A Phase IV, Registry-based, Randomised, Controlled, Open-label Trial Investigating the Potential for Patiromer-facilitated Use of Higher Doses of MRAs in Addition to Standard Care to Improve Congestion, Well-being, Morbidity and Mortality
Phase: PHASE4
Conditions: Heart Failure，Congestive
Sponsor: NHS Greater Glasgow and Clyde

 
 
 
 
FULL/LONG TITLE OF THE TRIAL 
 
Patiromer-facilitated, dose-escalation of mineralocorticoid antagonists for the management of 
worsening congestion in people with heart failure and hyperkalaemia. 
 
A Phase IV, registry-based, randomised, controlled, open-label trial investigating the potential 
for patiromer-facilitated use of higher doses of mineralocorticoid antagonists in addition to 
standard care (compared to standard care alone) to improve congestion, well-being, morbidity 
and mortality. 
 
 
SHORT (Patient & Public Friendly) TRIAL TITLE 
 
Can patiromer (a substance that binds potassium in the gut) enable use of higher doses of 
medicines to improve outcomes for people with worsening heart failure?  
 
 
ACRONYM 
 
RELIEHF: RELieving Increasing oEdema due to Heart Failure 
 
 
 
 
 
 
 
PROTOCOL VERSION NUMBER AND DATE 
Version 5.0, 22 July 2021 
 
 

 
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RESEARCH REFERENCE NUMBERS 
 
IRAS number: 
253294 
 
EudraCT number: 
 
2018-003662-14 
ISRCTN number / Clinical trials.gov number: 
 
NCT04142788 
SPONSORS number: 
 
GN17CA082 
FUNDERS number: 
Ph4Study_0213 
 
 
 

 
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SIGNATURE PAGE 
 
The undersigned confirm that the following protocol has been agreed and accepted and that the Chief 
Investigator agrees to conduct the trial in compliance with the approved protocol and will adhere to the 
principles outlined in the Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 2004/1031), 
amended regulations (SI 2006/1928) and any subsequent amendments of the clinical trial regulations, 
GCP guidelines, the Sponsor’s (and any other relevant) SOPs, and other regulatory requirements as 
amended. 
 
I agree to ensure that the confidential information contained in this document will not be used for any 
other purpose other than the evaluation or conduct of the clinical investigation without the prior written 
consent of the Sponsor 
 
I also confirm that I will make the findings of the trial publically available through publication or other 
dissemination tools without any unnecessary delay and that an honest accurate and transparent 
account of the trial will be given, and that any discrepancies and serious breaches of GCP from the 
trial as planned in this protocol will be explained. 
 
For and on behalf of the Trial Sponsor: 
Signature:  
................................................................................................................ 
 
Date:  
8th /Nov/2021 
Name: Pamela Sandu 
 
 
Position: Research Coordinator 
Greater Glasgow & Clyde NHS Board 
 
 
 
 
Chief Investigator: 
Signature:  
................................................................................................................ 
 
Date:  
5th / Nov. / 2021 
Name: John GF Cleland 
Position: Director - Robertson Centre for Biostatistics & Glasgow CTU 
& Honorary Consultant Cardiologist 
               University of Glasgow / Greater Glasgow & Clyde NHS Board 
 
 
 
 
Statistician: 
 
 
Signature:  
................................................................................................................ 
 
Date:  
9th November 
2021 
Name: Michele Robertson 
 
 
Position: Assistant Director Commercial Biostatistics 
 
Robertson Centre for Biostatistics & Glasgow CTU 
 
University of Glasgow 
 
 
 
 
 

 
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KEY TRIAL CONTACTS: 
Chief Investigator 
Professor John GF Cleland 
Director: Robertson Centre for Biostatistics & Glasgow CTU 
Tel: 0141 330 4744 
Fax: 0141 357 5588 
E-mail: john.cleland@glasgow.ac.uk 
 
Trial Manager 
Sarah Weeden 
Glasgow Clinical Trials Unit 
Robertson Centre for Biostatistics, 11th Floor 
Boyd Orr Building 
University of Glasgow 
Glasgow G12 8QQ 
Tel: 0141 330 4744 
Email: RELIEHFsupport@glasgowctu.org 
 
Sponsor 
Dr Maureen Travers 
R&D Management Office 
Clinical Research and Development 
NHS Greater Glasgow & Clyde 
Ward 11, Dykebar Hospital 
Grahamston Road 
Paisley PA2 7DE 
Tel: 0141 314 4012 
E-mail: maureen.travers@ggc.scot.nhs.uk 
 
Joint-sponsor(s)/co-sponsor(s)  
Dr Debra Stuart 
University of Glasgow 
University Avenue 
Glasgow G12 8QQ 
Tel: 0141 330 4539 
Email: Debra.Stuart@glasgow.ac.uk 
 
Funder(s) 
Fabio Dorigotti 
VIFOR Pharma Management AG 
Flughofstrasse 61 
Postfach 
CH-8152 Glattbrugg 
Switzerland 
Tel: +41 58 851 80 00 
Email: fabio.dorigotti@viforpharma.com 
 
Provision of Trial Medication 
VIFOR Pharma 
 
Carmen Urech Zimmer, Clinical Trial Supplies Manager 
Flughofstrasse 61 
Postfach 
CH-8152 Glattbrugg 
Switzerland 
Direct phone: +41 58 851 89 97  
Mobile: +41 79 289 37 40 
Fax: +41 58 851 80 01 
Email: carmen.urech@viforpharma.com   
 

 
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Clinical Trials Unit 
Glasgow Clinical Trials Unit 
Robertson Centre for Biostatistics, 11th Floor  
Boyd Orr Building 
University of Glasgow 
Glasgow G12 8QQ 
Tel: 0141 330 4744 
Fax: 0141 357 5588 
 
Statistician 
Michele Robertson 
Glasgow Clinical Trials Unit 
Robertson Centre for Biostatistics, 11th Floor,  
Boyd Orr Building 
University of Glasgow 
Glasgow G12 8QQ 
Tel: 0141 330 4744 
 
Trials Pharmacist 
Dr Elizabeth Douglas 
Senior Clinical Trials Pharmacist R&D 
Clinical Research and Development  
NHS Greater Glasgow & Clyde 
Ward 11, Dykebar Hospital 
Grahamston Road 
Paisley PA2 7DE 
Tel: 0141 314 4073 
E-mail: elizabeth.douglas@ggc.scot.nhs.uk 
 
Committees 
Trial Steering Committee 
TBC 
 
Trial Management Group 
TBC 
 
Trial Endpoints Committee 
TBC 
 
Independent Data Monitoring & Ethics Committee 
TBC 
 
 
 
 
 

 
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Table of Contents 
 
RESEARCH REFERENCE NUMBERS ...................................................................................... 2 
SIGNATURE PAGE .................................................................................................................... 3 
LIST OF ABBREVIATIONS ........................................................................................................ 7 
TRIAL SUMMARY ...................................................................................................................... 9 
FUNDING AND SUPPORT IN KIND ......................................................................................... 11 
ROLE OF TRIAL SPONSOR AND FUNDER ............................................................................ 11 
ROLES AND RESPONSIBILITIES OF TRIAL MANAGEMENT COMMITTEES/GROUPS & 
INDIVIDUALS ........................................................................................................................... 12 
KEY WORDS:........................................................................................................................... 13 
TRIAL FLOW CHART ............................................................................................................... 14 
1. 
BACKGROUND ...................................................................................................... 16 
2. 
RATIONALE & DESIGN ......................................................................................... 17 
3. 
ASSESSMENT AND MANAGEMENT OF RISK ..................................................... 18 
4. 
OBJECTIVES AND OUTCOME MEASURES/ENDPOINTS ................................... 20 
5. 
TRIAL DESIGN ...................................................................................................... 25 
6. 
TRIAL SETTING ..................................................................................................... 25 
7. 
PARTICIPANT ELIGIBILITY CRITERIA ................................................................. 25 
8. 
TRIAL PROCEDURES ........................................................................................... 28 
9. 
TRIAL TREATMENTS ............................................................................................ 44 
10. 
SAFETY AND OUTCOME REPORTING ................................................................ 53 
11. 
STATISTICS AND DATA ANALYSIS ..................................................................... 59 
12. 
DATA MANAGEMENT ........................................................................................... 62 
13. 
MONITORING, AUDIT & INSPECTION .................................................................. 63 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS .............................................. 64 
15. 
DISSEMINATION POLICY ..................................................................................... 67 
16.  
APPENDICES ........................................................................................................ 68 
17.  
REFERENCE LIST ................................................................................................. 80 
 
 

 
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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
AR 
Adverse Reaction 
CEC 
Clinical Endpoints Committee 
CI 
Chief Investigator 
CRT-D 
Cardiac Resynchronisation Therapy Defibrillator 
CRT-P 
Cardiac Resynchronisation Therapy Pacemaker 
CTA 
Clinical Trial Authorisation 
CTIMP 
Clinical Trial of Investigational Medicinal Product 
 
CTU 
Clinical Trials Unit 
 
DSUR 
Development Safety Update Report 
eCRF 
Electronic Case Report Form 
eGFR 
Estimated Glomerular Filtration Rate 
EudraCT 
European Clinical Trials Database 
GCP 
Good Clinical Practice 
HRA 
Health Research Authority 
IB 
Investigator Brochure 
ICD 
Implantable Cardioverter Defibrillator 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation of technical requirements for registration of 
pharmaceuticals for human use. 
IDMC 
Independent Data Monitoring Committee 
IMP 
Investigational Medicinal Product 
ISF 
Investigator Site File (This forms part of the TMF) 
ISRCTN 
International Standard Randomised Controlled Trials Number 
MHRA 
Medicines and Healthcare products Regulatory Agency 
MRA 
Mineralocorticoid antagonist 
NHS R&D National Health Service Research & Development   
NYHA 
New York Heart Association 
PGA 
Patient Global Assessment 
PI 
Principal Investigator 
PIS 
Participant Information Sheet 
REC 
Research Ethics Committee 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SDV 
Source Data Verification 
SOP 
Standard Operating Procedure  

 
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SmPC 
Summary of Product Characteristics  
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
TMF 
Trial Master File  
TMG 
Trial Management Group 
TSC 
Trial Steering Committee 
 
 

 
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TRIAL SUMMARY 
 
Trial Title 
RELieving Increasing oEdema due to Heart Failure 
Internal ref. no. (short title) RELIEHF  
Clinical Phase  
Phase IV 
Trial Design 
A registry-based, randomised (two equal-sized groups),open-label trial  
Trial Participants 
People with heart failure, worsening symptoms and signs of congestion 
and serum potassium >5.0mmol/L (participants may or may not already 
be receiving a mineralocorticoid antagonist) 
Planned Sample Size 
Phase A: 400 participants completing 60 days follow-up 
Phase B: 2,000 participants 
Treatment duration 
Up to 5 years 
Follow up duration 
Trial follow-up will continue until a minimum of 750 patients has incurred 
a primary outcome event. It is anticipated that this will occur 
approximately 5 years after recruitment of the first patient.  
Patients will be followed by linkage to their electronic medical records for 
hospitalisation and death for up to 5 years after trial completion.  
Planned Trial Period 
Up to 5 years 
 
Objectives 
Outcome Measures 
Primary for the 
Randomised Trial (long-
term follow-up) 
• 
To reduce morbidity and 
mortality 
• 
Composite of time to need for 
parenteral diuretic therapy 
(subsequent to initial discharge) 
for worsening or recalcitrant 
heart failure,  
(re-)hospitalisation for worsening 
heart failure or non-cancer 
deaths. 
Other Primary 
Registry: 
• 
To assess morbidity and 
mortality 
Randomised Trial –to Day 60: 
• 
To improve congestion 
Registry: 
• 
Composite of time to  
(re-)hospitalisation or death 
Randomised Trial –to Day 60: 
• 
“Congestion Index” on Day 60 
Key Secondary 
Registry: 
• 
To describe participants 
characteristics and assess 
morbidity and mortality 
(Note that the registry also 
includes all patients in the 
randomised trial.) 
Registry 
• 
Time to cardiovascular  
(re-)hospitalisation or non-cancer 
death 
• 
Time to heart failure  
(re-)hospitalisation or non-cancer 
death 

 
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• 
Incidence rate for hospitalisation 
(all-causes, cardiovascular 
causes, heart failure causes, 
cancer causes – separately) 
• 
Time to death (all-causes, 
cardiovascular causes, heart 
failure causes, cancer causes, 
and other) 
Key Secondary 
Randomised Trial – to Day 60:  
• 
Dose of MRA achieved 
• 
Further evidence of improved 
congestion 
Randomised Trial – to Day 60:  
• 
Dose of MRA (Days 7 & 60) 
• 
Congestion Index (Days 7& 60) 
• 
Days dead or hospitalised during 
the first 60 days 
• 
Individual Components of the 
Congestion Index (Days 7 &60) 
• 
Quality of Life at (Days 7 &60) 
• 
NYHA class (Days 7 &60) 
• 
Patient Global Assessment 
(PGA) (Days 7 &60) 
Key Secondary 
Randomised Trial (long-term 
follow-up): 
• 
To reduce mortality 
• 
To reduce morbidity, increase 
longevity and increase quality-
adjusted life-years. 
Randomised Trial (long-term 
follow-up): 
• 
Mortality 
- All-Cause  
- Non-Cancer 
- Cardiovascular 
• 
Days lost to hospitalisation for 
heart failure or non-cancer 
deaths over 12 months        
• 
Days lost to any hospitalisation 
or any death over 12 months 
• 
Quality adjusted life-years for the 
duration of the trial 
• 
Proportion alive & well at 12 
months (well-being defined by 
quality of life score) 
• 
Dose of MRA at 6 & 12 months 
• 
Dose of oral diuretics other than 
MRA at 6 & 12 months 
• 
NYHA class at 6 & 12 months 
• 
Patient Global Assessment 
(PGA) at 6 & 12 months 
Investigational Medicinal 
Product(s) 
• 
Patiromer (compared to no patiromer) 
• 
Spironolactone/Eplerenone (dose should differ between those 
assigned to patiromer or not) 

 
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Formulation, Dose, Route 
of Administration 
Patiromer: initially 8.4g/day as a powder dissolved in water or apple 
juice taken orally. Should be titrated, with the patient’s agreement, to 
16.8g/day or 25.2g/day depending on serum potassium. 
 
Spironolactone: oral tablets in doses ranging from 25mg once or more 
per week up to 200mg/day guided by serum potassium concentrations. 
(Licensed dose is up to 200mg/day for oedema and 400mg/day for ascites – 
many patients in this trial will have both conditions). 
 
Eplerenone: oral tablets in doses ranging from 25mg once per week to 
50mg/day guided by serum potassium concentrations for patients who 
have developed troublesome gynaecomastia or other troubling feminising 
side-effects from spironolactone. (Licensed dose is up to 50mg/day; note that 
50mg of eplerenone probably equates only to 30-40mg/day of spironolactone) 
 
Patients taking Eplerenone who have no contraindications to 
spironolactone should switch to spironolactone at baseline or during the 
run-in phase. 
 
FUNDING AND SUPPORT IN KIND 
 
FUNDER(S) 
 
FINANCIAL AND NON FINANCIALSUPPORT 
GIVEN 
VIFOR Pharma Management AG 
 
Fabio Dorigotti 
Flughofstrasse 61 
Postfach 
CH-8152 Glattbrugg 
Switzerland 
 
Tel: +41 58 851 80 00 
Email: fabio.dorigotti@viforpharma.com 
 
According the outstanding contract: 
Financial support for the clinical trial and 
provision and distribution of patiromer 
(Veltassa). 
 
