additional endpoints listed below (Other Endpoints), will 
also be summarized descriptively by treatment arm in the full 
analysis set: 
• 
Emergency treatment for hyperkalemia (hospitalization or 
emergency room) 
• 
Patient-reported outcome: EQ-5D-5L questionnaire 
• 
Proportion of subjects with change in the patient-reported 
outcome, KCCQ, greater than 5 points at 8 months after 
randomization 
• 
Time to first occurrence of HF hospitalization (or 
equivalent in outpatient clinic) 
• 
Total CV hospitalizations (or equivalent in outpatient 
clinic) 
• 
Proportion of subjects on any dose of MRA at the EoS 
Visit 
• 
Proportion of subjects on any dose of ACEi, ARB, or 
ARNi at the EoS Visit 
• 
Change in proteinuria from Screening 
• 
Change in NT-proBNP from Screening 
• 
Change in high sensitivity troponin from Baseline 
• 
Functional status by NYHA class 
• 
30-day HF re-hospitalization after a prior HF 
hospitalization 
• 
HEOR analyses 
• 
Durable hyperkalemia-free enablement to 
stay on the MRA target dose (days on 50mg MRA 
without presence of hyperkalemia) 
• 
Hyperkalemia toxicity events with serum 
K+ >6.5 mEq/L 
• 
Hyperkalemia toxicity events with serum 
K+ >6.0-6.5 mEq/L 
• 
Emergency treatment for hyperkalemia 
(hospitalization or emergency room) 
• 
Total number of hyperkalemia toxicity events 
with serum K+ >5.0-6.0 mEq/L 
• 
KCCQ questionnaire - OSS, CSS and TSS 
• 
Investigator reported events of hyperkalemia 
(recurrent events) 
• 
Proportion of subjects on ≥50% of target dose 
of ACEi, ARB, or ARNi and ≥50% of target dose 
of MRA at the EoS Visit 
• 
Time to first occurrence of CV death or CV 
hospitalization 
38 
Section12.8.4 
 
- 
• 
CV Death 


 
 
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• 
First and recurrent CV hospitalizations 
• 
First and recurrent HF hospitalizations (or 
equivalent in outpatient clinic) 
• 
Patient-reported outcome: EQ-5D-5L 
questionnaire 
• 
Proportion of subjects on any dose of MRA at 
the EoS Visit 
• 
Proportion of subjects on any dose of ACEi, 
ARB, or ARNi at the EoS Visit 
• 
Change in proteinuria from Screening 
• 
Change in NT-proBNP from Screening 
• 
Change in high sensitivity troponin from 
Baseline 
• 
Functional status by NYHA class 
• 
30-day HF re-hospitalization after a prior HF 
hospitalization 
• 
HEOR analyses 
• 
Changes in serum K+ from Baseline to 
individual visits 
39 
Section 12.9 
 
Safety Evaluations 
• Serum K+ 
 
Safety Evaluations 
• 
Laboratory parameters other than those 
defined as efficacy endpoints 
40 
Section 12.10 
 
The blinded monitoring of event rates is planned throughout 
the study to check the assumptions used for the sample size 
calculations to predict the timing of interim and final analyses. 
In addition, an independent DSMB will meet periodically to 
monitor the study. As part of these reviews, the DSMB will 
No interim analysis is planned. 


 
 
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receive summaries of study conduct measures as well as 
unblinded safety and efficacy data. 
To protect the study from prematurely being closed for a 
finding of efficacy, the DSMB will be requested to use the 
O’Brien-Fleming (Lan-DeMets implementation) for evaluating 
the primary efficacy endpoint in a formal interim analysis of 
efficacy. A single such evaluation is planned when 50% of the 
planned primary endpoint events are positively adjudicated. 
The final analysis will take into account the interim analysis. 
As such, the significance level at the final analysis will be 
adjusted, following Lan-DeMets, to take into account the exact 
timing of the interim analysis. 
41 
Section 18 
 
- 
40. Pocock SJ, Ariti CA, Collier TJ, and Wang T. 
The win ratio: a new approach to the analysis of 
composite endpoints in clinical trials based on 
clinical priorities, European Heart Journal, 
Volume 33, Issue 2, January 2012, Pages 176–182, 
https://doi.org/10.1093/eurheartj/ehr352 7. 
42 
Section 18 
 
- 
36. Rosano GMC, Tamargo J, Kjeldsen KP, 
Lainscak M, Agewall S, Anker SD, et al. Expert 
consensus document on the management of 
hyperkalaemia in patients with cardiovascular 
disease treated with renin angiotensin aldosterone 
system inhibitors: coordinated by the Working 
Group on Cardiovascular Pharmacotherapy of the 
European Society of Cardiology. Eur Heart J 
Cardiovasc Pharmacother. 2018;4(3):180–8. 
 

SAP_001.pdf: 
 
 
©Vifor Pharma 
 
Page 1 of 24 
 
STATISTICAL ANALYSIS PLAN (SAP) 
 
Investigational Drug: 
Patiromer for Oral Suspension 
 
 
Treatment: 
Heart Failure 
 
 
Study Phase: 
Phase 3b 
Study Title: 
A Multicenter, Double-blind, Placebo controlled, Randomized 
Withdrawal, Parallel Group Study of Patiromer for the 
Management of Hyperkalemia in Subjects Receiving Renin 
Angiotensin-Aldosterone System Inhibitor (RAASi) 
Medications for the Treatment of Heart Failure (DIAMOND) 
 
 
Protocol Number: 
PAT-CR-302 
Protocol Version: 
4.0 
Protocol Version date: 
23 June 2021 
Sponsor: 
Viforpharma, Inc. 
200 Cardinal Way 
Redwood City, CA 94063, USA 
 
 
 
 
SAP Version: 
4.0 
SAP Version Date: 
24 November 2021 
SAP Author: 
 
Sr Director, Biostatistics 
Vifor Pharma, Inc. 
 