ROLE OF TRIAL SPONSOR AND FUNDER 
 
NHS Greater Glasgow & Clyde and The University of Glasgow will be Co-sponsors of the trial. Prior to 
trial initiation, a non-commercially funded clinical trial co-sponsorship agreement will be put in place 
between NHS Greater Glasgow & Clyde and The University of Glasgow.  The roles and liabilities each 
organisation will take under The Medicines for Human Use (Clinical Trials) Regulations, 2004 SI 
2001:1031 are laid out in this agreement signed by both organisations.  The University of Glasgow 
shall be responsible for carrying out the obligations and responsibilities set out in the aforementioned 
agreement, and shall be deemed “sponsor” for the purposes of, Part 3 of the regulations in relation to 
the trial.  NHS Greater Glasgow & Clyde shall be responsible for carrying out the responsibilities set 
out in the agreement, and shall be deemed “sponsor” for the purposes of, Parts 4, 5, 6 and 7 of the 
Regulations in relation to the trial. 
 
The Co-Sponsors will delegate specific roles to the Chief Investigator, Glasgow CTU and other third 
parties. These arrangements will be clearly documented in agreements and/or the Sponsor Delegated 
Roles and Responsibilities Matrix. 
 

 
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This is an investigator-initiated trial. Vifor Pharma will supply and deliver Patiromer free of charge and 
fund the trial (including the cost of acquiring generic spironolactone and eplerenone at standard NHS 
prices and any cost for labelling and dispensing for trial purposes). Vifor Pharma does not have a 
designated role or responsibility in trial design, conduct, data analysis and interpretation, manuscript 
writing, or dissemination of results. Two representatives from Vifor Pharma will be invited to attend 
TSC meetings as observers. Support from Vifor Pharma will be acknowledged in any publications 
related to the trial. 
 
The Funder has the opportunity to comment on any aspect of the trial and open minutes of the Trial 
Steering and Independent Data Monitoring Committees but will not have access to individual patient 
de-identified data until after the trial is completed and the primary result has been accepted for 
publication. Access to data obtained from linkage to electronic medical records will be subject to 
national regulations. The Funder may withdraw funding subject to contract conditions and this may 
influence the Sponsors’ decision on whether to continue with the trial. 
 
Glasgow Clinical Trials Unit will manage the trial, which will be conducted in up to 100 centres in the 
UK, including designing the case report form, providing randomisation, managing data and statistical 
analyses. 
 
ROLES AND RESPONSIBILITIES OF TRIAL MANAGEMENT COMMITTEES/GROUPS & 
INDIVIDUALS 
 
• Trial Steering Committee (TSC) 
The TSC will provide overall supervision of the trial, ensure that it is conducted in accordance with 
the principles of GCP and relevant regulations and be responsible for interpretation, manuscript 
writing and dissemination of the primary results 
 
The TSC will include the chief investigator, clinical experts, a statistician, a non-clinical 
representative of the trial management group, at least two patient or carer representatives, up to 
two VIFOR Pharma representatives (non-voting) and a sponsor’s representative. The TSC may 
invite other attendees from the trial team to present or participate in discussions on particular 
topics.  These attendees will be non-voting members. 
 
The TSC will have its own charter outlining the role and responsibilities of its members, as well as 
meeting and reporting formats. Decisions about continuation or termination of the trial or substantial 
amendments to the protocol will be the responsibility of the TSC who will advise the sponsor and 
the funder. The TSC will meet at the start of the trial, and regularly thereafter. Meetings can also be 
requested by co-sponsors and/or funder.  
 
• Independent Data Monitoring Committee (IDMC) 
The IDMC will comprise at least two independent medical experts (covering the domains of renal and 
cardiovascular disease one of whom will act as chair) and an independent biostatistician. The 
Glasgow CTU will provide regular reports on participant safety, trial progress and serious adverse 
events. The IDMC will have a formal charter; this will outline the responsibilities of the IDMC 
members, Glasgow CTU and the co-sponsors.  
 
Responsibilities include: 
- ensuring the safety of trial participants 
- reviewing information (in full knowledge of treatment allocation and treatment actually received) 
provided by the Glasgow CTU including trial recruitment, adverse events and outcomes 
- advising the TSC if it is safe and appropriate for the trial to continue. 
 
The IDMC may recommend to the TSC that the trial should stop prematurely because of concerns 
about patient safety or conclusive evidence of overwhelming benefit. The IDMC will meet after 100, 

 
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200, 400, 1,000, 1,500 and 2,000 patients have completed 60-day follow-up and at other times as 
decided by the committee/requested by Co-sponsors. 
 
• Trial Management Group (TMG) 
The TMG will consist of the chief investigator, one or more nominated delegates from the trial team, 
a project manager and representatives from the Glasgow CTU, NHS Greater Glasgow & Clyde 
(NHS GG&C) and the University of Glasgow. The TMG will monitor practical aspects of the conduct 
and progress of the trial, ensure that the protocol is adhered to and take appropriate action to 
safeguard participants and the quality of the trial itself.  
 
• Clinical Endpoints Committee (CEC) 
The CEC will use a charter developed within the Glasgow CTU to adjudicate cardiovascular and 
heart failure events. The CEC will be chaired by an independent consultant cardiologist who will 
provide guidance and training to a group of physicians under their direction. 
 
 
KEY WORDS: 
Heart Failure, Congestion, Oedema, Mineralocorticoid 
Antagonist, Aldosterone Antagonist, Spironolactone, 
Eplerenone, Potassium, Patiromer, Randomised Trial  
 
 

 
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TRIAL FLOW CHART 
 
(i) 
Simplified flow chart 
 
## According to the British National Formulary the maximum permitted dose of spironolactone is 400mg/day but 
of eplerenone only 50mg/day with a starting dose for the management of oedema (including heart failure) of 
100mg/day and 25mg/day respectively. Spironolactone is the predominant MRA used in the UK and, we 
anticipate, in this trial. Most patients are currently treated with spironolactone or eplerenone in doses of 
25mg/day or less. Eplerenone 50mg/day probably has similar MRA activity to ~35mg/day of spironolactone. 

 
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(ii) 
Full flow chart including screening log and registry 
 
 
 
 

 
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1. BACKGROUND 
 
Poor control of congestion is one of the most important unmet needs for patients with heart failure (1). 
Congestion is an important cause of symptoms, disability and recurrent hospitalisation that commonly 
results in death due to heart failure, respiratory infection or multiple organ failure. 
 
About half of all hospital admissions with a primary diagnosis of heart failure present with peripheral 
oedema (>50,000 per year in the UK) (2), usually associated with orthopnoea and dyspnoea on 
minimal exertion (although often not at rest when sitting upright). The underlying pathophysiology in 
these cases is fluid retention that has developed over days or weeks (3, 4). It is perhaps misleading to 
use the term “acute” heart failure in such cases, which implies a medical emergency requiring a 
response within minutes. The term “subacute” heart failure may better convey the status of such 
patients, for whom a response time measured in days or weeks is appropriate. Indeed, there is 
growing interest in managing such patients with home-based subcutaneous furosemide or day-care 
‘furosemide lounges’ (5). Although the presentation of “sub-acute” heart failure is less dramatic than 
for acute pulmonary oedema, patients with sub-acute congestion typically have longer hospital stays 
(in excess of 10 days) and a poorer prognosis, perhaps reflecting more advanced “right heart” 
dysfunction and organ congestion (1, 6). Hepatic congestion, which impairs the degradation of 
aldosterone, and renal congestion both exacerbate sodium retention and congestion.  
 
Although many studies of acute heart failure have been conducted, these have focussed on 
emergency treatment of breathless patients rather than the management of subacute worsening of 
congestion. Few substantial studies focussing on patients with worsening congestion and 
peripheral oedema have been published. The CARRESS study of ultrafiltration conducted in the 
USA is perhaps the closest precedent. It failed to show that ultrafiltration was superior to high-dose 
intra-venous furosemide. By 60 days, almost 40% of patients had died or been re-hospitalised for 
heart failure (mortality was 15%) (7). A sub-group analysis of the RELAX-AHF trial (6) suggested that 
15% of those with moderate/severe oedema would die or be re-admitted for heart failure by 60 days 
(mortality was about 6%). 
 
Spironolactone, a mineralocorticoid antagonist (MRA), is on the World Health Organization's List of 
Essential Medicines. It has been used to treat congestive heart failure for >50 years. Until the advent 
of angiotensin converting-enzyme (ACE) inhibitors, doses of 100-200mg/day were commonly used (8). 
With the advent of ACE inhibitors in the late 1980s, use and doses of MRA declined. However, in 
1999, the RALES trial showed that, for patients receiving ACE inhibitors, spironolactone, titrated up to 
50mg/day, markedly reduced re-hospitalisation and mortality in advanced heart failure (9). Pilot-trials 
suggested that higher doses of spironolactone (75mg/day) were limited by hyperkalaemia (10). 
Subsequently, two large trials of eplerenone (up to 50mg/day) and several smaller trials of other MRA 
demonstrated reductions in morbidity and mortality in a broad range of patients with left ventricular 
dysfunction after myocardial infarction or heart failure. 
 
MRA increase urinary sodium excretion, helping relieve congestion, and cause potassium retention. 
Some also believe that MRA have effects on sympathetic activation and fibrosis that may be beneficial 
(11). Whether higher doses of MRA are more effective at improving congestion or reducing fibrosis is 
uncertain. However, several factors limit the use and dose of MRA for patients with heart failure, 
particularly hyperkalaemia (12).  
 
Patients with heart failure and severe congestion usually have moderate to severe renal impairment 
and are therefore at high risk of hyperkalaemia when treated with MRA. MRA may worsen renal 
function in patients who are not severely congested. However, congestion may be one of the causes 
of renal dysfunction in this population due to high renal vein pressures. Reduction in severe 
congestion by MRA might improve renal function (13). MRA may also reduce arterial pressure in 
patients who are not severely congested but this may be due to excessive reduction in left ventricular 

 
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filling pressures. This may not occur until overt clinical congestion is corrected and might then be 
managed by reducing doses of loop diuretics.  
 
There is a wealth of evidence to show that MRA improve outcome when added to ACE inhibitors. 
However, the incremental value and safety of using higher doses (as in the pre-ACE inhibitor era) for 
patients with hepatic congestion and renal dysfunction at high risk of hyperkalaemia is unknown. 
Higher doses might be highly effective, no more effective than conventional management or might be 
unsafe unless closely monitored. 
 
Patiromer is an oral potassium-binding agent that reduces serum potassium concentrations in patients 
with heart failure and renal dysfunction taking contemporary therapy for heart failure including MRA 
(14, 15). Routine administration of patiromer should allow more patients to be treated with MRA and at 
higher doses, which may help treat and control congestion more effectively, leading to improved 
symptoms and reduced morbidity and mortality. Hypotension and renal dysfunction may also limit the 
use of MRA but can be managed by using lower doses of conventional diuretics or of other 
medications that don’t have important dose-related benefits in severe heart failure (e.g. ACE inhibitors 
(16, 17)) or in atrial fibrillation (e.g. beta-blockers (17, 18), which is likely to affect >50% of patients in 
this trial. Moreover, controlling congestion might reduce renal venous pressure and improve renal 
function (13). Thus, patiromer-facilitated use of higher doses of MRA might manage congestion more 
effectively. Although patiromer is not absorbed and has a favourable benefit-risk profile, there are 
concerns about adherence to medication; if a patient stops taking an MRA but continues on patiromer 
then they are at risk of hypokalaemia; if they stop taking patiromer but continue with an MRA then they 
are at risk of hyperkalaemia. Educating participants and investigators to ensure adherence and to 
seek medical advice before adjusting the dose/intake of either is essential.  
 
Accordingly, we plan to conduct a randomised controlled trial to investigate the potential of patiromer 
to facilitate the use of higher doses of MRA for patients with heart failure, worsening congestion and 
hyperkalaemia to find out whether this strategy improves the control of congestion and patient well-
being and reduces morbidity and mortality.  
 
2. RATIONALE & DESIGN 
 
Rationale: People with worsening congestive heart failure may benefit from treatment with higher 
doses of MRA if they are administered patiromer to treat or prevent hyperkalaemia.  
 
Design: We will identify potential participants with worsening heart failure identified by their care-
teams. Those considered eligible will be asked to provide consent for participation in a registry and 
give permission for collection of further medical information and personal identifiers to enable long-
term follow-up through electronic medical records. Patients who are not approached (e.g. those with 
severe cognitive dysfunction) or who decline to participate will have only a small amount of (de-
identified) data collected from their medical records in a screening log, as recommended by the 
Health Research Authority. 
 
The consented registry has several functions: 
1. The registry has no exclusion criteria (other than the need for consent) and therefore should be 
similar to the population requiring management of congestion in clinical practice. This will identify 
the proportion of people in clinical practice who are potentially eligible for patiromer. 
2. We believe that the registry will boost trial recruitment, as it will be relatively easy to enrol a large 
number of potential participants and to randomise trial participants from this pool. This will address 
low levels of investigator engagement often caused by demanding protocols that create a vicious 
downward spiral of low recruitment leading to low research resource allocation. 

 
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3. The registry will provide an opportunity to investigate why potential participants are not enrolled in 
trials. 
4. Participants will be asked if they are willing to be approached about future research. 
The randomised trial will investigate whether patiromer allows patients with worsening heart failure 
to be titrated to higher doses of MRA (predominantly spironolactone). Participants who are not 
assigned to patiromer should have titration to guideline-recommended doses of MRA attempted, 
although many are anticipated not to achieve this. Patients assigned to patiromer may be titrated to 
200mg/day of spironolactone (highest licensed dose 400mg/day) or the highest licensed dose of 
eplerenone (50mg/day). (Eplerenone 50mg/day has similar MRA potency to about 35mg/day of 
spironolactone; accordingly, spironolactone is the preferred MRA. We expect that the median dose of 
spironolactone (or eplerenone) in the control group will be 25mg/day and that up to 25% will not 
tolerate any dose of MRA due to hyperkalaemia or other reasons.) We expect that the median dose of 
spironolactone in the patiromer-facilitated arm will be about 100mg/day because hypotension and 
renal dysfunction will prevent many patients from being titrated to 200mg/day and that almost all 
randomised patients will tolerate some dose of MRA. 
The trial is open-label, which reduces complexity for participants (those assigned to the control group 
are not required to take a placebo), increases participant-safety (participants taking patiromer know 
that if they stop taking either patiromer or MRA this may cause problems), helps investigators and 
other health professionals manage clinical problems and reduces the logistic complexity of pharmacy 
trial-supply. 
 
There are two phases to the randomised trial: during the first 60 days, the main aim is to control 
congestion, thereby improving well-being and reducing the need for hospital care; the long-term aim is 
to reduce morbidity and mortality. Good control of congestion might reduce the risk of death not only 
from heart failure but also from arrhythmias (including atrial fibrillation and therefore stroke), 
bronchopneumonia and end-stage renal disease but is unlikely to alter mortality due to cancer within 
the time-frame of this trial and consequently cancer deaths will not comprise part of the primary 
endpoint, although they will be recorded. Potentially spironolactone could have a favourable effect on 
some cancers (e.g. prostate cancer (19)). Evidence for a detrimental effect on sex-hormone sensitive 
cancers is lacking (20, 21). 
 