©Vifor Pharma 
 
Page 2 of 24 
 
 
 
Table of Contents
1 
STUDY DESCRIPTION ....................................................................................................................................... 5 
1.1 
OBJECTIVES ................................................................................................................................................. 5 
1.2 
STUDY DESIGN ............................................................................................................................................. 5 
1.3 
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS ................................................................................... 5 
1.4 
BLINDING ................................................................................................................................................... 5 
1.5 
SAMPLE SIZE ............................................................................................................................................... 6 
2 
STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ............................................................................ 6 
2.1 
POPULATIONS ANALYSED ............................................................................................................................... 6 
2.1.1 
Randomized Set ................................................................................................................................... 6 
2.1.2 
Full Analysis Set ................................................................................................................................... 6 
2.1.3 
Safety Set ............................................................................................................................................ 6 
2.1.4 
Run-in Phase Set .................................................................................................................................. 6 
2.2 
GENERAL CONSIDERATIONS ............................................................................................................................ 7 
2.3 
SUBJECT DISPOSITION.................................................................................................................................... 7 
2.4 
PROTOCOL DEVIATIONS ................................................................................................................................. 7 
2.5 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS................................................................................................ 7 
2.6 
GENERAL MEDICAL HISTORY ........................................................................................................................... 8 
2.7 
STUDY DRUG DOSING AND COMPLIANCE ........................................................................................................... 8 
2.8 
PRIOR/CONCOMITANT MEDICATIONS AND PROCEDURES ....................................................................................... 8 
2.9 
STUDY ENDPOINTS........................................................................................................................................ 9 
2.10 
STATISTICAL ASSESSMENT OF EFFICACY ENDPOINTS ............................................................................................ 11 
2.10.1 
Primary Analyses ........................................................................................................................... 11 
2.10.2 
Secondary Endpoint Analyses ........................................................................................................ 11 
2.10.3 
Other Secondary Endpoint Analyses .............................................................................................. 13 
2.10.4 
Other Analyses .............................................................................................................................. 14 
2.11 
ANALYSES OF DATA IN THE RUN-IN PERIOD ...................................................................................................... 15 
2.12 
BASELINE AND SCREENING DEFINITIONS........................................................................................................... 16 
2.13 
STUDY DAY AND VISIT WINDOWS .................................................................................................................. 18 
2.14 
HANDLING OF MISSING DATA ....................................................................................................................... 18 
2.14.1 
Missing Information for Adverse Events ........................................................................................ 18 
2.14.2 
Missing Dates or Partially Missing Dates ....................................................................................... 18 
2.15 
SUBGROUP ANALYSES ................................................................................................................................. 19 
2.16 
POOLING STRATEGY FOR STRATA ................................................................................................................... 20 
2.17 
SAFETY ANALYSES ....................................................................................................................................... 20 
2.17.1 
Adverse Events .............................................................................................................................. 20 
2.17.2 
Laboratory and Vital Sign Parameter Analyses .............................................................................. 20 
2.17.3 
Death ............................................................................................................................................ 21 
2.17.4 
Physical Examination..................................................................................................................... 21 
2.17.5 
12-lead Electrocardiogram (ECG)................................................................................................... 21 
2.17.6 
Special Situation ............................................................................................................................ 21 
2.17.7 
Pregnancy Reports ........................................................................................................................ 21 


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2.18 
INTERIM ANALYSIS AND DATA MONITORING ..................................................................................................... 21 
3 
CHANGES FROM THE PROTOCOL ................................................................................................................... 22 
4 
REFERENCES .................................................................................................................................................. 22 
APPENDIX A: IMPUTATION OF DATES .................................................................................................................... 23 


 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ADaM  
Analysis data model 
AE 
 
Adverse event 
CI  
 
Confidence interval 
CMH 
 
Cochran-Mantel-Haenszel 
COVID-19 
Coronavirus disease 2019  
CRF  
 
Case report form 
CV 
 
Cardiovascular 
DSMB  
Data Safety Monitoring Board 
EAC 
 
Event Adjudication Committee 
ECG 
 
Electrocardiogram  
EF 
 
Ejection fraction 
EGFR  
Estimated glomerular filtration rate 
EoS 
 
End of study 
ESRD  
End-stage renal disease 
ET  
 
Early termination 
FAS  
 
Full analysis set  
GCP  
 
Good clinical practice 
HF 
 
Heart failure 
HFrEF  
Heart failure with reduced ejection fraction 
ICH  
International Council for Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use 
IVRS 
 
Interactive voice response system 
IWRS  
Interactive web response system 
KCCQ  
Kansas City Cardiomyopathy Questionnaire 
MedDRA  
Medical dictionary for regulatory activities 
MRA 
 
Mineralocorticoid receptor antagonist 
N  
 
Number 
NYHA  
New York Heart Association  
PD 
 
Protocol deviation 
PP  
 
Per protocol 
PPS 
 
Per protocol set  
PT 
 
Preferred term 
PV  
 
Protocol violation 
RAASi  
Renin angiotensin-aldosterone system inhibitor  
SAE  
 
Serious adverse event 
SAP  
 
Statistical analysis plan 
SD 
 
Standard deviation 
SE 
 
Standard error 
SOC 
 
System organ class  
SOP  
 
Standard operating procedure 
SS 
 
Safety set 
TEAE  
Treatment emergent adverse event 
TFL 
 
Tables, figures and listings 
TOC 
 
Table of content 
WHO 
 
World health organization 
 
 
 


 
 
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1 STUDY DESCRIPTION 
Patiromer is being studied in subjects receiving renin angiotensin-aldosterone system inhibitor 
(RAASi) medications for the treatment of heart failure with reduced ejection fraction (HFrEF). This 
study will assess the effects of patiromer on serum potassium (K+) and use of RAASi / 
mineralocorticoid receptor antagonist (MRA) medications in heart failure (HF) patients. 
1.1 
Objectives 
Study PAT-CR-302 (DIAMOND Study) has the following primary objective: 
• 
To determine whether patiromer treatment of subjects who developed hyperkalemia while 
receiving RAASi medications will result in changes in serum potassium levels from baseline at 
randomization 
1.2 
Study Design 
The DIAMOND study is a prospective Phase 3b multinational, multicenter, double-blind, placebo-
controlled, randomized withdrawal, parallel group study that includes screening and an up to 12-week 
Run-in Phase (all subjects will have patiromer initiated and RAASi medications, including MRA, 
optimized) and a randomized withdrawal Double-Blinded Treatment Phase.  The primary efficacy 
assessment will be based upon the data collected during the Double-Blinded Treatment Phase. 
During the Run-in Phase, which is single blind to the subject, the Investigator will manage RAASi 
initiation and/or dose escalation as recommended by practice guidelines, using clinical judgment to 
customize RAASi addition or dose escalation based on subject response. Assessment of serum 
potassium will occur at each visit. The patiromer dose will be titrated based on the subject’s potassium 
level. 
After completing the Run-in Phase and found eligible for the Double-Blinded Treatment Phase of the 
study, subjects will be randomized. Randomized subjects will begin treatment with patiromer or placebo 
using the same number of packets established for patiromer at the end of the Run-in Phase and will 
continue the RAASi regimen being administered at the end of the Run-in Phase 
The study will continue until reaching at least the Week 6 visit for each subject. An independent Data 
Safety and Monitoring Board (DSMB) will act in an advisory capacity to monitor the safety of subjects 
who participate in this study.  
1.3 
 Method of Assigning Subjects to Treatment Groups 
Subjects will be randomized to the treatment arms (1:1 assignment) using permuted block randomization 
stratified by region. Randomization will take place using a centralized list accessed electronically on the 
day of randomization after Double-Blinded Treatment Phase eligibility is determined (Day 1).   
1.4 
Blinding 
This is a double-blind study.  The sponsor will not have access to unblinded data during the study (with 
the exception of Viforpharma Drug Safety staff in situations where unblinding is necessary to comply 
with Regulatory requirements), and there is no expectation that the study data (e.g. adverse events, 
dosing, or lab results) will unblind the sponsor, investigator or subjects. While study data (e.g. serum 
potassium changes) may provide some suggestion of the assigned treatment, sufficient variability is 
expected to prevent true unblinding.  The DSMB will have access to unblinded study data as needed.  