This research will determine whether patiromer allows more patients to be treated with higher doses 
of an MRA, thereby potentially improving the management of congestive heart failure, shortening 
hospital stay, improving patient well-being, reducing re-interventions and readmissions for worsening 
heart failure and reducing non-cancer deaths (we do not anticipate an effect on cancer deaths). Both 
clinicians and patient-advisers believe these goals of treatment are worthwhile. 
 
3. ASSESSMENT AND MANAGEMENT OF RISK 
 
The independent data monitoring committee (IDMC) will review all serious adverse events with 
particular attention to interventions for and serious consequences of hypo- and hyperkalaemia, 
symptomatic hypotension and renal dysfunction and may recommend changes to the protocol during 
the course of the trial. 
 
Patiromer binds potassium in the gut and is not absorbed. It has no direct cardiovascular action. The 
initial dose is 8.4g/day suspended in water or apple juice and it may be increased to 16.8g or 
25.2g/day, either by taking multiple sachets or a higher-dose sachet. Patiromer suspension has a 
slightly gritty texture that some patients may be unwilling to take regularly. A test dose will be given 
prior to randomisation to ensure that the patient understands how to prepare patiromer and is willing to 
take patiromer long-term.  Due to the potential for patiromer to bind to co-administered oral medicines 
in the gastrointestinal tract, administration of patiromer should be separated by at least 3 hours from 
other oral medicinal products. However, at investigator-discretion, patiromer may be co-administered 
with other medicines if data are available to indicate bioavailability is unlikely to be affected, based on 

 
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in vivo (in healthy volunteers) and in vitro studies (22, 23).  A list of medicines that may be co-
administered with patiromer is provided in section 9.8.   
 
Patiromer may cause constipation in some people. This may be managed by diet, treatments for 
constipation or by reducing the dose of patiromer. 
 
Patiromer may cause hypokalaemia and hypomagnesaemia (defined in this protocol as serum 
magnesium <0.75mmol/L) if insufficient doses of MRA are given (this may apply to participants in 
either arm of this trial). If the dose of MRA cannot be increased due to hypotension or renal 
dysfunction, this may be corrected by magnesium supplements or by reducing the dose of patiromer.  
 
For patients who do not already have a serum potassium >5.0mmol/L, the initial dose of 
spironolactone will be 25mg/day for those who are spironolactone naïve and 50mg/day for those 
already receiving spironolactone or eplerenone at doses <50mg/day. Spironolactone may be 
increased to 100mg/day if serum potassium remains <5.0mmol/L despite 50mg/day of spironolactone 
or eplerenone. Only if serum potassium rises to >5.0mmol/L is the patient eligible for randomisation. If 
eGFR falls below 30ml/min/1.73m2 or systolic blood pressure <90mmHg (and this cannot be corrected 
by altering the dose of other medications), then the patient is not eligible for the randomised trial and 
will return to standard care. The clinicians caring for the patient should then decide on the most 
appropriate dose of MRA. 
 
Participants who have or develop a serum potassium >5.0mmol/L can be randomised directly into the 
trial provided they do not require intravenous treatment or a potassium binding agent for the treatment 
of severe hyperkalaemia in the investigator’s opinion. Severe hyperkalaemia should be managed 
according to the UK Renal Association guidelines of 2020 
(https://renal.org/sites/renal.org/files/RENAL%20ASSOCIATION%20HYPERKALAEMIA%20GUIDELINE%2020
20.pdf). Participants may be reconsidered for the trial once such interventions are no longer 
considered necessary. For patients assigned to patiromer, the dose of MRA should not be increased 
until serum potassium drops below 5.0mmol/L (see titration schedule). The dose of patiromer may be 
increased to achieve a serum potassium in the target range. For patients assigned to the standard 
care control group, the dose of MRA should be reduced to allow serum potassium to fall into the target 
range. 
 
MRA (spironolactone or eplerenone) may cause hyperkalaemia, hypotension or renal dysfunction. 
Hyperkalaemia can be corrected by patiromer, which forms part of the rationale for this trial. If 
hypotension is symptomatic or renal function deteriorates, this can often be managed by adjusting 
doses of concomitant medications, including conventional diuretics and non-steroidal anti-
inflammatory drugs or, failing that, the dose of MRA may be reduced.  
 
In the RALES trial that enrolled patients with advanced heart failure and eGFR >30mls/minute and a 
serum potassium <5.0mmol/L, the target dose of spironolactone was 50mg/day and the mean daily 
dose achieved at two years was 26mg/day (compared to 31mg/day of the corresponding placebo). 
The median increase in serum potassium was 0.3mmol/L in those assigned to spironolactone 
compared to placebo. Of 1,663 patient randomised, 5.6% of those assigned to placebo developed a 
serum potassium >5.5mmol/L compared to 19.0% of those assigned to spironolactone. The treatment 
benefit of spironolactone was “maintained at least until serum potassium exceeded 5.5mmol/L” (24)  
Few patients developed severe hyperkalaemia (serum potassium >6.0mmol/L) in either arm of the trial 
(1.2% versus 3.9%). No change in average blood pressure occurred and the median increase in 
serum creatinine was <10umol/L. Worsening renal function, defined as a fall in eGFR by >30% 
occurred in 7% of those assigned to placebo and 17% of those assigned to spironolactone and 
appeared unrelated to changes in blood pressure. However, the greatest benefit of spironolactone on 
morbidity and mortality was observed amongst those with the worst renal function (25). The RALES 
pilot trial, 5% of patients developed a serum potassium >5.5mmol/L compared to 20% of those 
assigned to 50mg/day of spironolactone and 24% of those assigned to 75mg/day after 12 weeks of 

 
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therapy (26). The mean reduction in systolic blood pressure was 6mmHg.and rise in serum creatinine 
was 22umol/L. In the recent ATHENA trial (27), patients with acute heart failure were assigned to 
three days of at least partially-blinded treatment with a standard dose of spironolactone or 100mg/day 
followed subsequently by standard care. No difference in outcome at 30 days was noted. Serum 
potassium increased by 0.31mmol/L with 100mg/day of spironolactone compared to 0.15mmol/L in the 
control group (between group difference p=0.08). eGFR declined by about 5ml/minute/1.73m2 in both 
groups. No patient in the higher dose group developed a serum potassium >5.5mmol/L. 
A dose-adjustment algorithm for spironolactone is provided in this protocol (Section 9). Spironolactone 
(tablets of 25mg, 50mg or 100mg) will be supplied (open-label) in appropriately labelled containers for 
trial purposes. For patients who develop gynaecomastia or other feminising side effects on 
spironolactone, eplerenone (tablets of 25 or 50mg) will be supplied as an alternative. We assume that 
10% of patients assigned to higher doses of spironolactone will develop gynaecomastia requiring a 
switch to eplerenone on average about 6 months into the trial. This is anticipated to apply to fewer 
than 200 patients. Switching patients to eplerenone may lead to a reduction in the effective MRA dose, 
which may then also require a reduction in the dose of patiromer. Investigators will be alerted to this 
possibility and monitor serum potassium accordingly (Appendix 3). 
 
Currently, there is no evidence that facilitating the use of or higher-doses of MRA by using patiromer 
improves outcomes for people with heart failure. Currently, patients with hyperkalaemia would usually 
be managed by reducing the dose of, or stopping, the MRA. 
 
An important risk is the discontinuation of one agent (either patiromer or MRA) but not the other. 
Participants will be educated accordingly by investigators and provided educational material, and 
reminders on the labelling of the relevant IMP. Participants will also be provided with a trial safety-card 
which they will be asked to carry with them at all times and show the card to any doctors or healthcare 
professionals who are involved in their care. Investigators will be educated by the protocol, site 
initiation visits, webinars and regular teleconferences. Participants’ primary care physicians will be 
sent information by letter. Patients will receive supplies of both patiromer and MRA as appropriately 
labelled trial medications. They should be taken approximately three hours apart as indicated in 
patiromer’s license. Treatment will be open-label, which will reduce confusion and uncertainty and 
avoid the needs and complexity of emergency un-blinding. 
 
Patients will be closely monitored in this trial, with regular measurements of potassium, magnesium, 
renal function and blood pressure. 
 
Women with childbearing potential will be excluded as the risks of patiromer in pregnancy are 
unknown (although unlikely to be a problem) and spironolactone poses risks to the developing foetus. 
Moreover, few women of childbearing potential are likely to be eligible for this trial. Most patients will 
be aged >60 years. Patiromer is not absorbed and therefore poses no risk to female partners of men 
who take patiromer.  
 
This trial is categorised as Type B = somewhat higher than the risk of standard medical care. 
 
4. OBJECTIVES AND OUTCOME MEASURES/ENDPOINTS 
 
Hypothesis: Compared to standard care, administering patiromer to patients who have worsening 
congestion due to heart failure and hyperkalaemia (defined as a serum potassium >5.0mmol/L) allows 
use of higher doses of mineralocorticoid receptor antagonists (MRA) thereby improving congestion 
and reducing cardiovascular morbidity and mortality.  
 
4.1 
Primary Objective 
 
To find out whether patients with worsening congestion due to heart failure and hyperkalaemia who 
are randomised to patiromer (thus enabling the use of higher doses of MRA) have a lower rate of 

 
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worsening heart failure [defined as a composite of need for parenteral diuretic therapy (either 
intravenous [IV] or subcutaneous [SC]) for worsening or recalcitrant heart failure (subsequent to 
discharge from index episode of care), re-hospitalisation for worsening heart failure or non-cancer 
mortality] compared to patients assigned to a control group that does not receive patiromer. 
 
4.2 
Other Primary Objectives 
 
For the Registry 
 
To investigate the willingness of patients with worsening heart failure who require higher doses of 
diuretics to control worsening symptoms and signs of congestion to participate in a research registry 
and/or, in principle, a randomised trial (not necessarily this particular trial). Participants may or may 
not satisfy the criteria for enrolment in the RELIEHF randomised trial. Registry participants will be 
followed up only through their electronic health records to assess mortality and morbidity. No further 
research visits are required. 
 
For the Randomised Trial until Day 60 
 
To find out whether administering patiromer and higher-dose MRA improves evidence of congestion 
on Day 60 (±10 days) compared to standard care. 
 
4.3 
Secondary Objectives 
 
For the Registry 
 
To describe the characteristics and outcome of patients with worsening heart failure who require 
higher doses of diuretics to control worsening symptoms and signs of congestion. 
 
For the Randomised Trial until Day 60 
 
To find out whether patients with worsening congestion due to heart failure and hyperkalaemia who 
are randomised to patiromer receive higher doses of MRA and have less severe symptoms and signs 
of congestion, quality of life and hospital length of stay compared to patients assigned to those who 
are randomised to standard care. 
 
Randomised Trial (long-term follow-up) 
 
To find out whether patients with worsening congestion due to heart failure and hyperkalaemia who 
are randomised to patiromer receive higher doses of MRA, have improved long-term quality of life, 
spend less time in hospital and have lower all-cause mortality compared to patients assigned to 
standard care. 
 
4.4 
Outcome Measures/Endpoints 
 
Endpoints have been chosen to reflect the clinical aims of managing patients with worsening 
congestion due to heart failure. The ‘narrative’ is that better management of congestion by patiromer-
facilitated, dose-escalation of MRA will improve symptoms and signs of congestion, leading to a 
shorter hospital stay, improved quality of life, less need for intravenous and intensified oral diuretic 
therapy, fewer readmissions for worsening heart failure and increased longevity. 
 
4.5 
Primary Endpoint 
 
Composite of time to need for IV or SC diuretics for worsening or recalcitrant heart failure (subsequent 
to discharge from index episode of care), (re-)hospitalisation for worsening heart failure or non-cancer 

 
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deaths. The trial is powered on time-to-first event but analysis will include first and recurrent events for 
the primary endpoint. 
 
4.6 
Other Primary Endpoints 
 
For The Registry 
 
Time to first (re-)hospitalisation or death 
 
Randomised Trial until Day 60 
 
• 
Congestion Index on Day 60, comprising changes from baseline in 
i. 
Weight 
ii. 
Severity of peripheral pitting oedema 
iii. 
Breathlessness symptom score 
iv. 
Dose of loop and thiazide diuretics 
v. 
Walk Test Time (will be considered zero at baseline if not available) 
vi. 
Plasma concentration of NT-proBNP 
vii. 
Plasma concentration of CA125 
 
4.7 
Secondary Endpoints 
 
Registry 
 
• 
Time to first cardiovascular (re-)hospitalisation or non-cancer death as judged by primary and 
secondary ICD-10 codes 
• 
Time to first heart failure (re-)hospitalisation or non-cancer death as judged by primary and 
secondary ICD-10 codes 
• 
Incidence-rate for hospitalisation, all-causes and due separately to cardiovascular causes, heart 
failure or cancer, and other as judged by primary and secondary ICD-10 codes 
• 
Time to death 
- All-cause and due to cardiovascular, heart failure, cancer and other based on hospitalisation 
data and death certificates. 
 
The data for all registry outcome events will be obtained solely by linkage to electronic medical 
records. 
 