 
 
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The sponsor, investigator and subjects will not have access to the unblinded DSMB reports, which will 
be prepared by an independent statistician and programmers not otherwise involved with the conduct 
of the study. 
1.5 
Sample Size 
The sample size of 410 subjects per treatment arm (total of 820 subjects) has been calculated to provide 
90% power to detect a difference between the control group (placebo) and the active group (patiromer) 
in change in K+ levels from Baseline. This sample size calculation is based upon the following 
assumptions: alpha level of 5% (2-sided); difference between group means of 0.116; a SD of 0.5; and 
5% loss to follow-up. 
 
2 STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES 
2.1 
Populations Analysed 
Four analysis populations will be defined.   
2.1.1 
Randomized Set 
All subjects randomized to study treatment. 
2.1.2 
Full Analysis Set  
The full analysis set (FAS) consist of all subjects who satisfy the following criteria: 
• 
Randomized to treatment 
• 
Received at least 1 dose of randomized treatment 
The full analysis set will be the primary population used for the evaluation of efficacy. 
2.1.3 
Safety Set 
The safety set (SS) consists of all randomized subjects who have taken at least 1 dose of randomized 
study medication. The subjects in this group will be analysed based on the treatment they received, with 
data summarized separately for the Run-in and Double-Blinded Treatment Phases of the study.  
2.1.4 
Run-in Phase Set 
The Run-in Phase Set will consist of subjects who signed informed consent and received patiromer 
during the Run-in Phase but were not randomized.  This set will be used to summarize safety related 
events that may be related to patiromer treatment. 
At the beginning of the Covid-19 pandemic, in order to ensure subject safety, all subjects who were in 
the Run-in Phase were discontinued.  These subjects were given the opportunity to be re-screened once 
Covid-19 restrictions were eased in their respective locations.  Those who were still eligible were entered 
into the Run-in Phase again.   
Details for handling the adverse event, laboratory and concomitant medication data for subjects with 
two separate periods of Run-in Phase are provided in the appropriate sections below.  


 
 
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2.2 
General Considerations  
Efficacy analyses will be performed by planned treatment (i.e. as randomized), and safety analyses by 
actual treatment received.   
For continuous variables, descriptive statistics will include the number of subjects, mean, standard 
deviation (SD), standard error (SE), median, 25th and 75th percentiles, minimum and maximum. 
For categorical variables, descriptive statistics will include frequencies and percentages in each 
category. 
For time-to-event variables, the descriptive statistics will include the median, 95% CI, 25th and 75th 
percentiles, minimum and maximum.  Counts (percentages) of subjects with events and of subjects 
censored will also be provided. 
When mean change from baseline is summarized, subjects will only be included in the analysis if they 
have both a baseline value and a post-baseline value at the time point of interest. 
Detailed statistical analyses are specified in sections below. 
On June 24, 2021, sites were informed that the study would be closing and that subjects should be 
brought in for their End of Study (EoS) visit as soon as possible.  After this date, many sites incorrectly 
began to titrate and/or discontinue blinded study drug medication prior to the EoS visit.  Because this 
practice was wide-spread, data after June 24, 2021 will be censored for purposes of efficacy analyses.  
Sensitivity analyses, including data after June 24, 2021, will be conducted for the primary and key 
secondary endpoints.  Safety and exposure analyses will primarily be conducted using all data.  Some 
sensitivity analyses may be conducted using data only through June 24, 2021, as appropriate. 
 
2.3 
Subject Disposition 
The number and percentage of subjects randomized, subjects who receive randomized study treatment, 
and subjects who complete study (or are terminated early) will be summarized by treatment group and 
overall.  The number and percentage of randomized subjects terminating from the study early will be 
presented by reason. In addition, a summary of subject disposition as of June 24, 2021 will be provided. 
The Randomized Set, FAS, and SS will be summarized by treatment group and overall.  
The number and percentage of subjects who signed informed consent, screen failures and screen failure 
reasons will be summarized. The number and percentage of subjects in the Run-in phase, subjects who 
receive patiromer during the Run-in phase, and the reasons for the subjects not randomized at the end 
of the Run-in Phase will be summarized. Listings of subject disposition will be provided. 
2.4 
Protocol Deviations 
Protocol deviations will be summarized for the Randomized Set. The number and percentage of subjects 
with protocol deviations will be summarized by category of deviation, separately for the Run-in Phase 
and the Blinded Treatment Phase, for each treatment group and overall.  A listing of protocol deviations 
will be provided. 
2.5 
Demographics and Baseline Characteristics 
Demographics will be summarized for the Randomization Set, the Full Analysis Set, and the Run-in Set.  
Baseline and screening characteristics will be summarized for the Randomized Set and the Full Analysis 
Set.  Screening characteristics will be summarized for the Run-in Phase Set. 