Randomised Trial until Day 60 
 
• 
Dose of MRA (Days 7 & 60) 
• 
Congestion Index (Days 7& 60) 
• 
Days dead or hospitalised during the first 60 days 
• 
Individual Components of the Congestion Index (Days 7 &60) 
• 
Quality of Life at (Days 7 &60) 
• 
NYHA class (Days 7 &60) 
• 
Patient Global Assessment (PGA) (Days 7 &60) 
 
 Randomised Trial (long-term follow-up) 
 
• 
Mortality 
- All-Cause  
- Non-Cancer 

 
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- Cardiovascular 
• 
Days lost to hospitalisation for heart failure or non-cancer mortality over 12 months        
• 
Days lost to any hospitalisation or death over 12 months 
• 
Quality adjusted life-years for the duration of the trial using EQ5D 
• 
Proportion alive & well at 12 months (well-being defined by KCCQ quality of life score) 
• 
Dose of MRA taken at the time of the 6 and 12 month visits 
• 
Dose of oral diuretics other than MRA taken at the time of the 6 and 12 month visits 
• 
NYHA class at 6 and 12 months 
• 
Patient Global Assessment (PGA) at 6 and 12 months 
 
4.8 
Safety Endpoints 
 
• 
During scheduled follow-up assessments the percentage of patients in each arm of the trial  with: 
o Hypokalaemia defined at various thresholds of serum potassium  
 
<4.0mmol/L or<3.5mmol/L or <3.0mmol/L 
o Hyperkalaemia defined at various thresholds of serum potassium 
 
>5.5mmol/L or >6.0mmol/L or >6.5mmol/L 
o Hypomagnesemia defined as <0.75mmol/L (<1.5mEq/L or <1.8mg/dL). 
o eGFR  
 
<30mL/min/1.73m2 or <20mL/min/1.73m2 or <10mL/min/1.73m2 
o Systolic blood pressure  
 
<100mmHg or <90mmHg or<80mmHg 
o Heart rhythm 
 
Sinus rhythm / atrial fibrillation / other rhythm 
• 
Doses of MRA, ACE inhibitors, Angiotensin Receptor Blocker and angiotensin-neprilysin 
inhibitors, diuretics and beta-blockers 
• 
Heart rate at each scheduled visit according to heart rhythm 
 
• 
Adverse reactions and Serious Adverse events related to 
o Hyper- or hypo-kalaemia or hypo-magnesaemia – any record defined according to serum 
concentrations above 
o Renal failure – defined as renal dialysis or death preceded by an eGFR <10ml/min/1.73m2 
(last measurement before death) 
o A decline in eGFR by >30% from baseline [24] 
o A doubling in serum creatinine from baseline 
o Symptomatic Hypotension 
 
 

 
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4.9 
Table of Endpoints/Outcomes 
 
Objectives 
Endpoint 
Time-point(s) of 
evaluation of this 
outcome measure (if 
applicable) 
Primary 
 
 
Overall (long-term) 
Composite of time to need for IV diuretics for 
worsening or recalcitrant heart failure 
(subsequent to discharge from index episode of 
care), (re-)hospitalisation for worsening heart 
failure or non-cancer deaths. 
End of trial 
Other  Primary 
 
 
For Registry 
Composite of time to (re-)hospitalisation or death 
Periodically up to 10 years 
Until Day 60 
Congestion Index at Day 60 
 
After 400 patients have 
been evaluated at  60 
days 
Secondary 
 
 
Randomised Trial 
(long-term follow-
up) 
• Mortality 
- All-Cause  
- Non-Cancer 
- Cardiovascular 
End of trial 
 
• 
Days lost to hospitalisation for heart failure or 
non-cancer mortality  
12 months 
 
• 
Days lost to any hospitalisation or death 
12 months 
 
• 
Proportion alive & well (defined by KCCQ) 
12 months 
 
• 
Quality adjusted life-years using EQ5D 
End of trial 
 
• 
Dose of MRA 
6 and 12 months 
 
• 
Dose of oral diuretics other than MRA 
6 and 12 months 
 
• 
NYHA 
6 and 12 months 
 
• 
Patient Global Assessment (PGA) 
6 and 12 months 
Until Day 60 
 
 
 
• 
Dose of MRA  
Days 7 and 60 
 
• 
Congestion Index   
Days 7 and 60 
 
• 
Individual Components of Congestion Index 
Days 7 and 60 
 
• 
Days dead or hospitalised  
Day 60 
 
• 
Quality of Life (EQ5D & KCCQ) 
Days 7 and 60 
 
• 
NYHA 
Days 7 and 60 
 
• 
Patient Global Assessment (PGA) 
Days 7 and 60 
Registry 
 
 
 
• 
Composite of time to cardiovascular  
(re-)hospitalisation or non-cancer death 
• 
Composite of time to heart failure  
(re-)hospitalisation or non-cancer death 
• 
Incidence rate for hospitalisation (all-causes, 
cardiovascular causes, heart failure causes, 
cancer causes – separately) 
• 
Time to death (all-causes, cardiovascular 
causes, heart failure causes, cancer causes, 
and other) 
Periodically up to 10 years 
 
 
 

 
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5. TRIAL DESIGN 
 
A Phase IV, registry-based, randomised (1:1), open-label trial investigating whether administration of 
patiromer enables use of higher doses of mineralocorticoid antagonists and thereby improves the 
severity of congestion and patients’ well-being, morbidity and mortality for patients with heart failure, 
worsening congestion and hyperkalaemia. 
 
Hospitalisations and mortality will be adjudicated independently blind to treatment allocation. 
 
6. TRIAL SETTING 
 
This is a multi-centre trial that will be conducted in approximately 100 UK NHS Trusts/Boards 
responsible for managing patients with heart failure who have sufficiently severe manifestations of 
congestion that they are being considered for intravenous diuretic therapy.  
 
Principal investigators will be experts in the management of heart failure and may either be a) doctors 
or b) nurses/pharmacists working under the supervision of a doctor with expertise in the management 
of heart failure. The TSC will review the curricula vitae of all proposed principal investigators to ensure 
they are suitably qualified and experienced to conduct the trial with adequate support. Either a 
principal investigator who is medically qualified or a designated medical practitioner on the delegation 
log will verify that all inclusion/exclusion criteria have been met. Doctors and appropriately qualified 
non-medical prescribers who have been delegated this task by the local principal investigator may 
prescribe MRA and patiromer as described in this protocol and as randomly assigned, provided this is 
in accordance with local policies and procedures. 
 
Participants are typically ‘known’ to heart failure services and are hospitalised or require 
intensive management either as day-cases or by community heart failure services. 
 
 
Participants will be identified from primary or secondary care services, including hospital wards and 
clinics and community heart failure services. The precise set-up of heart failure services/pathways will 
vary according to locality. If a patient moves away from their original trial site and they can attend visits 
at an alternative trial site they may continue with their randomised treatment allocation. Otherwise, 
patients will be withdrawn from trial follow-up visits and those assigned to receive patiromer will revert 
to standard care. These patients will continue to be followed for hospitalisations and deaths by the 
investigators until the end of the trial or by record linkage in the extended follow-up phase. 
 
7. PARTICIPANT ELIGIBILITY CRITERIA 
 
7.1 
Inclusion Criteria 
 
For the Screening Log (no follow-up envisaged nor linkage to electronic medical records) 
1. ≥18 years 
2. Heart failure in the investigators opinion (new onset or decompensated chronic heart failure) 
3. Planned to receive >80mg/day of furosemide or equivalent* (IV, SC, or oral) in the next 24 hours. 
4. Worsening symptoms & signs of congestion in the prior10 days requiring at least one of the 
following: 
a) hospitalisation 
b) administration of intravenous diuretics 
c) 
an increase in the dose of loop diuretic by at least 40mg/day of furosemide (or equivalent**) 
to a total of at least 80mg/day of furosemide (or equivalent*) 
d) addition of a thiazide diuretic to treatment with a loop diuretic 
 
 

 
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* a dose of 80mg/day of furosemide is considered equivalent to 2mg/day of bumetanide or 
20mg/day of torasemide. 
** a dose of 40mg/day of furosemide is considered equivalent to 1mg/day of bumetanide or 10 
mg/day of torasemide. 
 
For the Consented Registry (with linkage to electronic medical records) 
1. Fulfils the criteria for the screening log 
2. Able and willing to provide written informed consent for registry participation 
 
For Randomised Trial Run-in  
1. Fulfils criteria for the consented registry 
2. Clinical diagnosis of heart failure for at least 4 weeks  
3. Congestion as shown by at least one of the following: 
a) Peripheral oedema 
b) Raised venous pressure 
c) 
Inferior vena cava diameter >20mm 
4. Cardiac dysfunction documented by at least one of the following in the previous three years: 
a) A LVEF<50%or a report of moderate or severe left ventricular dysfunction 
b) Left atrial diameter >3.0cm/m2 (body surface area) 
c) 
Elevated BNP or NT-proBNP 
i. BNP >150ng/L if in sinus rhythm or >450ng/L if not in sinus rhythm 
ii. NT-proBNP >500ng/L if in sinus rhythm and >1500ng/L if not in sinus rhythm 
5. Able and willing to provide written informed consent for the randomised trial 
 
For Randomisation 
1. Serum potassium >5.0mmol/L 
• Patients with a serum potassium >5.0mmol/L may be randomised immediately unless they 
have severe hyperkalaemia requiring, in the investigators opinion, intravenous treatment or a 
potassium binding agent. 
• Severe hyperkalaemia should be managed according to the UK Renal Association guidelines 
of 2014 (https://renal.org/wp-content/uploads/2017/06/hyperkalaemia-guideline-1.pdf). 
Participants may be reconsidered for the trial once such interventions are no longer considered 
necessary. 
• Patients with a serum potassium ≤5.0mmol/L should be initiated on spironolactone or have the 
dose increased up to 100mg/day and randomised only if serum potassium exceeds 5.0mmol/L. 
Those intolerant of or unwilling to take spironolactone should be offered eplerenone titrated to 
a maximum dose of 50mg/day. 
• A run-in period of up to 35 days is permitted (the run-in period will usually occur during 
hospitalisation or a course of day-care or intense management). 
2. After ingestion of a test-dose of patiromer,  
a) the patient is willing to continue in the trial 
b) the investigator considers the patient can follow instructions on preparing patiromer 
 
7.2 
Exclusion criteria 
 
For the Screening Log & Registry 
- None 
 
For the Randomised Trial 
1. eGFR <30ml/minute/1.73m2 (if clinically appropriate, the dose of other agents such as loop 
diuretics, ACE inhibitors, angiotensin receptor blockers, beta-blockers and sacubitril-valsartan may 
be adjusted to allow eGFR to increase) 
2. Systolic BP <90mmHg 
3. Uncorrected valve disease as the main cause of heart failure in the investigators opinion 

 
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4. Hepatic encephalopathy or known severe liver disease 
5. Infection currently requiring intravenous antibiotics or temperature >38oC 
6. Myocardial ischaemia currently requiring intravenous therapy or coronary intervention in the 
previous 7 days 
7. Arrhythmia requiring urgent cardioversion or intravenous therapy 
8. Severe hyperkalaemia requiring, in the investigator’s opinion, intravenous treatment or a 
potassium-binding agent 
9. The patient is already receiving a potassium-binding agent (this includes patiromer) or the treating 
physician has already decided to use one 
10. Known hypersensitivity to patiromer or any of the excipients 
11. Known intolerance to both spironolactone and eplerenone (not including hyperkalaemia) 
12. Known hypersensitivity to the active substance or excipients of spironolactone and eplerenone as 
per the current Summary of Product Characteristics (Note: actual medicine supplied to participants 
will vary depending on local arrangements) 
13. Women of childbearing potential. For the purposes of this trial this means any woman aged <60 
years unless they have had a hysterectomy or bilateral tubal ligation or are aged >50 years and 
have undergone the menopause and had  amenorrhea for at least 3 years 
14. Patients taking the following systemic medicines: 
• strong inhibitors of CYP 3A4 (e.g. itraconazole, ketoconazole, ritonavir, nelfinavir, 
clarithromycin, telithromycin and nefazodone) 
• Lithium 
• Tacrolimus or Cyclosporin 
15. The combination of an angiotensin converting enzyme (ACE) inhibitor and an angiotensin receptor 
blocker (ARB) 
16. Rare hereditary problems of galactose or fructose intolerance, Lapp lactase deficiency or glucose-
galactose malabsorption 
17. Known amyloid heart disease 
18. Cancer likely to cause death or major disability within the next three years 
19. Patients requiring mechanical circulatory support, and 
20. Patients who do not develop a serum potassium >5.0mmol/L despite receiving up to 100mg/day of 
spironolactone or 50mg/day of eplerenone during the run in phase. 
 
Potentially suitable patients may be considered for the randomised controlled trial as soon as 
arrhythmia, infection, renal dysfunction, hypotension etc. have been corrected to the satisfaction of the 
investigator and the above noted exclusion criteria no longer exist. 
 
Serum magnesium will be measured during the trial and magnesium supplements given if serum 
magnesium drops below 0.75mmol/L (1.5mEq/L or 1.8mg/dL). Accordingly, hypo-magnesaemia is not 
an exclusion criterion for participation. Potassium sparing diuretics (amiloride or triamterene) other 
than MRA and potassium supplements should be withdrawn unless the patient is hypokalaemic and 
as soon as hypokalaemia resolves to allow higher doses of MRA to be used.  
 
Co-enrolment in observational studies of routine clinical practice is permitted. Sponsors and CIs must 
be contacted to discuss in advance. 
Co-enrolment in interventional observational studies or randomised trials requires agreement between 
the Chief Investigators, Trial Steering Committees and Sponsors for the respective studies/trials. The 
following issues will be taken into account when making this decision: 
• 
Participant burden: does participation in both studies increase the number of participant visits, pill-
burden or other activity and if so, by how much? 
• 
Potential interactions between investigational medicinal products that might affect participant 
safety 
• 
Study design: co-enrolment into double-blind trials should generally be avoided 
• 
Endpoints: could participation in both studies influence the outcome of either study? 

 
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8. TRIAL PROCEDURES 
 
Patients with worsening heart failure, either in hospital or in the community, will be identified. Limited 
information (as advised by the HRA) will be retained in a screening log for those who do not consent or 
who are not approached for the registry. Patients who consent to participate in the registry will have 
personal identifiers and further medical information collected and will be followed-up, long-term, through 
linkage to their electronic medical records. Registry participants will be asked to take part in the 
randomised trial if they fulfil all of the eligibility criteria. Consenting patients who have a serum potassium 
>5.0mmol/L will be randomised (after an 8.4g test-dose of patiromer to ensure participant acceptance; 
note - there is no requirement for the participant to consume the full dose and failure to do so will not 
constitute a protocol deviation) either to patiromer or not (open-label). If serum potassium is <5.0mmol/L, 
MRA will be initiated or increased to target doses for a “run-in” period of up to 35 days. If serum 
potassium increases to >5.0mmol/L, the participant may be randomised. Those who do not develop 
hyperkalaemia despite receiving the run-in target dose of MRA within 35 days of enrolment are not 
eligible for randomisation and will return to standard care. 
 
 
 

 
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8.1 
Schedules of Procedures 
 
8.1.1 
Schedule of Procedures for Screening Log (-00), the Registry (-0) and Randomised Trial 
(up to 60 days) 
 
 
Mostly in hospital / day-care 
Majority of care at 
follow-up in clinic 
Visit  
-00 
-0 
0 
RI 
R 
T1 
T2 
T3 
T4 
T5 
T6 
Days 
 
 
 
-X 
1 
3 
5 
7* 
14 
30 
60 
Window +/- days 
 
 
NA 
35 
1 
1 
2 
3 
5 
10 
14 
Consent 
 
X 
X 
 
 
 
 
 
 
 
 
History 
X 
X 
 
 
 
 
 
 
 
 
 
Frailty Scale 
X 
(X) 
 
 
 
 
 
 
 
 
 
Symptoms/NYHA 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
PGA 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
CV Therapy 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Non-CV Med♦ 
 
X 
 
 
X 
 
 
X 
 
 
X 
Height 
X 
X 
 
 
X 
 
 
X 
 
 
X 
Weight 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X* 
 
X 
X* 
X 
X 
X* 
X 
X 
X* 
Physical Exam 
 
X 
 
 
X 
 
 
X 
 
 
X 
Oedema Grade 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Orthopnoea Test 
 
X 
 
 
X 
 
 
X 
 
 
X 
ECG trace 
 
X 
 
 
 
 
 
 
 
 
 
Electronic ECG 
 
Opt 
 
 
X 
 
 
X 
 
 
X 
Echocardiogram 
X 
Opt 
 
 
 
 
 
 
 
 
Opt 
Haematology 
 
X 
 
 
X 
 
 
X 
 
 
X 
Biochem Safety 
X 
 
 
X 
 
X 
X 
 
X 
X 
 
Biochem+ 
 
X 
 
 
X 
 
 
X 
 
 
X 
Spot Urine 
 
X 
 
 
X 
 
 
X 
 
 
X 
Biomarkers 
 
Opt 
 
 
X 
 
 
X 
 
 
X 
KCCQ/EQ5D 
 
Opt 
 
 
X 
 
 
X 
 
 
X 
Walk Test @ 
 
Opt 
 
 
X 
 
 
X 
 
 
X 
Titration/Compliance 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
AE 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
SAE 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Dispensing  
 
 
 