 
 
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The summary of demographic information will include age, sex, race and ethnicity.  The summary of 
patient characteristics at baseline will include, but is not limited to weight, height, body mass index, 
hyperkalemia status, prespecified medical history (for example, diabetes types, heart failure including 
New York Heart Association (NYHA) class, ejection fraction (EF), myocardial infarction, stroke, other 
arrhythmias, serum potassium, estimated glomerular filtration rate (eGFR)).  
Listings of demographics and baseline characteristics will be provided. 
2.6 
General Medical History 
General medical and surgery history will be coded in accordance with MedDRA 23.0 or an updated 
version and summarized for the Randomized Set, the FAS, and the Run-in Phase Set by body system 
(or procedure) for each treatment group and overall.  
A listing of general medical history will be provided. 
2.7 
Study Drug Dosing and Compliance  
The following summaries of exposure to blinded study drug (patiromer or placebo) will be provided for 
the SS, by treatment group: 
• 
Duration: calculated as [last dose date]-[first dose date]+1.  
• 
Total dose: calculated for each subject as the total dosage received  
• 
Mean daily dose: calculated for each subject as the total dose divided by the duration of study 
drug exposure  
• 
Number and type of titrations (up or down)  
• 
Number of non-zero dose days 
Treatment compliance will be calculated for each subject and summarized by treatment group. Dosing 
compliance will be derived from the total dose of study drug taken by a subject divided by the prescribed 
total dose over the treatment period, multiplied by 100. Descriptive statistics will be provided for dose 
compliance. The summary of study drug dosing and compliance will be presented separately for the 
Run-in and Double-Blinded Treatment Phases. 
The primary exposure analyses will be conducted using all data.  Sensitivity analyses may be conducted, 
using only the data through June 24, 2021. 
A listing of all study drug dosing and compliance data will be provided.  
2.8 
Prior/Concomitant Medications and Procedures 
All prior and concomitant medications including heart failure and RAASi drugs will be coded using the 
current version of the World Health Organization Drug dictionary (WHO Drug Global B3 March 2019). 
Prior and concomitant medications, including heart failure and RAASi drugs, will be separately 
summarized in the SS.  Counts and percentages of subjects using each medication will be computed 
and summarized by treatment group.  
Prior medications are medications with start date before the date of first dose of patiromer in the Run-
in phase.   
Summaries of concomitant medications will be provided separately for the Run-in and Double-Blinded 
Treatment Phases.  


 
 
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Concomitant medications during the Run-in Phase are medications with a start date on or before the 
end of the Run-in Phase and a stop date on or after the first patiromer dose date in the Run-in Phase, 
or no stop date at all.  For subjects who were in the Run-in Phase twice, data from the second Run-in 
will be summarized. Data from the first Run-in will be included in listings only. 
Concomitant medications in the Double-Blinded Treatment Phase are medications with a stop date on 
or after the first date of treatment in the Randomized Treatment Phase, or no stop date at all. Additional 
summaries may be provided for concomitant medications of interest.  
Summaries of the percent of subjects at 100% and 50% of the target dose for ACEi, ARB, ARNi, MRA 
and beta blockers will be provided at Baseline, Day 3, and Weeks 1, 2, 6, and 18 for the Safety Set, by 
treatment group. 
Listings of all prior and concomitant medications will be provided. 
Listings of concomitant procedures will be presented. 
 
2.9 
Study Endpoints 
Study PAT-CR-302 (DIAMOND Study) has the following primary endpoint: 
• 
Changes in serum potassium levels from baseline  
Hierarchical Key Secondary Endpoints: 
1. Hyperkalemia events with a serum K+ value >5.5 mEq/L 
2. Durable enablement to stay on the MRA target dose (50 mg daily spironolactone or 
eplerenone), as assessed by the between-treatment-group difference of the cumulative 
frequency of subjects not staying on that target dose 
Note: Discontinuation of the target dose for at least 14 days (or less if at the end of study) is 
required to confirm this endpoint. 
3. Investigator reported events of hyperkalemia (first and recurrent) 
4. Hyperkalemia related hard outcomes endpoints (Win Ratio) 
a. Time to cardiovascular (CV) death 
b. Total number of CV hospitalizations 
c. Total number of hyperkalemia toxicity events with serum K+ >6.5 mEq/L 
d. Total number of hyperkalemia events with serum K+ >6.0-6.5 mEq/L 
e. Total number of hyperkalemia events with serum K+ >5.0-6.0 mEq/L 
5. RAASi Use Score (Win Ratio) 
 
Other Secondary Endpoints: 
• 
Durable enablement to stay on the target dose of ACE/ARB/ARNI, as assessed by the 
between-treatment-group difference of the cumulative frequency of subjects not staying on 
that target dose 
Note: Discontinuation of the target dose for at least 14 days (or less if at the end of study) is 
required to confirm this endpoint. 


 
 
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• 
Durable hyperkalemia-free enablement to stay on the MRA target dose (days on 50mg MRA 
without presence of hyperkalemia) 
• 
Total number of hyperkalemia toxicity events with serum K+ >6.5 mEq/L 
• 
Total number of hyperkalemia events with serum K+ >6.0-6.5 mEq/L 
• 
Emergency treatment for hyperkalemia (hospitalization or emergency room) 
• 
Total number of hyperkalemia events with serum K+ >5.0-6.0 mEq/L 
• 
KCCQ questionnaire, OSS, CSS and TSS during the treatment phase 
• 
Investigator reported events of hyperkalemia (first event) 
• 
Proportion of subjects on ≥50% of target dose of ACEi, ARB, or ARNi and ≥50% of target dose 
of MRA at the End of Study (EoS) Visit 
• 
Time to first occurrence of CV death or CV hospitalization 
• 
Time to MRA discontinuation  
Note: Discontinuation of MRA, and no re-introduction after the event.. 
• 
Time to first occurrence of MRA discontinuation or death 
• 
Time to ACEi/ARB/ARNi discontinuation  
Note: Discontinuation of ACEi/ARB/ARNi, and no re-introduction after the event.. 
• 
Time to first occurrence of ACEi/ARB/ARNi discontinuation or death 
 
Other Endpoints: 
• 
CV death 
• 
First and recurrent CV hospitalizations 
• 
First and recurrent HF hospitalizations (or equivalent in outpatient clinic) 
• 
Patient reported outcome: EQ-5D-5L questionnaire 
• 
Proportion of subjects on any dose of MRA at the EoS Visit 
• 
Proportion of subjects on any dose of ACEi, ARB or ARNi at the EoS Visit 
• 
Change in proteinuria from Day 3 of the Blinded Treatment Phase  
• 
Change in NT-proBNP from screening 
• 
Change in high sensitivity troponin from baseline at randomization 
• 
Functional status by NYHA class  
• 
30-day HF re-hospitalization rate after a prior HF hospitalization 
• 
Changes in serum K+ from Baseline to individual visits 
• 
Slope of eGFR change during the study 
 


 
 
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Safety Endpoints: 
• 
Adverse events 
• 
All-cause mortality 
• 
Decline in eGFR > 50% or end-stage renal disease (ESRD), renal death, or need for dialysis 
• 
Laboratory parameters other than those defined as efficacy endpoints 
2.10 Statistical Assessment of Efficacy Endpoints 
2.10.1 Primary Analyses 
The primary analysis will be based upon the mean change in serum K+ levels from Baseline and is 
analysed by means of a mixed model for repeated measures (MMRM) approach. The model will include 
data through the last scheduled visit for which at least 10% of subjects have assessments. 
The primary analysis will include only local laboratory serum potassium data from assessments on or 
before June 24, 2021.  A sensitivity analysis will be performed that also includes data after June 24, 
2021. 
All analyses will be restricted to serum K+ assessments and not substituted by plasma values as they 
are known to be systematically lower.  A Gaussian linear model for repeated measures will be used, 
with treatment, geographic region, sex, baseline T2DM status, and visit as factors, and baseline K+ level, 
baseline eGFR as covariates. The error terms are assumed to follow a multivariate normal distribution 
with unstructured covariance. Least squares mean changes from Baseline will be reported for both 
treatment groups with 95% CIs, as well as the difference between the least squares group means with 
95% CI and p-value testing the null hypothesis of no treatment effect.  
Changes in treatment effect over follow-up time will be explored by including treatment by visit 
interactions in the above-mentioned model. In addition, sensitivity analyses accounting for potentially 
informative missingness will be based upon a Win Ratio approach [1, 2].  
The following additional sensitivity analyses will be conducted by re-running the primary MMRM as 
follows: 
• 
Using local serum potassium data without a cutoff at June 24, 2021 
• 
Using both local and central serum potassium data on or before June 24, 2021 (if both values 
are present at a visit, the centrally assessed serum potassium will be used) 
• 
Using only central serum potassium data on or before June 24, 2021: 
2.10.2 Secondary Endpoint Analyses 
Key secondary efficacy endpoints will be tested sequentially in the order listed below (i.e. fixed-
sequence method to preserve the familywise type I error rate) using the full analysis set, and will be 
summarized descriptively through the calculation of point estimates by treatment group along with 95% 
confidence intervals (CI) for the treatment differences.   
For each key secondary endpoint, the primary analysis will use only data through June 24, 2021. A 
sensitivity analysis that includes all data will also be performed for each key secondary endpoint. 


 
 
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The following lists the secondary endpoints and the analysis methods to be used: 
• 
Hyperkalemia events: The time to the first event of hyperkalemia with a serum K+ value >5.5 mEq/L, 
as per the measured values from the central or local laboratories, is analysed using a Cox 
proportional hazards regression model. The treatment difference will be reported as hazard ratio 
(HR) with 95% CI and p-value from a Wald-type test considering the null hypothesis that the HR is 
equal to 1. The event probabilities will be estimated using the Aalen-Johansen estimator of the 
cumulative incidence function accounting for competing events such as death. 
• 
Durable enablement to stay on the MRA target dose (50 mg spironolactone or eplerenone): The 
time to the first event of reduction of the MRA dose below target is analysed using a Cox proportional 
hazards regression model. The treatment difference will be reported as hazard ratio (HR) with 95% 
CI and p-value from a Wald-type test considering the null hypothesis that the HR is equal to 1. The 
event probabilities will be estimated using Aalen-Johansen estimator of the cumulative incidence 
function accounting for competing events such as death. 
Note: Discontinuation of the target dose for at least 14 days (or less if at the EoS) is required to 
confirm this endpoint.  
• 
Investigator reported AEs of hyperkalemia (first and recurrent) are analysed using a negative 
binomial regression with the logarithm of the individual follow-up time as offset. The treatment 
difference will be reported as rate ratio (RR) with 95% CI and p-value from a Wald-type test 
considering the null hypothesis that the RR is equal to 1. A joint frailty model of the total (first and 
recurrent) hyperkalemia events and time to death as terminating event may be implemented. If all-
cause mortality is substantial in number and differential between the treatment groups, then the joint 
frailty model would become the main analysis approach.  
• 
Hyperkalemia-related hard outcomes are analysed using the un-matched Win Ratio approach with 
the following hierarchical components (all assessed during comparable follow-up times): 
1. Time to CV death 
2. Total number of CV hospitalizations 
3. Total number of hyperkalemia toxicity events with serum K+ >6.5 mEq/L 
4. Total number of hyperkalemia events with serum K+ >6.0-6.5 mEq/L 
5. Total number of hyperkalemia events with serum K+ >5.0-6.0 mEq/L 
A death with cause classified as “undetermined” by the event adjudication committee will be 
considered as a CV death. 
• 
RAASi Use Score will be analysed using the Win Ratio approach for each pair of patients at the end 
of the comparable follow-up period that is appropriate for that pair of patients, based on the following 
additive components. Points are accumulated from two components at the respective time for each 
patient in each comparison: 
Component A: 
− 
If during the follow-up (to the respective end of follow-up in the comparator subject) there was 
a death, the subject is assigned 0 points 


 
 
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− 
If during the follow-up (to the respective end of follow-up in the comparison) there was a CV 
hospitalization, but the subject is alive at the end of that follow-up, the subject is assigned 1 
point 
− 
If during the follow-up (to the respective end of follow-up in the comparison) there was no CV 
hospitalization and the subject is alive at the end of that follow-up, the subject is assigned 2 
points 
Component B: 
Further points are collected for the treatment status at the respective end of follow-up in the 
comparison: 
− 
For ACEi/ARB/ARNi use: >50% of the target dose = 2 points 
− 
For ACEi/ARB/ARNi use: >0 and up to 50% of the target dose = 1 point 
− 
For MRA use: >50% of the target dose = 2 points 
− 
For MRA use: >0 and up to 50% of the target dose = 1 point 
− 
For beta-blocker use: >50% of the target dose = 2 points 
− 
For beta-blocker use: >0 and up to 50% of the target dose = 1 point 
In summary, each subject in each comparison can have 0-8 points (sum of Components A and B) 
and all subjects are compared using this score at the respective appropriate follow-up time point.  
Regression analyses will be adjusted for geographic region as the stratification factor of the 
randomization and relevant baseline characteristics of the subjects. 
For analyses based upon the negative binomial distribution, the subject level count data will be modelled 
as a function of treatment with the natural log of the subject level follow-up time taken into account in 
the estimation of the event rate.  
2.10.3 Other Secondary Endpoint Analyses 
The additional endpoints listed below (Other Secondary Endpoints) will be summarized by treatment 
arm.  When treatment comparisons are made, 95% CI and unadjusted p-values will be presented in the 
FAS set.   
For each of these additional secondary endpoints, the analysis will be conducted using only data through 
June 24, 2021. Endpoints originally planned to be assessed at the EoS visit will instead be assessed 
using the last available data on or before June 24, 2021.  
• 
Durable enablement to stay on the target dose of ACE/ARB/ARNi 
 