X 
X 
 
 
X 
 
 
X 
-00 = screening log; -0 = consented registry; 0 = consent for trial; RI = run-in phase awaiting rise in potassium. R = randomisation.  
T = titration visit. Day 7* = day 7 or discharge if sooner. EOS = end of trial. CV = cardiovascular. X* vital signs measured during orthopnoea 
(orthop) test. Opt = optional  
Local Haematology = Haemoglobin, Haematocrit, White Cell Count, Neutrophils, Lymphocytes.  
Local Biochemistry = Sodium, Potassium, Urea, Creatinine.  
Local Biochemistry+ = Sodium, Potassium, Magnesium, Bicarbonate, Calcium, Phosphate, Urea, Creatinine, Bilirubin, Transaminases, 
Alkaline Phosphate, Albumin.  
KCCQ = Kansas City Cardiomyopathy Questionnaire. EQ5D = EuroQol 5-dimension questionnaire. NYHA = New York Heart Association 
functional class. PGA = patient global assessment on a 7-point scale ranging from much worse to much better. 
@ for patients who feel unable to do these tests, the reason will be recorded. AE / SAE = adverse / serious adverse events. 
♦ includes vaccine history 
 
 

 
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8.1.2 
Schedule of Procedures for the Randomised Trial (long-term follow-up) 
 
 
Majority of care at follow-up in clinic 
Visit 
T7 
T8 
T9 
T10 
T11 
T12 
T13 
T14 
TX 
EOS 
Months 
3 
6 
9 
12 
15 
18 
21 
24 
+3 
 
Window +/- days 
14 
14 
14 
14 
14 
14 
14 
14 
14 
NA 
Consent 
 
 
 
 
 
 
 
 
 
 
History 
 
 
 
 
 
 
 
 
 
 
Symptoms/NYHA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PGA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CV Therapy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Non-CV Med 
 
X 
 
X 
 
 
 
X 
 
 
Height 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X* 
X 
X* 
X 
X 
X 
X* 
X 
X 
Physical Exam 
 
 
 
 
 
 
 
 
 
 
Oedema Grade 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Orthopnoea Test 
 
X 
 
X 
 
 
 
X 
 
 
ECG trace 
 
 
 
 
 
 
 
 
 
 
Electronic ECG 
 
X 
 
X 
 
 
 
X 
 
 
Echocardiogram 
 
Opt 
 
Opt 
 
 
 
Opt 
 
 
Haematology 
 
X 
 
X 
 
 
 
X 
 
 
Biochem Safety 
X 
 
X 
 
X 
X 
X 
 
X 
X 
Biochem+ 
 
X 
 
X 
 
 
 
X 
 
 
Spot Urine 
 
X 
 
X 
 
 
 
X 
 
 
Biomarkers 
 
X 
 
X 
 
 
 
X 
 
 
KCCQ/EQ5D 
 
X 
 
X 
 
 
 
X 
 
 
Walk Test @ 
 
X 
 
X 
 
 
 
X 
 
 
Titration/Compliance 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE/ SAE 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispensing  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
T = titration visit. TX = repeat visits every 3 months for dispensing and titration. EOS = end of trial. CV = cardiovascular. X* vital signs 
measured during orthopnoea (orthop) test. Opt = optional  
Local Haematology = Haemoglobin, Haematocrit, White Cell Count, Neutrophils, Lymphocytes.  
Local Biochemistry = Sodium, Potassium, Urea, Creatinine.  
Local Biochemistry+ = Sodium, Potassium, Magnesium, Bicarbonate, Calcium, Phosphate, Urea, Creatinine, Bilirubin, Transaminases, 
Alkaline Phosphate, Albumin.  
KCCQ = Kansas City Cardiomyopathy Questionnaire. EQ5D = EuroQol 5-dimension questionnaire. NYHA = New York Heart Association 
functional class. PGA = patient global assessment on a 7-point scale ranging from much worse to much better. 
@ for patients who feel unable to do these tests, the reason will be recorded. AE / SAE = adverse / serious adverse events. 
 
Key visits for the assessment of clinical efficacy and endpoints are 
• 
Day 7 (+/-3 days or discharge from hospital or day-care) 
• 
Day 60 (+/-14 days) 
• 
And at 6 months (+/-14 days) months,12  months (+/- one month) and 24 months (+/- one month)  
 
Additional visits are required to assess symptoms and safety (serum potassium/magnesium, renal 
function, blood pressure). Patients may be evaluated in the community or clinic setting as convenient but 
will have to attend hospital visits to obtain trial IMP (patiromer, spironolactone/eplerenone).  
 
In addition, if doses of patiromer or MRA are changed, blood pressure and serum electrolytes and 
creatinine should be re-checked both after 7-12 days and after 30-45 days. If the patient becomes acutely 
unwell for any reason, blood pressure, serum electrolytes and creatinine should be re-checked. Serum 
potassium should also be checked within 48 hours of stopping patiromer. 

 
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8.2 
Recruitment 
 
8.2.1 
Participant identification 
 
Potential participants (including in-patients, clinic patients and community services)will be known to 
the heart failure team (for example doctors, specialist heart failure nurses, heart failure pharmacists) 
directly involved in their care because patients with worsening heart failure and peripheral oedema 
require intensification of treatment. 
 
The clinical team directly involved with the care of potential participants, who will usually also be an 
investigator or close colleague, will notify the research team.   
 
In accordance with Health Research Authority guidance, a de-identified screening log of all potential 
participants will be kept (Section 7.1 of CTIMP Protocol Development Tool: “... give details … including 
information to be collected regarding participants who are screened … but not randomised … for 
reporting the generalisability of the results… including the reason not eligible for trial participation, or if 
they are eligible but declined”). 
 
The eligibility criteria for the registry and trial should be available in the existing medical record 
provided the patient is being managed according to existing guidelines. 
 
8.2.2 
Screening 
 
Patients will be brought to the attention of the investigators by clinical heart failure services. 
 
8.2.3 
Payment  
 
If patients are required to make visits in addition to normal clinical care, reasonable travel expenses will 
be reimbursed. No payment is made to patients for participation in this trial. 
 
8.3 
Consent  
 
In accordance with Health Research Authority guidance, a de-identified register of all potential 
participants will be kept (Section 7.1 of CTIMP Protocol Development Tool: “.give details including 
information to be collected regarding participants who are screened but not randomised or reporting 
the generalisability of the results including the reason not eligible for trial participation, or if they are 
eligible but declined”).  
 
Informed consent for the registry and trial will be obtained by medical staff or delegated support staff 
with appropriate training. A medical practitioner, either the principal investigator or delegated medical 
co-investigator, will verify that all inclusion/exclusion criteria have been met. 
 
Potential registry participants with worsening heart failure, who fulfil the inclusion criteria, will be 
invited to read an ethics committee-approved participant information sheet and provide written consent 
(Consent Form 1) for inclusion in the registry. We will ask patients who participate in the registry 
whether they are happy to be contacted about future (hypothetical) research, either observational or 
randomised trials. This may include sending questionnaires directly to participants. However, 
enrolment in further trials would only be done in collaboration with local investigators and care-teams. 
Consent will specifically be sought for the collection and use of routine clinical data for research 
purposes and for long-term follow-up through the participant’s electronic medical record (e.g. Hospital 
Episode Statistics). 
 
Potential trial participants will be identified from amongst those consenting to the registry. Registry 
participants who fulfil the trial’s inclusion/exclusion criteria will be invited to read an ethics committee-

 
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approved participant information sheet and provide written consent (Consent Form 2) for the trial 
before any research-related procedures are done.  
 
Following written consent, each signature will be dated by the signatory, the original retained in the 
site file, one copy provided to the patient/relative, one copy inserted into the patient’s medical notes 
and a scanned electronic copy uploaded via the trial web portal and stored at the University of 
Glasgow (Glasgow Clinical Trials Unit). 
 
Patients will be given enough time to consider whether or not they wish to participate and to discuss 
participation with relatives and friends. Most patients are likely to be in hospital or under frequent 
outpatient review. Patients may be consented and included in the registry within 24 hours but should 
have at least 24 hours to consider whether they should participate in the randomised trial.  
 
Sites will be required to scan and upload signed consent forms including participants’ names into a 
secure trial database for each consented participant via a secure trial web portal. Participants will be 
asked to consent to this and for their personal information, including data of birth, address and NHS 
identification number, to be held securely by the Glasgow Clinical Trials Unit. The central storage of 
consent forms will facilitate remote monitoring of participants’ consent by the Sponsor’s monitors who 
will be given secure access to view the consent forms including the patient’s name. 
 
All personal data will be encrypted in a separate linked database that is not accessible to individuals 
working on the research database containing clinical data for the registry and trial. All personal details 
will be managed according to ISO 27001:2013 compliant standard operating procedures. These data 
are required for linkage to electronic health records. 
 
To comply with the Welsh Language Act 1993, the Participant Information Sheets and Consent forms 
will be translated into Welsh or provided bilingually where this is requested by a participant at a 
research site. 
 
Where a participant consents but subsequently becomes incapacitated and is unable to take oral 
medication or where the incapacity puts medication compliance in doubt, patiromer will be stopped 
and the dose of MRA adjusted in accordance with standard care. Participants will be classified as 
withdrawn from trial treatment but continue to be followed through their routine medical records 
(including electronic records) but will not have to undergo any further protocol-specified assessment. 
 
Additional consent provisions for collection and use of participant data and biological 
specimens in ancillary studies, if applicable 
 
All patients enrolled in the registry will be asked to provide a blood sample that will be stored in a 
central repository and shared with academic or commercial partners for this and future research into 
heart failure (which may include markers of heart, vascular, renal, endocrine, skeletal muscle, 
pulmonary, hepatic or nervous system dysfunction). The consent will make it clear that this potentially 
includes genetic testing.  
 
For the registry, the blood sample for central storage is optional. Samples will be stored locally in a 
freezer at -20oC or cooler and transferred periodically (at least annually) to a central laboratory.   
 
Patients in either the registry or trial may decline to have genetic material stored. Results of genetic 
tests will not be linked to personally identifiable data. Participants will be informed that they will not 
receive the results of such genetic tests. Should genetic testing identify a possible benefit for clinical 
practice, the findings will be published to inform debate within the NHS. 
 
Stored samples will be barcoded. Investigators may convey information to the CTU indicating that a 
patient wishes their samples to be disposed of, in which case the samples (including any shared with 

 
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partners) will be identified and safely disposed of. The patient may also request that the results of any 
research biomarkers or genetic tests be deleted from the database. This does not apply to blood tests 
required to assess safety or efficacy prior to the date of withdrawal of consent. The Biobank, 
laboratories and research partners will not be able to trace results back to patient-identifiable data. 
Patients will be informed of this during the consenting procedure. 
 
8.4 
The randomisation scheme 
 
Eligible and consenting patients will be randomised on a 1:1 basis to the two groups using a mixed 
randomisation/minimisation algorithm that includes trial site, eGFR group (above or below 
45ml/minute/1.73m2) and systolic BP (above or below 110mmHg). 
 
8.4.1 
Method of implementing the randomisation/allocation sequence 
 
All patients included in the registry or trial will receive a participant registration number that will be used to 
identify the participant throughout the registry and trial. 
 
Randomisation using a web-based randomisation system will be provided by Glasgow CTU. The 
investigator will provide the participant identifier and minimisation information and, if eligible, the 
randomisation group will be allocated. 
 
New participant randomisation e-mail confirmations will be sent to the research nurse(s), investigator 
and pharmacy staff as required.  
 
Trial participants will be provided with a patient alert card providing details of trial participation which they 
will be asked to carry at all times.   
 
8.5 
Blinding 
 
Both patiromer and MRA (spironolactone or eplerenone) will be administered open-label. 
Endpoints will be evaluated blinded to treatment allocation by a clinical endpoints committee. 
 
8.6 
Emergency Unblinding 
 
Not applicable. Electrolyte abnormalities, hypotension and renal dysfunction should be managed 
according to guidelines and best clinical practice.  
 
 

 
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8.7 
Data Collection 
 
MR = from Medical Records. If not in the existing record, variables will be recorded as “not available” 
X = a test, measurement or question that research staff will do/ask if not in the existing medical record; 
MR/X = either approach to obtaining data is possible; shaded cells = data not collected in this period 
To be read in conjunction with schedule of assessments and narrative subsequent to this table. 
 
 
Randomised Trial 
 
Screening 
Log # 
Registry 
Baseline 
60 Day 
Long-
Term 
Fulfil Entry Criteria 
MR 
MR 
MR/X 
 
 
Willingness to 
Participate in Research 
X 
X 
 
 
 
Year of Birth 
MR 
 
 
 
 
Date of Birth 
 
MR 
 
 
 
Sex 
MR 
 
 
 
Ethnicity 
 
MR/X  
 
 
 
Smoking History 
 
MR/X 
 
 
 
Alcohol Intake 
 
MR/X 
 
 
 
Contact Details 
 
MR/X 
 
 
 
Hospitalisation Status 
MR 
MR/X 
MR/X 
 
 
Aetiology 
MR 
MR/X 
 
 
 
Co-morbidity 
 
MR/X 
 
 
 
Duration of Heart Failure 
MR/X 
 
 
 
Causes of Worsening 
 
MR/X 
 
 
 
Frailty Score 
X 
(X) 
 
 
 
Symptom Severity 
 
X 
X 
X 
X 
NYHA Class 
 
X 
X 
X 
X 
PGA 
 
 
X 
X 
X 
CV Therapy  
MR (limited) 
MR/X 
MR/X 
MR/X 
MR/X 
Non-CV Therapy  
 
MR/X 
MR/X 
MR/X 
MR/X 
Height 
MR 
X 
X 
X 
 
Weight 
MR 
X 
X 
X 
X 
Vital Signs 
MR (limited) 
X 
X 
X 
X 
Physical Exam 
 
X  
X 
X 
X 
Orthopnoea Test # 
 
X 
X 
X 
X 
ECG 
 
MR/X 
X 
X 
X 
Echocardiogram or 
other imaging test 
MR 
(anytime) 
MR/X  
(in prior 3 yrs) 
 
 
Haematology 
 
MR 
MR/X 
MR/X 
MR/X 
Biochemistry 
 
MR 
• 
Sodium 
• 
Potassium 
• 
Creatinine 
• 
Urea 
MR 
• 
Full Panel 
MR/X 
MR/X 
MR/X 
Spot Urine 
 
MR 
X 
X 
X 
Biomarkers  
(Core Lab) 
 
X (optional) 
X 
X 
X 
KCCQ 
 
X (optional) 
X 
X 
X 
EQ5D 
 
X (optional) 
X 
X 
X 
10 metre Walk Test 
 
X (optional) 
X 
X 
X 
Events & SAE 
 
 
X 
X 
X 
# See HRA guidance in section 7.1.1. 

 
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8.7.1 
Screening Log 
 
If the patient provides consent for the registry skip this step as the information will also be 
collected in the consented registry 
 
Only complete the screening log for patients who fulfil the inclusion criteria for the registry and 
have either not been approached or have declined to participate in the consented registry. Recording 
a limited amount of information on unconsented patients is recommended by the Health Research 
Authority (see section 7.1.1) in order to gauge how representative registry and trial participants are of 
the population encountered in clinical practice. Only existing data from the medical record should be 
used for the screening log.   
 
Eligibility for Screening Log (no linkage to electronic medical records and no follow-up) 
1. 
≥ 18 years 
2. 
Clinical diagnosis of heart failure (new onset or decompensated chronic heart failure) 
3. 
Planned to receive ≥80mg/day of furosemide or equivalent* (IV, SC, or oral) in the next 24 hours. 
4. 
Worsening symptoms & signs of congestion in the prior 10 days requiring at least one of the 
following: 
a) hospitalisation 
b) administration of intravenous diuretics 
c) 
an increase in the dose of loop diuretic by at least 40mg/day of furosemide (or equivalent**) 
to a total of at least 80mg/day of furosemide (or equivalent*) 
d) addition of a thiazide diuretic to treatment with a loop diuretic 
 
* a dose of 80mg/day of furosemide is considered equivalent to 2mg/day of bumetanide or 
20mg/day of torasemide. 
**a dose of 40mg/day of furosemide is considered equivalent to 1mg/day of bumetanide or 10 
mg/day of torasemide. 
  
Willing to Participate in Research 
Was the patient asked to give consent to participate in the registry: 
• 
If no, why not? (mark all that apply: Patient too frail; Cognitive Dysfunction; Insufficient research 
time; Care-team considered participation inappropriate; other (specify)) 
• 
If yes, but refused, what was the reason given? (mark all that apply: not interested; too unwell; too 
old; too frightened; concerned about personal privacy; other (specify)) 
 
Demographics 
• 
Year of Birth and Sex 
 
Hospital Status:  
• 
In-Patient: Yes/No 
 
Aetiology of Heart Failure 
• 
Yes/No (mark all that apply): Ischaemic Heart Disease; Idiopathic Dilated Cardiomyopathy; 
Hypertension; Mitral Valve Disease; Aortic Valve Disease; Hypertrophic Cardiomyopathy; Amyloid 
Heart Disease; Uncertain Cause; Atrial Fibrillation; Other (text field) 
• 
Primary Cause – pick from above list 
 
Duration of Heart Failure 
(Defined either as initiation of loop diuretic therapy or first hospitalisation for heart failure) 
• 
Choose one: <1 month; 1-6 months, >6-12 months, >12-18 months, >18 months 
 
 

 
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Assessment of Frailty (only needs to be completed if not done on screening log) 
• 
Using the Clinical Frailty Scale developed for the Canadian Study on Health & Aging by Dalhousie 
University, investigators will be asked to rate the severity of frailty on a scale of 1 (least severe) to 
9 (most severe), giving a) the best score in the previous month and b) the current score.  (See 
https://www2.gov.bc.ca/assets/gov/health/practitioner-pro/bc-guidelines/frailty-full_guideline.pdf.) 
 
Concomitant Cardiovascular Therapy (if yes - names from a drop-down list) on day of 
assessment 
• 
Loop Diuretic   
 
 
 
 Name, Route and Total Daily Dose 
• 
MRA   
 
 
 
-  
 Name and Total Daily Dose 
• 
ACE Inhibitor  
 
 
 
- Yes/No 
• 
Angiotensin Receptor Blocker 
 
- Yes/No 
• 
Angiotensin-Neprilysin Inhibitor 
 
- Yes/No 
• 
Beta-blocker  
 
 
 
- Yes/No 
• 
Digitalis glycoside 
 
 
 
- Yes/no 
• 
Ivabradine 
 
 
 
 
- Yes/No 
• 
Thiazide 
 
 
 
 
- Yes/No 
• 
Potassium Sparing Diuretic other than MRA - Yes/No 
• 
Potassium Binding Agent 
 
 
- Yes/No 
• 
Devices 
 
 
 
 
 Pacemaker, ICD, CRT-D, CRT-P, MCS 
• 
NSAIDs other than aspirin 
 
 
- Yes/No 
• 
Insulin  
 
 
 
 
- Yes/No 
• 
Other Hypoglycaemic Therapy 
 
- Yes/No 
 
Most recent result from patient records (dates not required) 
• 
Height and weight from case notes or state “not available” (to calculate eGFR) 
• 
Systolic Blood Pressure 
• 
Serum Sodium, Potassium, Creatinine, Urea 
 
Echocardiogram (most recent) 
• 
Test Available Yes/No 
• 
Left Ventricular Function 
• 
Left ventricular ejection fraction 
and/or 
• 
Systolic Dysfunction – None, Mild, Moderate, Severe, Don’t Know  
and/or 
• 
HFrEF, HFmrEF, HFpEF or Don’t Know 
• 
Left Atrial Enlargement 
• 
None, Mild, Moderate, Severe, Don’t Know 
• 
Valve Disease 
• 
Mitral Regurgitation (none / mild / mod. / severe / or state “not available”) 
• 
Aortic Stenosis (none / mild / mod. / severe / or state “not available”) 
• 
Tricuspid Regurgitation (none / mild / mod. / severe / or state “not available”) 
 
8.7.2 
Consented Registry 
 
Willing to Participate in Future Research? 
 
Further observational research: yes/no. If not, why not? Lack of interest; Too many requests; 
Concerns about personal privacy; other (specify) 
 
Randomised trials: yes/no. If not, why not? Not interested; Too unwell; Too old; Too Frightened; 
Concerned about personal privacy: Other (specify) 

 
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Demographics& Contact Details 
• 
Date of birth 
• 
Sex 
• 
Ethnic group: using Office of National Statistics Classification 
• 
https://www.ons.gov.uk/peoplepopulationandcommunity/culturalidentity/ethnicity/articles/ethnicityandnationalidentit
yinenglandandwales/2012-12-11 
• 
Smoking status: current/ex/never 
• 
Alcohol intake: none, occasional, frequent, heavy 
• 
Unique identifier for medical record linkage (e.g. NHS number in England & Wales, Community 
Health Index (CHI) in Scotland, Health & Social care number in N. Ireland) 
• 
Name, Home Address & Postcode 
 
Hospital Status:  
• 
In-Patient: Yes/No 
• 
If yes,  
o Date of admission 
o Is heart failure the cause of or major contributor to this admission? Yes/No 
• 
If no,  
o Date of last discharge for any reason 
o Date of last discharge for an admission where heart failure was the cause or major 
contributor 
 
Aetiology of Heart Failure 
• 
Yes/No (mark all that apply): Ischaemic Heart Disease; Idiopathic Dilated Cardiomyopathy; 
Hypertension; Mitral Valve Disease; Aortic Valve Disease; Hypertrophic Cardiomyopathy; Amyloid 
Heart Disease; Uncertain Cause; Atrial Fibrillation; Other (text field) 
• 
Primary Cause – pick from above list 
 
Prior Medical History and Co-morbidity 
• 
Yes/No (mark all that apply): Coronary Artery Disease (and, if yes, further specify if prior 
Myocardial Infarction, Percutaneous Coronary Intervention, Coronary Bypass Surgery or Other 
evidence), Diabetes, Atrial Fibrillation, Stroke, Severe Cognitive Dysfunction, Chronic Lung 
Disease, Cancer (and, if yes, further specify if  a) in remission or cured b) locally invasive c) 
metastatic d) has required chemotherapy at any time e) has required radiotherapy to thorax at any 
time), Other (text field) 
o Other co-morbidities will be ascertained from other fields, including anaemia, iron 
deficiency, renal dysfunction and valve disease   
 
Duration of Heart Failure 
(Defined either as initiation of loop diuretic therapy or first hospitalisation for heart failure) 
• 
Choose one: <1 month; 1-6 months, >6-12 months, >12-18 months, >18 months 
 
Causes of Worsening Heart Failure 
• 
Yes/No (mark all that apply): Worsening cardiac function, worsening renal function, poor dietary 
compliance, poor medicines compliance, anaemia, infection, recent myocardial ischaemia or 
infarction, new-onset atrial fibrillation, other arrhythmia, hypertension, iatrogenic (e.g. NSAIDs), 
other (specify) 
• 
Primary Cause – pick from above list 
 
Symptoms 
• 
NYHA Class 
• 
Symptom severity (see appendix for questionnaire) 

 
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Assessment of Frailty (only needs to be completed if not done on screening log) 
Using the Clinical Frailty Scale developed for the Canadian Study on Health & Aging by Dalhousie 
University, investigators will be asked to rate the severity of frailty on a scale of 1 (least severe) to 9 
(most severe), giving a) the best score in the previous month and b) the current score. (See 
https://www2.gov.bc.ca/assets/gov/health/practitioner-pro/bc-guidelines/frailty-full_guideline.pdf.) 
 
Concomitant Cardiovascular Therapy (if yes - names from a drop-down list) on day of 
assessment 
• 
Loop Diuretic   
 
 
 
- Name, Route and Total Daily Dose 
• 
MRA   
 
 
 
-  
Name and Total Daily Dose 
• 
ACE Inhibitor  
 
 
 
- Name and Total Daily Dose 
• 
Angiotensin Receptor Blocker 
 
- Name and Total Daily Dose 
• 
Angiotensin-Neprilysin Inhibitor 
 
- Name and Total Daily Dose 
• 
Beta-blocker  
 
 
 
- Name and Total Daily Dose 
• 
Digitalis glycoside 
 
 
 
- Name and Total Daily Dose 
• 
Ivabradine 
 
 
 
 
- Name 
• 
Thiazide 
 
 
 
 
- Name 
• 
Potassium Sparing Diuretic other than MRA - Name 
• 
Potassium Binding Agent 
 
 
- Name 
• 
Lipid lowering agents  
 
 
- Name 
• 
Antiplatelet 
 
 
 
 
- Name (more than one possible) 
• 
Anticoagulant  
 
 
 
- Name 
• 
Devices 
Pacemaker, ICD, CRT-D, CRT-P, MCS 
 
Current Concomitant Non-Cardiovascular Therapy (if yes - names from a drop-down list) 
• 
NSAIDs other than aspirin 
 
 
- Name 
• 
Insulin  
 
 
 
 
- Yes/No 
• 
Other Hypoglycaemic Therapy 
 
 Name(s) 
• 
Antibiotics 
 
 
 
 
- Name 
• 
Oral Steroids  
 
 
 
- Name 
• 
Inhaled Medicines 
 
 
 
- Name 
• 
Iron (oral or IV) 
 
 
 
- Name 
• 
Treatments for indigestion 
 
 
- Name 
• 
Other Medicines 
 
 
 
- Name 
 
Taken in the prior month for those not currently receiving 
• 
MRA 
 
Yes/No 
• 
ACE Inhibitor  
 
 
 
- Yes/No 
• 
Angiotensin Receptor Blocker 
 
- Yes/No 
• 
Angiotensin-Neprilysin Inhibitor 
 
- Yes/No 
• 
Beta-blocker  
 
 
 
- Yes/No 
• 
Digitalis glycoside 
 
 
 
- Yes/No 
• 
Ivabradine 
 
 
 
 
- Yes/No 
• 
Thiazide 
 
 
 
 
- Yes/No 
 
Taken in the prior 12 months 
• 
Oral iron   
 
 
Yes/No 
• 
IV iron  
 
 
 
Yes/No; if yes, number of times 
 
Vaccine and COVID History 

 
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• 
History of COVID vaccination 
• 
COVID vaccination details 
• 
Other vaccination details (including but not limited to influenza, pneumococcal, and shingles 
vaccination) 
Height & Weight 
• 
Height to the nearest centimetre 
o For patients who cannot stand, patient-reported height should be reported 
o Height will be reported as measured or patient-reported 
• 
Weight to nearest 100g in light clothing, empty pockets and without shoes 
o For patients who cannot be weighed, patient-reported weight should be recorded 
o Weight will be reported as measured or patient-reported 
 
Vital Signs (this should be done as part of the orthopnoea test at this visit) 
Heart rate and blood pressure should be measured with the patient sitting comfortably with the back 
supported. Blood pressure and heart rate should be measured using an automated 
sphygmomanometer. Sphygmomanometers should be calibrated regularly according to local standard 
operating procedures. 
 
Oedema Grade  
• 
Swelling of legs / ankles (mild = ankle, moderate = between ankle and knee, severe = above knee) 
• 
Left and right ankle circumferences (cm) 
 
Orthopnoea Test 
Start with patient sitting up supported by pillows. . Patients may be sat in a chair. Measure heart and 
respiratory (for at least 30 seconds) rate and blood pressure. Then lie the patient flat with one pillow 
for comfort for up to 10 minutes. Repeat measurements of heart and respiratory rate and blood 
pressure. If the patient must sit up sooner than 10 minutes, then help them and measure vital signs as 
soon as possible afterwards. If a patient feels unable to lie flat, please record this and omit the test. If 
the test is not done for another reason, record heart and respiratory rate and blood pressure and 
record that the test was not done although you considered the patient might have been able to do it. 
Record: 
• 
Time (up to 600secs) 
• 
Heart Rate (bpm) before and after 
• 
Resp. Rate (rpm) before and after 
• 
Systolic Blood Pressure before and after 
• 
Diastolic Blood Pressure before and after 
 
Electrocardiogram 
Record the following from the most recent electrocardiogram 
• 
Ventricular Rate 
• 
Rhythm 
o Sinus Rhythm 
o Atrial Fib. 
o Paced 
o Other 
• 
PR Interval (if available) 
• 
QRS Duration 
o If QRS duration is >140msec does this reflect Left or Right Bundle Branch Block or Neither 
• 
QT Duration (uncorrected) 
 

 
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Haematology (most recent test, preferably from electronic records rather than case notes; date not 
required) 
• 
Haemoglobin, Mean Corpuscular Haemoglobin Concentration (MCHC), White Blood Cell, 
Neutrophil and Lymphocyte Counts 
 
Biochemistry(**most recent test**, preferably from electronic records rather than case notes, dates 
not required, all results do not need to come from a single blood sample or date; state not available if 
no record found) 
• 
Serum Sodium, Potassium, Bicarbonate, Calcium, Phosphate, Urea, Creatinine, Bilirubin, alanine 
and aspartate aminotransferase, Alkaline Phosphate, Albumin, Magnesium. 
• 
The following if done in the previous two years only (low availability anticipated) 
o Plasma Brain Natriuretic Peptide (BNP) or NT-proBNP 
o Serum iron, transferrin saturation, ferritin 
o Urine for albumin/creatinine ratio 
 
Echocardiogram (most recent test) 
• 
Test Available Yes/No 
o If yes, date  
• 
Left Ventricular Function 
• 
Left ventricular ejection fraction (provide value; may be done by an alternative imaging method for 
instance nuclear scan, magnetic resonance imaging or computed tomography) 
and/or 
• 
Systolic Dysfunction – None, Mild, Moderate, Severe, Don’t Know  
and/or 
• 
HFrEF, HFmrEF, HFpEF or Don’t Know 
• 
Left Atrial Enlargement 
• 
None, Mild, Moderate, Severe, Don’t Know 
• 
Valve Disease(may also be assessed by magnetic resonance imaging) 
• 
Mitral Regurgitation (none / mild / mod. / severe / or state “not available”) 
• 
Aortic Stenosis (none / mild / mod. / severe / or state “not available”) 
• 
Tricuspid Regurgitation (none / mild / mod. / severe / or state “not available”) 
• 
Other valve disease (none / mild / mod. / severe / or state “not available”) 
• 
Dimensions 
• 
LV end-diastolic 
• 
Left atrial dimension 
• 
Please provide video (optional) 
 
**The Following Questionnaires and Sets of Tests are Optional for The Registry** 
 
Physical Examination  
An appropriately trained health professional should measure these. If an appropriately qualified person 
is not available, then this unavailability should be recorded.  
• 
Jugular Venous Pressure (optional for registry) 
o Not visible, Normal (<4cm above sternal angle), Raised 4-10cm above sternal angle, 
Raised >10cm above sternal angle 
• 
3rd Heart Sound (optional for registry) 
o Present / Absent 
• 
Lung crepitations (optional for registry) 
o Absent, Unilateral, Bilateral Basal, Bilateral to Mid-Zone, All Lung-Fields  
• 
Hepatomegaly 
o Present / Absent 
 

 
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Biomarkers 
• 
10mL of blood taken into EDTA tubes (see laboratory manual for preparation and transport to core 
laboratory). 
• 
Sample taken (Yes/No)  
• 
If Yes, barcode 
 
Quality of Life Assessment  
• 
EQ5D 
• 
Kansas City Cardiomyopathy Questionnaire (KCCQ) 
 
Electrocardiogram (ECG) 
• 
Transmit 12-lead electrocardiogram electronically. 
 