 
Note: Discontinuation of the target dose for at least 14 days (or less if at the EoS) is required to 
confirm this endpoint 
• 
Durable hyperkalemia-free enablement to stay on the MRA target dose (days on 50 mg MRA without 
presence of hyperkalemia) 
 
• 
Hyperkalemia toxicity events with serum K+ >6.5 mEq/L 
 
• 
Hyperkalemia events with serum K+ >6.0-6.5 mEq/L 
 


 
 
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• 
Emergency treatment for hyperkalemia (hospitalization or emergency room) 
 
 
• 
Total number of hyperkalemia events with serum K+ >5.0-6.0 mEq/L 
 
 
• 
Investigator reported events of hyperkalemia (time to first event) 
. 
• 
Proportion of subjects on ≥50% of target dose of ACEi, ARB, or ARNi and ≥50% of target dose of 
MRA at the EoS Visit 
 
 
• 
Time to first occurrence of CV death or CV hospitalization 
 
 
• 
Time to MRA discontinuation, 
 
  
  
• 
Time to first occurrence of MRA discontinuation or death, 
 
 
• 
Time to ACEi/ARB/ARNi discontinuation, 
 
  
  
• 
Time to first occurrence of ACEi/ARB/ARNi discontinuation or death, 
 
 
 
2.10.4 Other Analyses 
The analyses listed below will be conducted using only data through June 24, 2021, except for the 
analysis of high sensitivity troponin.  
 
 
 
  
Endpoints originally planned to be assessed at the EoS visit will instead be assessed using the last 
available data on or before June 24, 2021. 
• 
CV death
 
• 
First and recurrent CV hospitalizations
 
 
• 
First and recurrent HF hospitalizations (or equivalent in outpatient clinic) 
 
 
• 
KCCQ questionnaire - OSS, CSS and TSS 
 
  
 
   
• 
Mean change in EQ-5D-5L total score based on a visual analog scale from randomization to each 
time point measured post-randomization 
 


 
 
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• 
Proportion of subjects on any dose of MRA at the EoS Visit,
 
   
• 
Proportion of subjects on any dose of ACEi, ARB or ARNi at the EoS Visit, 
 
   
• 
Mean Change in proteinuria from Day 3 of the Blinded Treatment Phase to the EoS Visit, 
 
 
• 
Mean Change in NT-proBNP from screening to each time point measured post-randomization for 
which at least 10% of subjects have an assessment, 
 
• 
Mean Change in high sensitivity troponin from randomization at the EoS Visit, 
 
 
 
• 
Change in Functional status by NYHA class 
 
t 
• 
30-day HF re-hospitalization rate after a prior HF hospitalization, 
 
 
• 
Mean changes in serum K+ from Baseline to individual visits 
• 
Slope of eGFR change during the study, 
 
 
 
 
   
 
 
 
 
.   
 
2.11 Analyses of Data in the Run-in Period 
The analyses described in this section will use a modified Run-in Set.  Subjects in the Run-in Set who 
were discontinued prematurely from Run-in during Spring 2020 due to Covid-19 or were discontinued 
prematurely after study closure was announced on June 24, 2021, will be excluded. 
Screening Characteristics 
Differences between the modified Run-in and Randomized Sets will be summarized for selected 
characteristics at Screening.   
Predictors of Selected Outcomes During Run-in 
Summary statistics will be provided for the following outcomes in Run-in, separately for the 
Randomized Set and the modified Run-in Phase Set: 
• 
Inability to achieve MRA target dose (stable for at least one week) during Run-in 
• 
Inability to achieve ACEi/ARB/ARNi target dose (stable for at least 1 week) during Run-in 


 
 
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• 
Inability to achieve at least 50% of the ACEi/ARB/ARNi target dose (stable for at least 1 week) 
during Run-in 
• 
Hyperkalemia event during Run-in (K+ > 5.5) 
• 
Hypokalemia event during Run-in  
For the above outcomes, selected screening characteristics will be assessed as potential predictors.  
Characteristics to be assessed may include, but are not limited to:  
• 
eGFR < 60;  
• 
NT-proBNP 
• 
Systolic BP 
• 
Ischemic cause of heart failure (Y/N) 
• 
Diabetes Mellitus (Y/N) 
• 
Sex (M/F) 
• 
NYHA (I, II vs. III vs. IV) 
• 
BMI 
• 
Hyperkalemia (Y/N) – as a predictor of inability to reach target dose 
 
RAASi Medication Use 
Use and dose level of RAASi heart failure medications will be summarized at the end of the Run-in 
Period, separately for the modified Run-in Set and the Randomized Set. 
KCCQ 
Summary statistics will be provided for the FAS for the KCCQ Overall Summary Score at Screening, at 
Baseline, and for the Change from Screening to Baseline.  
 
2.12 Baseline and Screening Definitions 
2.12.1 Baseline 
Unless otherwise specified, Baseline is defined as the value of a variable at the Day 1/Baseline Visit.  
If there is a missing value at the Day 1/Baseline Visit, Baseline is defined as the last available non-
missing value on or before and ≤ 10 days prior to the first dose of blinded study medication. 
For randomized but not treated subjects, Baseline is defined as the value at the Day 1/Baseline Visit; if 
missing, it is defined as the last available non-missing value on or before and ≤ 10 days prior to the 
date of randomization  
Some laboratory tests are assessed by both the central laboratory and a local laboratory.  In these 
cases, the following baseline values are defined: 
• 
Local Baseline (Bsl_L) is defined as above using only local values 
• 
Central Baseline (Bsl_C) is defined as above using only central values 


 
 
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• 
Central/Local Baseline (Bsl_CL) is defined as the Central Baseline (Bsl_C) if available, and 
as the Local Baseline (Bsl_L) if the Central Baseline is missing 
• 
Local/Central Baseline (Bsl_LC) is defined as the Local Baseline (Bsl_L) if available, and as 
the Central Baseline (Bsl_C) if the Central Baseline is missing 
In general, if an analysis includes only local laboratory test results for a specific laboratory test value, 
Bsl_L is used to calculate change from Baseline and is used as the baseline covariate in models;  if 
the analysis includes only central laboratory test results, Bsl_C is used;  if the analysis includes both 
central and local test results,  Bsl_CL or Bsl_LC is used.  
Tables and figures will specify what baseline is being used for the table or figure. 
The following are specific exceptions to these rules: 
• 
For eGFR, Bsl_CL is defined differently than for other laboratory parameters.  The definition 
is: the value of the Central Baseline (Bsl_C); if missing, the value of the Local Baseline 
(Bsl_L); if missing, the value at Day 3, with preference for the central value 
• 
Urine ACR is assessed only by the central laboratory, and is collected only during Run-in, 
at Day 3, Week 2, Week 18, and at each 3-month visit during the Double-blinded Treatment 
Phase. For analyses of proteinuria, Baseline is defined as the central value of urine ACR at 
the Day 3 Visit. 
2.12.2  Screening 
Unless otherwise specified, the screening value of a variable is defined as the value of the variable at 
the Screening Visit.  If there is a missing value at the Screening Visit, the screening value is defined as 
the earliest available non-missing value on or before the first dose of patiromer in the Run-in Phase 
and on or after the first date in the Screening period.  If a subject was screened more than once, only 
the last screening that was associated with entry into Run-in will be considered.  If the subject never 
entered Run-in, only the last screening period for the subject will be considered. 
For laboratory tests that are assessed by both a local and a central laboratory at Screening, the 
following Screening values are defined: 
• 
The Local Screening value (Scr_L) is defined as above using only local values 
• 
The Central Screening value (Scr_C) is defined as above using only central values 
• 
The Central/Local Screening value (Scr_CL) is defined as the Central Screening value 
(Scr_C) if available, and as the Local Screening value (Scr_L) if the Central Screening 
value is missing 
If an analysis includes only local laboratory test results, Scr_L is used to calculate change from 
Screening; if the analysis includes only central laboratory test results, Scr_C is used;  if the analysis 
includes both central and local test results,  Scr_CL is used.  
NT-proBNP is assessed by the local and central laboratories at Screening, but after Screening is 
assessed only by the central laboratory, at Week 18 and at each 3-month visit during the Double-
blinded Treatment Phase.  For analyses of change from Screening, the Scr_CL value will be used. 


 
 
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Two sets of subgroups are defined by laboratory screening values.  These are the CKD and NT-
proBNP subgroups.  In both cases, Scr_CL will be used to determine subgroup assignments. 
 
2.13 Study Day and Visit Windows 
The first date of dosing with the study medication (patiromer/placebo) will be used as the Reference 
Date for Study Day calculation.   
The Study Day for date of first dosing is Day 1.  The Study Day for all other study events is defined as 
follows: 
• 
If a date is prior to the Reference Date, Study Day is defined as [date] - [Reference Date], so 
the Study Day for the day before date of first dose is defined as Day -1.  
• 
If a date is on or after the Reference Date, Study Day is defined as [date] - [date of blinded study 
drug] +1; hence, the Study Day for the day after first dose is defined as Day 2. 
Unless otherwise specified, summaries by visit will use the visit weeks/months reported in the database 
and include the results collected at scheduled visits.   
The analyses which are not limited to scheduled visits (e.g. adverse events, 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. 
2.14 Handling of Missing Data 
Missing data will be reflected primarily through the use of censoring for incomplete follow-up. The 
approach will depend on the particular analysis. 
2.14.1 Missing Information for Adverse Events 
For subjects with the missing information for adverse events, the following imputation rules will be 
applied: 
• 
An adverse event with onset date equivalent to the first dosing date will be considered to be 
treatment-emergent unless there is evidence to conclude that it is not. 
• 
An adverse event with missing severity will be assigned to the highest severity observed for the 
subject, among all events with the same preferred term; if there are no other adverse events (AEs) 
with same preferred term and non-missing severity, the adverse event will be counted as severe. 
• 
An adverse event with missing relationship to study drug (patiromer/placebo) will be assigned to 
possible relationship (i.e. related). 
 
2.14.2 Missing Dates or Partially Missing Dates 
Missing or partially missing dates will be imputed conservatively for prior and concomitant 
medications/procedures, medical history, and adverse events.  Specific rules for handling missing or 
partially missing dates are provided in “Appendix A: Imputation of Dates”. Appendix A: Imputation of 
Dates 
No imputations for any other missing safety data will be undertaken. 


 
 
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2.15 Subgroup Analyses  
Descriptive analyses (including the presentation of 95% confidence intervals) will be produced for the 
subgroups specified below for the primary and key secondary endpoints. These descriptive analyses 
will be summarized graphically through the use of forest plots.  
The key subgroups to be analysed are: 
• 
At screening, hyperkalemic vs normokalemic with a history of hyperkalemia 
• 
BMI 
• 
Ejection fraction (< versus ≥ median observed value) 
• 
AF ongoing at screening (Yes versus No) 
• 
Ischemic vs non-ischemic  
• 
Screening use of ARNi (Yes versus No) 
• 
Screening use of MRA (Yes versus No) 
• 
Screening comorbidity: 
o 
Diabetes mellitus (Yes versus No) 
• 
Baseline comorbidity: 
o 
CKD stage  
▪ 
eGFR ≥ 60 versus < 60  
▪ 
eGFR ≥ 45 versus < 45  
o 
NYHA class (II vs III-IV) 
• 
Region (D vs A, B, C) 
• 
Sex (Male or Female) 
• 
Age (< versus ≥ median observed value) 
• 
NT-proBNP at screening (≤  versus > median observed value) 
 
The following subgroups will also be analysed: 
• 
History of AF (Yes versus No) 
• 
Region  
o 
US vs Non-US  
o 
Georgia + Ukraine vs all other countries 
Note: depending on actual patient recruitment, additional comparisons between other 
regions, e.g., Latin America, Western Europe, Eastern Europe, Japan may be conducted 
• 
Age < 65 versus ≥ 65  
• 
Age < 75 versus ≥ 75 
• 
Age < 80 vs ≥ 80 
 


 
 