10 metre Walk Test (in triplicate) https://www.physio-pedia.com/10_Metre_Walk_Test 
• 
Attempted (Yes/No/ If no, provide reason (many will be unable to attempt this at baseline) 
• 
Not attempted (reasons)– 
• 
patient feels unable due to a) breathlessness, b) fatigue, c) joint or muscle pains d) dizziness / 
instability e) not ambulatory (more than one may apply) 
• 
Patient feels able but unwilling 
• 
Insufficient investigator a) time, b) space, c) both 
• 
Duration 
o 1st Attempt (seconds) 
o 2nd Attempt (seconds) 
o 3rd Attempt (seconds) 
• 
After final test (this may be after one, two or three tests) 
o Breathlessness rating, Fatigue rating, Respiratory rate, Heart rate 
 
 
8.7.3 
Clinical Trial 
 
Baseline 
Data gathered for the registry may be used as the baseline data for the randomised trial providing the 
dates are the same. If the dates differ, tests as shown in the schedule of assessments should be 
repeated. In addition, the following tests and measurements are mandatory prior to randomisation: 
1. Blood collection for biomarkers 
2. EQ5D and KCCQ questionnaires 
3. Walk Tests 
4. Electronic transmission of the ECG: record and transmit 12-lead ECG to the Glasgow 
electrocardiology core laboratory. ECGs will be identified only by participant registration number. 
 
Follow-up 
Assessments will be repeated as at baseline on Days 7 and 60 and at 6, 12 and 24 months. 
 
For safety visits (in addition to those above), vital signs consist only of measurements of heart rate, 
blood pressure and oedema grade and for biochemistry only includes sodium, potassium, urea and 
creatinine. 
 
A Patient Global Assessment (PGA) which assesses the change compared to baseline will also be 
done at each follow-up visit as an assessment of symptoms. 
 
Trial assessments 
There will be two types of clinical assessments in this trial 
a) Assessments for Efficacy at 7 and 60 days and at 6, 12 and 24 months 

 
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b) Assessments for Safety at 1, 3, 5, 14, 30days and at 3, 9, 15, 18, 21, 27 months and every 3 
months thereafter until the end of the trial. 
 
Visits for assessment of efficacy require all baseline assessments to be repeated with the exception of 
demography and prior medical history. Echocardiography is optional. 
 
Visits for assessment of safety require evaluation only of symptoms, weight, concomitant 
cardiovascular therapy, severity of oedema, blood pressure and a blood test for measurement of 
serum sodium, potassium, urea and creatinine. 
 
Longer-term efficacy and safety during the randomised trial will be assessed by reports of adverse 
reactions, serious adverse events and the primary composite endpoint and its components. 
 
Participants should be encouraged at each visit to bring any remaining trial medicines (patiromer/ 
spironolactone or eplerenone).  An assessment of compliance will be made at each trial visit by 
research staff and documented in the eCRF. Unused IMP should be returned to the site pharmacy 
where it will be logged and disposed of safely. 
 
Participant retention in the randomised trial will be enhanced by regular contact with the research 
team and a “frequently asked questions & answers” section on a publicly accessible trial website. 
 
Investigators will be asked to interrogate their own hospital’s electronic record to identify 
hospitalisations and deaths for randomised patient on a quarterly basis to ensure that events that the 
participant fails to mention are recorded. 
 
Most patients will initially be hospitalised. NICE guidance recommend that patients with heart failure 
should be evaluated by an expert at least once every 6 months but patients with advanced heart 
failure require more intensive surveillance and management. Accordingly, many (more than half) of 
these evaluations would be required for routine care. 
 
Vaccine Follow-Up 
The following details will be captured at 6, 12 and 24 months: 
• 
COVID vaccination details 
• 
Other vaccination details (including but not limited to influenza, pneumococcal, and shingles 
vaccination) 
8.8 
Long term follow-up after trial completion 
 
At the end of the trial, participants will be returned to usual care as defined by local and national 
guidelines at that time. The results of the trial may of course have an impact on these guidelines and 
the future care of patients with heart failure.  
 
Patients will be followed through their electronic medical records via record linkage for up to 10 years 
after the end of the trial. This will not interfere with their routine care. 
 
Patients will be deemed lost to follow-up on the date that contact with the investigator team ceases or 
the date on which the last event is recorded in their electronic medical record, whichever is later. 
 
8.9 
Withdrawal criteria  
 
Participants may choose to withdraw at any time, either from the intervention (patiromer or MRA), the 
follow-up procedures or from follow-up through their electronic medical record. Reasons for withdrawal 
will be recorded, providing the participant agrees. Participants who withdraw from the intervention or 

 
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follow-up procedures should cease to take IMP and revert to standard-care. The costs of patiromer or 
MRA would no longer be reimbursed from the trial budget. 
 
Participants who choose to stop patiromer-IMP only should have the dose of MRA adjusted to prevent 
hyperkalaemia. Participants who choose to stop MRA-IMP only should have the dose of patiromer 
adjusted to prevent hypokalaemia. Further guidance is provided in Appendix 3. Changes in serum 
potassium and clinical status should be evaluated carefully after any dose adjustments. 
 
Participants may be withdrawn from IMP by their investigators if deemed appropriate (e.g. the 
investigator is concerned about a participant’s safety because of uncertainty about adherence to IMP). 
Safety will be assessed by research nurses and/or investigators at each visit and after the occurrence 
of each SAE/SAR. Participants who have had an SAR (e.g. a hospital admission for the management 
of hyper- or hypo-kalaemia) should be reassessed for their ability to understand and comply with IMP 
dosing instructions.  
• 
If the participant is, in the investigator’s opinion, no longer able or willing to comply with treatment 
instructions, then they should stop one or both IMP and revert to standard-care, even if they have 
not experienced an SAE or SAR.  
• 
Participants who are assigned to patiromer and who have or develop hyperkalaemia (serum 
potassium >5.0mmol/L), even if they have been withdrawn from spironolactone or eplerenone IMP, 
may continue on or restart patiromer.  
• 
For participants with recurrent (two or more within a 6 month period) or life-threatening 
hyperkalaemia, investigators should reduce the dose of spironolactone or eplerenone to a 
maximum of 25mg/day or less (this includes a zero-dose), unless in the opinion of the investigator 
the benefit/risk ratio of receiving higher doses of spironolactone / eplerenone IMPs is still believed 
to be positive (e.g. the participant’s heart failure has responded well to higher doses of 
spironolactone or eplerenone). Participants assigned to patiromer should have the doses adjusted 
to achieve a serum potassium between 4.1 to 4.9mmol/L (inclusive). 
IMP may be re-initiated at any time if the investigator believes it is safe to do so and the participant is 
willing. However, participants should continue to have their protocol-specified assessments as far as 
possible whether or not on therapy. Reasons for withdrawal will be recorded. 
 
Participants who withdraw from IMP will not be replaced. This view may be revised by the IDMC. 
 
The IDMC may recommend that the trial should be stopped for efficacy, safety or futility and will inform 
the TSC of this decision.  
 
8.10 
Storage and analysis of clinical samples 
 
10mls of venous blood will be withdrawn and collected in pre-chilled sterilins tubes containing EDTA 
and aprotonin. Blood will be centrifuged at 1500g for 20mins at 4oC. Plasma will be siphoned, 
aliquoted and stored at -20oC or cooler until transport to the central laboratory on dry ice. At the time of 
analysis plasma samples will be defrosted at room temperature and analysed in a single batch after 
400 patients have completed 60-day follow-up and at the end of the trial. Further details are provided 
in a laboratory manual. 
 
8.11 
End of trial 
 
The overall trial will be deemed complete once 750 patients have experienced a first-event. At that time, 
an end of trial date will be declared and investigators will be asked to contact all patients on or after that 
date for a final trial evaluation.  
 

 
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The 60-day outcome will be assessed after 400 patients have had their 60-day evaluation. It is anticipated 
that database lock will occur within three months and that these data will be analysed and presented 
during the course of the main trial. 
 
9. TRIAL TREATMENTS 
 
9.1 
Name and description of investigational medicinal product(s) 
 
Patiromer(as patiromer sorbitex calcium) is a non-absorbed cation exchange polymer that binds free 
potassium excreted into the gastrointestinal lumen thus increasing faecal potassium excretion and 
decreasing serum potassium concentrations.   
 
Spironolactone and eplerenone 
 
Spironolactone and eplerenone are mineralocorticoid (aldosterone) receptor antagonists (MRA) that 
block the actions of aldosterone, causing increased sodium excretion and potassium retention. They 
are both indicated for the treatment of heart failure. Spironolactone is on the World Health 
Organization's List of Essential Medicines 
 
9.2 
Regulatory status of trial medicines 
 
Patiromer: Patiromer (Veltassa®) is currently licensed in the EU and UK for treatment of 
hyperkalaemia in adults.   
 
Spironolactone and eplerenone: There are no restrictions on the brand(s) of spironolactone or 
eplerenone that may be used within the trial provided a Marketing Authorisation is held for the product 
in the UK.   
 
9.3 
Product Characteristics 
 
The sponsor will use the Summary of Product Characteristics (SmPC) for Veltassa and will select a 
reference SmPC for spironolactone and eplerenone for the Reference Safety Information from the 
following website https://www.medicines.org.uk/emc/. See Section 10 for further information.   
 
9.4 
Patiromer supplies and storage  
 
Trial sites will be supplied with Veltassa®8.4g powder for oral suspension free of charge for 
participants assigned to the intervention arm.  Patiromer will be supplied directly to participating 
pharmacies by the funder (Vifor) free of charge and will not be modified in relation to its Marketing 
Authorisation. 
 
Supplies will only be released to trial sites by the sponsor once all the appropriate regulatory and 
governance approvals are in place.  All patiromer packs must be stored in a locked, secure area with 
access limited to the Investigator and authorised site staff.  Supplies must be used as directed in the 
trial protocol and should not be supplied to any persons other than trial participants.   
 
Investigators may prescribe patiromer for participants assigned to the standard care control group if 
they believe this is in their best interests. Participants should continue to have follow-up assessments 
as described in the protocol. However, participants assigned to standard care must not receive trial 
specific supplies of patiromer-IMP. Any costs associated with patiromer treatment in the standard care 
group will not be reimbursed from the trial budget and must be met by local payers. 
 
Patiromer must be stored at the site pharmacy between 2oC and 8oC. Once dispensed for participant 
use, packs can be stored at room temperature below 25oC for up to six months. Visits are planned to 

 
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occur at no more than 3-month intervals. Supplies must not be used beyond the expiry date.  Where 
possible, supplies of patiromer will be utilised in such a way as to minimise unnecessary wastage.   
 
Further information on ordering, receipt, distribution and destruction of trial medicines is provided in 
the RELIEHF IMP Management and Accountability Manual.   
 
9.5  
Spironolactone and eplerenone supplies and storage 
 
Spironolactone and eplerenone for use in the trial will be sourced from routine NHS hospital supplies 
and supplied to participants by local investigator site pharmacies.  
 
Depending on participant dose and trial phase, site pharmacies may be required to supply 
spironolactone 25mg, 50mg and 100mg tablets and eplerenone 25mg and 50mg tablets. There is no 
requirement to ‘ring-fence’ supplies for use in the RELIEHF trial and there are no restrictions on the 
brand(s) of spironolactone or eplerenone that may be used within the trial provided a Marketing 
Authorisation for the product is held in the UK. Where possible, supplies of spironolactone or 
eplerenone will be utilised in such a way as to minimise unnecessary wastage.  Reimbursement will 
be available from the trial budget where MRA usage is additional to standard care. All supplies should 
be stored in accordance with the relevant current Summary of Product Characteristics.  Further 
information is provided in the RELIEHF IMP Management and Accountability Manual. 
 
9.6 
Preparation and labelling of Investigational Medicinal Products 
 
Veltassa (Patiromer): Sites will be provided with Annex 13 compliant labels by the sponsor for 
application at the time of dispensing.   
 
Spironolactone & Eplerenone: Sites will be required to label original packs of spironolactone or 
eplerenone with Annex 13 compliant labels at the time of dispensing. Usual NHS ward supplies may 
be used in the run-in phase for in-patient participants where it is in line with local arrangements.  
 
Further information is provided in the RELIEHF IMP Management and Accountability Manual. 
 
9.7 
Dosage schedules 
 
Patients with a serum potassium >5.0mmol/L will be shown how to prepare and ingest a single 8.4g 
test dose of patiromer to ensure that they are willing to take patiromer on a regular basis and to assure 
the investigator that they understand how to prepare the suspension and requirement to take at least 3 
hours before or after other medicines (with key exceptions – see Section 9.8). 
 
Dosing of patiromer and MRA during run-in and at randomisation will be as follows: 
• 
Participants with a serum potassium >5.0mmol/L will be randomised to patiromer 8.4g once daily 
or not and then follow the scheme shown below with evaluation of serum potassium on Days 3, 5 and 
7 and periodically thereafter (see schedule of procedures). 
• 
Participants with a serum potassium <5.0mmol/L who are not currently receiving an MRA will 
first be given spironolactone (or eplerenone#) 25mg once daily and randomised to patiromer or not, if 
and when their serum potassium is >5.0mmol/L. If serum potassium does not exceed 5.0mmol/L 
within 72 hours, the dose of spironolactone may be increased to 50mg/day and after a further 72 
hours to 100mg/day. Those intolerant of or unwilling to take spironolactone should be offered 
eplerenone (maximum dose 50mg/day). 
• 
Participants with a serum potassium <5.0mmol/L who are currently receiving an MRA at a dose 
of <50mg/day will be initiated on spironolactone 50mg once /daily (or eplerenone#) or if currently 
already receiving 50mg/day, spironolactone 100mg/day (the maximum dose of eplerenone is 

 
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50mg/day). They will be randomised to receive patiromer or not, only once their serum potassium is 
>5.0mmol/L.  
• 
Immediately after randomisation: Those assigned to standard care should have the dose of MRA 
reduced unless serum potassium is >6.0mmol/L, in which case MRA should be temporarily 
suspended altogether until serum potassium is <5.0mmol/L. Patients with a serum potassium 
>5.0mmol/L who are not taking any dose of MRA may need the dose of other agents that increase 
potassium reduced. Those assigned to patiromer should continue to receive the dose of MRA 
administered at the time of randomisation unless serum potassium is >6.0mmol/L, in which case MRA 
should be temporarily suspended and patiromer continued until serum potassium is <6.0mmol/L. If 
serum potassium is >6.0mmol/L, also seek medical advice and treat according to guidelines. If 
intravenous treatment or a potassium-binding agent for the treatment of severe hyperkalaemia is 
required in the investigators opinion, the participant can be randomised only after these treatments 
have been stopped. 
• 
Maintenance Phase: doses should follow the scheme shown in the tables below.  
• 
Participants who do not develop a serum potassium >5.0mmol/L despite 100mg/day of 
spironolactone or 50mg/day of eplerenone within 35 days are not eligible for the randomised trial and 
will return to standard care. The clinician responsible for care should select the most appropriate dose 
of MRA for the participant. Under these circumstances, this will usually be 50mg/day of 
spironolactone or eplerenone. Participants will continue to be followed in the registry and may be 
reconsidered for the trial at any time should they become eligible. 
If eGFR falls below 30mls/min/1.73m2or systolic blood pressure below 90mmHg prior to 
randomisation, the participant is not eligible for randomisation until these exclusion criteria have 
resolved. Under these circumstances, clinicians responsible for care should decide whether to 
continue the MRA and at what dose. Those excluded will continue to be followed in the registry and 
may be reconsidered for the trial at any time should they become eligible. 
 