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2.16 Pooling Strategy for Strata  
The number of subjects randomized is quite large relative to the number of strata.  As such, no pooling 
of strata is planned for data analysis. 
2.17 Safety Analyses 
Statistical analyses will be descriptive in nature and will not be routinely tested for statistical significance. 
Safety analyses will be based upon the clinical database only.  Events recorded in the safety database 
will be reconciled with the clinical database prior to database lock.  
The primary safety analyses will be conducted using all data. Some sensitivity analyses using the data 
cutoff as June 24, 2021 may be undertaken, as appropriate.  
For subjects who were in the Run-in Phase twice, data from the second Run-in will be summarized. 
Data from the first Run-in will be included in listings only. 
2.17.1 
Adverse Events 
Adverse events (AEs) and serious adverse events (SAEs) coded using MedDRA (MedDRA version 23.0 
or an updated version), including all-cause mortality, will be summarized descriptively. 
AE summaries will be provided separately for the Run-in Phase and the Blinded Treatment Phase in the 
SS.   
AE summaries will consist of counts (%) by MedDRA SOC and PT in the Run-in Phase, and by MedDRA 
SOC, PT and treatment arm in the Treatment Phase. The following types of AEs will be summarized: 
• 
All treatment emergent adverse events (TEAEs) 
• 
TEAEs by severity 
• 
TEAEs related to study medication (patiromer/placebo)  
• 
TEAEs leading to study medication discontinuation (patiromer/placebo)  
• 
SAEs 
• 
SAEs related to study medication (patiromer/placebo)  
AE summaries will also be presented in the Run-in Phase Set.  
A listing of AEs will be provided, to include verbatim term, preferred term (PT), system organ class 
(SOC), intensity/severity, relationship to patiromer/placebo, whether serious, onset/end date, action 
taken and outcome of event. 
  
2.17.2 Laboratory and Vital Sign Parameter Analyses  
Laboratory parameters (central) and vital signs will be summarized descriptively using the SS by 
treatment arm for each scheduled visit where the parameter is measured.  Both the observed value and 
the change from baseline will be summarized. The summary of laboratory parameters will be provided 
for the Blinded Treatment Phase in the SS. The incidence of central laboratory test results in ranges of 
interest will be summarized by treatment group in the SS. 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 


 
 
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• 
Serum calcium > 10.2 mg/dL 
Central laboratory shift tables from Baseline to End of Study in the SS will be provided for selected 
laboratory results. 
Decline in eGFR > 50%, or end-stage renal disease (ESRD), or renal death, or need for dialysis at any 
time after randomization will be summarized by count (%).  If the number of subjects experiencing this 
composite endpoint is sufficient, Kaplan-Meir curves for each treatment arm in the SS will also be 
provided. 
Listings will include results from local and central labs, at both scheduled and unscheduled visits.  
Listings will be provided for all serum chemistry parameters, hematology, urinalysis, urine ACR, NT-
proBNP, and high sensitivity troponin.  Listings of all blood pressure, heart rate, weight, and height data 
will be provided. 
2.17.3 
Death 
A listing of all deaths will be provided.  The listing will include date of death, primary cause of death 
and any associated AEs.  
2.17.4 
Physical Examination 
Abnormalities found in physical examinations will be summarized in the SS by treatment group at 
Screening and at EoS/ET visit.   
A listing for all physical examination data will be provided. 
2.17.5 
12-lead Electrocardiogram (ECG) 
Number and percentage of subjects with normal/abnormal and clinically significant abnormal ECG 
findings at screening will be summarized in the SS. 
A listing for all 12-lead ECG data will be provided. 
2.17.6 
Special Situation 
A listing will be provided for all reported special situations. 
2.17.7 
Pregnancy Reports 
A listing for all pregnancy tests will be provided. 
A listing for all reports on exposure to medicine during pregnancy will be provided. 
 
2.18 Interim Analysis and Data Monitoring 
An independent Data and Safety Monitoring Board (DSMB) will meet periodically to monitor the study. 
As part of these reviews, the DSMB will receive summaries of study conduct measures as well as 
unblinded safety data. No interim analysis for efficacy will be conducted. 


 
 
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3  CHANGES FROM THE PROTOCOL 
The protocol specifies that blood samples be taken during the study in order to analyse subject MRA 
levels. 
The complete, validated MRA concentration data will not be available at the time of database lock, and 
analyses of that data will not be included for the CSR.  The complete and validated data will be delivered 
later and analysed separately. 
Slope of eGFR change during the study was proposed as a safety endpoint in the protocol. In the SAP 
it has been changed to an efficacy endpoint, and will be analysed using an mmrm model similar to those 
used for other efficacy endpoints. 
Analyses during Run-in have been added to the SAP. 
 
4 REFERENCES 
1. 
Finkelstein DM, Schoenfeld DA. Combining mortality and longitudinal measures in clinical trials. 
Statist Med. 1999;18:1341-54. 
2. 
Pocock SJ, Ariti CA, Collier TJ, Wang D. The win ratio: a new approach to the analysis of 
composite endpoints in clinical trials based on clinical priorities. Eur Heart J. 2012;33:176-82. 
Epub 2011 Sep 6. 
3. 
Lachin JM. Worst-rank score analysis with informatively missing observations in clinical trials. 
Controlled Clinical Trials. 1999; 20: 408-422. 
 
 
 


 
 
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APPENDIX A: IMPUTATION OF DATES 
1 
Imputation of Missing/Partially Missing Adverse Event Dates 
1.1 
Incomplete Start Date: 
Partially missing AE start/stop dates will be imputed in the analysis dataset model (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 a 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. 
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. 


 
 
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• 
If either the year of the partial date is not equal to the year of the last dosing date or the years of 
the partial date and the last dosing date are the same but the month of partial date is not equal to 
the month of the last dosing date, then the last day of the month will be assigned to the missing day. 
 
2 
Imputation of Dates for Prior/Concomitant Medications/Procedures 
Partially missing start/stop dates for prior/concomitant medications and partially missing start dates for 
prior/concomitant procedures will be imputed in the ADaM dataset for prior/concomitant 
medications/procedures.  However, listings of prior/concomitant medications/procedures data will 
present the date as is, with missing date components left blank. 
For prior/concomitant medications, if the stop date is complete with no missing year, month, or day, and 
the partially missing start date imputed by the rule below is after the stop date, then the start date will 
be imputed by the stop date. 
Partially missing prior/concomitant medication/procedure start dates will be imputed by the earliest 
possible date given the non-missing field(s) of the date. 
Partially missing prior/concomitant medication stop dates will be imputed by the latest possible date 
given the non-missing field(s) of the date. 
3. 
Imputation of Dates for Pre-specified Medical History 
Partially missing start dates for pre-specified medical history will be imputed in the ADaM dataset for 
pre-specified medical history. However, listings of pre-specified medical history data will present the 
date as is, with missing date components left blank. 
A partially missing pre-specified medical history start date will be imputed by the earliest possible date 
given the non-missing field(s) of the date and will be on or prior to the screening visit date.