The following maximum doses of MRA are permitted for participants in the intervention arm after 
randomisation: 
• 
Spironolactone: 200mg once daily.  All doses must be taken orally.  
• 
Eplerenone:  
50mg once daily.  All doses must be taken orally. 
 
# only those intolerant of, or unwilling to take, spironolactone should be offered eplerenone. 
 
 
 

 
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Titration of Patiromer and MRA for Patients Assigned to Patiromer 
Serum 
Potassium # 
Patiromer ##  
MRA ### 
Potassium 
Supplements 
Other Potassium 
Sparing Diuretics 
<3.5mmol/L 
Withhold Patiromer for 48 
hrs 
Increase MRA Dose unless 
already on highest dose 
tolerated 
Consider 
Consider 
3.5-4.0mmol/L 
Maintain Patiromer Dose 
(unless already on 
highest dose of MRA, in 
which case reduce dose 
of patiromer) 
Increase MRA Dose unless 
already on highest dose 
tolerated 
Withhold 
Withhold 
4.1-4.9mmol/L 
Maintain Patiromer Dose 
Increase MRA Dose unless 
already on highest dose 
Withhold 
Withhold 
5.0-5.9mmol/L 
Increase Patiromer Dose 
unless already on highest 
dose 
Maintain MRA Dose unless 
already on highest dose of 
patiromer, in which case 
reduce dose of MRA 
Withhold 
Withhold 
>6.0mmol/L∏ 
Increase Patiromer Dose 
unless already on highest 
dose 
Withhold MRA until serum 
potassium is <6.0mmol/L 
then re-start at lower dose. 
 
Seek medical advice and treat 
according to guidelines ∏ 
Withhold 
Withhold 
 
Titration of MRA for Patients Assigned to Control 
Serum 
Potassium # 
MRA ∞ 
Potassium 
Supplements 
Other Potassium 
Sparing Diuretics 
<3.5mmol/L 
Increase MRA Dose unless already on 50mg/day 
Consider 
Consider 
3.5-4.0mmol/L 
Increase MRA Dose unless already on 50mg/day 
Consider 
Consider 
4.1-4.9mmol/L 
Maintain MRA Dose 
Withhold 
Withhold 
5.0-5.9mmol/L 
Reduce MRA Dose  
Withhold 
Withhold 
>6.0mmol/L∏ 
Withhold MRA until serum potassium is <5.0mmol/L 
then re-start at lower dose 
 
Seek medical advice and treat according to guidelines ∏ 
Withhold 
Withhold 
 
# most recent serum potassium – usually measured on the same or previous day. If doses of patiromer or MRA are changed, 
blood pressure and serum electrolytes and creatinine should be re-checked both after 7-12 days and after 30-45 days. If the 
patient becomes acutely unwell for any reason, blood pressure, serum electrolytes and creatinine should be re-checked. Serum 
potassium should also be checked within 48 hours of stopping patiromer. 
## initial dose is 8.4g/day and may be increased in steps to 16.8g/day or 25.2g/day guided by serum potassium, investigator 
judgement and patient-acceptance of higher doses. The maximum possible dose is 25.2g/day. 
### the maximum dose of spironolactone is 200mg/day and of eplerenone 50mg/day and will be guided by serum potassium, 
symptoms of hypotension, renal dysfunction and patient-acceptance of higher doses. Only those intolerant of or unwilling to 
take spironolactone should be offered eplerenone. 
∞the maximum dose of spironolactone is 200mg/day and of eplerenone 50mg/day and will be guided by serum potassium, 
symptoms of hypotension, renal dysfunction and patient-acceptance of higher doses. Only those intolerant of or unwilling to 
take spironolactone should be offered eplerenone. 
∏ Management of hyperkalaemia with a serum potassium >6.0mmol/L will also follow the Renal Association guidelines of 
2020 (https://renal.org/sites/renal.org/files/RENAL%20ASSOCIATION%20HYPERKALAEMIA%20GUIDELINE%202020.pdf). 
Participants should be recalled urgently to have serum potassium rechecked, clinical review and an electrocardiogram. 
Referral to an accident & emergency department may be considered. Patiromer alone should not be used for the emergency 
treatment of hyperkalaemia. 
 
 

 
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9.8 
Preparation and administration of patiromer oral suspension 
 
The required number of patiromer sachets should be added to 40ml (3 tablespoons) of water in a 
glass and then stirred. A further 40ml (3 tablespoons) of additional water should be added and the 
suspension stirred thoroughly. The powder does not dissolve but instead forms a suspension. More 
water can be added to the mixture as needed for the desired consistency. The suspension should be 
taken as soon as prepared but it must be taken within 1 hour. If powder remains in the glass after 
drinking, more water should be added, the suspension stirred and the remaining solution drunk 
immediately. This should be repeated as needed to ensure the entire dose is administered.     
 
If required apple juice may be used instead of water to prepare the mixture. Whilst patiromer can be 
mixed with cranberry juice, its use should be avoided where possible in this trial due to the potential of 
interactions with other medicinal products. Other liquids should be avoided as they may contain high 
amounts of potassium. The patiromer suspension may be taken with or without food. The powder 
should not be heated (e.g. microwaved), added to heated foods or liquids, or taken as a dry powder. 
Further information is provided in the current Summary of Product Characteristics and package insert.  
 
Patiromer doses must not be split and should be taken as a single oral dose once daily. Patiromer should 
be taken preferably at the same time each day and should be taken at least 3 hours before or after other 
oral medicines. This recommendation is based on concerns about possible binding of patiromer to other 
medicines that might reduce their absorption. This has been tested in the medicines described below.  
 
Medicines where there is reduced bioavailability/potential interaction when co-administered with 
patiromer   
Administration of the following oral medicines with patiromer must be separated by at least 3 hours to 
prevent interaction  
• 
ciprofloxacin 
• 
levothyroxine 
• 
metformin 
• 
quinidine 
 
Medicines where there is considered to be no clinically significant effect on bioavailability/ 
potential interaction when co-administered with patiromer 
At the discretion of the Investigator, the following oral medicines may be co-administered/administered 
within 3 hours prior to or after taking patiromer:  
• 
spironolactone, furosemide, digoxin,  
• 
lisinopril, valsartan,  
• 
aspirin, clopidogrel,  
• 
atorvastatin 
• 
allopurinol, phenytoin 
• 
amoxicillin, cephalexin, trimethoprim* (* increased risk of hyperkalaemia) 
• 
apixaban, rivaroxaban, and warfarin.  
This list may be extended as further research becomes available.   
 
Note that at the current time there is no information available on co-administration with eplerenone 
therefore administration should be separated from patiromer by at least 3 hours.   
 
Missed and omitted patiromer doses 
 
Participants should not discontinue treatment without consulting the research team.   
 
If a dose of patiromer is missed, it should be taken as soon as possible on the same day unless it is 
almost time to take the next dose in which case you should not take the forgotten dose. A double dose 

 
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should not be taken on the following day to make up for a missed dose. Participants should just 
resume taking their next normal dose at their usual time.  If doses of patiromer are missed on more 
than two consecutive days, participants must contact the research team for advice. Participants must 
not discontinue patiromer without consulting the trial team. Increases in serum potassium may occur 
within 2-4 days after the last dose of patiromer.   
 
If the participant stops patiromer for any reason, they must also stop their MRA and contact the 
investigator. 
 
9.9 
Administration of spironolactone and eplerenone 
 
Spironolactone tablets must be administered orally and tablets should be swallowed whole with water 
and preferably taken with a meal. Eplerenone tablets must be administered orally and should be 
swallowed whole with water but may be taken with or without food. Use of unlicensed oral 
suspensions or solutions is not permitted. 
 
Missed and omitted spironolactone or eplerenone doses 
 
Participants should not discontinue treatment without consulting the research team.   
 
Participants should take a missed dose as soon as possible on the same day unless it is almost time 
to take the next dose in which case the forgotten dose should be omitted.  A double dose should not 
be taken on the following day to make up for a missed dose. Participants should just resume taking 
their next normal dose at their usual time. If doses of spironolactone or eplerenone are missed on 
three or more consecutive days, participants must be advised to contact the research team for advice.   
 
If the participant stops their MRA for any reason, then they should also stop their patiromer and 
contact the investigator. 
 
If the participant develops persistent vomiting and/or diarrhoea lasting more than two hours or if they 
become acutely unwell for any other reason they should stop MRA (control group) or both MRA and 
patiromer (intervention group) until they have recovered or, if symptoms are severe or persistent, seek 
medical advice either from their general practitioner or emergency services. The investigator should 
be contacted as soon as possible to determine the need for assessments of serum potassium and 
adjustment of MRA or patiromer dose. 
 
Dosage modifications  
 
The dose of patiromer and MRA should be altered according to the serum potassium concentration 
according to the schedule shown in section 8.6. 
 
Trial supplies of patiromer-IMP must not be used for the emergency treatment of hyperkalaemia in 
either group and must not be used to manage hyperkalaemia in patients assigned to standard care.  
 
The dose of MRA may also be limited by blood pressure and renal dysfunction. The dose of MRA 
should be reduced or stopped if the patient has symptomatic hypotension or eGFR falls persistently to 
<30mL/min/1.73m2 after other therapeutic actions to improve hypotension and renal dysfunction have 
been undertaken, if appropriate (see below). 
 
For eplerenone only:  
Co-administration with mild to moderate CYP3A4 inhibitors: Eplerenone dosing should not exceed 25 
mg daily when mild to moderate inhibitors of CYP3A4 are co-administered with eplerenone (e.g. 
erythromycin, saquinavir, amiodarone, diltiazem, verapamil, or fluconazole).  
 

 
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9.10 
Known drug reactions and interaction with other therapies 
 
Patiromer  
 
Patiromer binds potassium in the gastrointestinal tract. It is insoluble and is not absorbed.  Patiromer 
does however have the potential to bind with oral co-administered medicinal products, which could 
decrease their gastro-intestinal absorption. Therefore, as a precautionary measure, administration of 
patiromer should be separated by at least 3 hours from other oral medicines unless listed as permitted 
at investigator-discretion in Section 9.8.   
 
Spironolactone and eplerenone 
 
The concomitant use of medicines known to cause hyperkalaemia with spironolactone or eplerenone 
may result in severe hyperkalaemia and should be withdrawn unless the investigator believes this not 
in the patient’s best interest.  Management of hyperkalaemia that cannot be managed by adjusting 
doses of MRA (or patiromer if assigned to this group) will follow the Renal Association guidelines of 
2020 (https://renal.org/sites/renal.org/files/RENAL%20ASSOCIATION%20HYPERKALAEMIA%20GUIDELINE%202020.pdf). 
 
Controversy persists on possible adverse consequences of taking MRA in conjunction with the 
combination of both an angiotensin converting-enzyme (ACE) inhibitor and an angiotensin receptor 
blocker (ARB). Investigators should avoid such practice. 
 
Strong inhibitors of CYP 3A4 (e.g. itraconazole, ketoconazole, clarithromycin, telithromycin and 
nefazodone) may interfere with MRA metabolism and should be avoided wherever possible in patients 
taking MRAs. Eplerenone dosing should not exceed 25 mg daily when mild to moderate inhibitors of 
CYP3A4 are co-administered with eplerenone (e.g. erythromycin, saquinavir, amiodarone, diltiazem, 
verapamil, or fluconazole).  
 
Caution is required with co-administration of MRA with the following medicines: 
• 
Heparin and low molecular weight heparins 
• 
Non-steroidal anti-inflammatories (NSAIDs) 
• 
Trimethoprim or trimethoprim containing combination products e.g. co-trimoxazole 
• 
Alpha-1-blockers (e.g. prazosin, alfuzosine) and other antihypertensive medicines 
• 
Tricyclic anti-depressants, neuroleptics, amifostine, baclofen 
• 
Glucocorticoids, tetracosactide 
• 
Cholestyramine 
• 
Digoxin and warfarin: caution is warranted particularly when dosed near the upper limit of 
therapeutic range 
• 
Potassium supplements and potassium sparing diuretics e.g. amiloride.  
 
The current Summary of Product Characteristics should be consulted for detailed information on 
interactions with other medicinal products. 
 
9.11 
Concomitant medication 
 
Permitted concomitant medicines 
 
All patients should be receiving loop diuretics and most will already be taking an MRA. 
 
We expect that most patients will also be receiving one (only one) of the following agents: ACE 
inhibitors, ARBs, sacubitril-valsartan. Many will also receive beta-blockers and anti-thrombotic agents. 
Some patients will also be receiving thiazide diuretics, digoxin and ivabradine. Many patients will be 
receiving non-cardiovascular medications for various indications. 
 

 
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The patients enrolled in this trial are inherently unstable and therefore no attempt to stabilise 
medications prior to enrolment is considered feasible. Investigators should attempt to stabilise and 
optimise treatment after randomisation during follow-up according to guidelines (investigators may 
choose to follow NICE, SIGN or ESC guidelines). 
 
Where the dose of MRA is limited by hypotension or renal dysfunction, the investigator should 
consider whether reducing the dose of loop diuretic is possible. Thiazide diuretics could also be 
withdrawn but that may lead to marked fluid retention and therefore care is required. If the patient is 
severely congested and it is not possible to reduce the dose of diuretics then: 
 
a) The dose of ACE inhibitor may be reduced to 2.5mg/day of Ramipril or enalapril 2.5mg bd or 
similar, since there is little evidence from randomised trials that outcomes are better on higher 
compared to lower doses of ACE inhibitors for patients with moderate or severe heart failure 
(14). This may also be true for ARB and sacubitril-valsartan. 
b) For patients in atrial fibrillation (about half of this population) there is little evidence that beta-
blockers are effective and evidence that reducing ventricular rate below 75bpm may be 
deleterious (16). Accordingly, reducing the dose of beta-blockers is advised to allow resting 
heart rate to rise above 75bpm. 
 
Prohibited concomitant medicines 
The following medicines are prohibited for all participants for safety reasons: 
• 
Combined use of both an ACE inhibitor and ARB 
• 
Lithium 
• 
Cyclosporin 
• 
Tacrolimus 
 
The following medicines are prohibited for participants treated with eplerenone (patients must be 
switched to spironolactone during co-administration of these agents) 
• 
Strong inhibitors of CYP 3A4 e.g. itraconazole, ketoconazole, ritonavir, nelfinavir, 
clarithromycin, telithromycin and nefazodone.   
• 
Strong CPY3A4 inducers (e.g. rifampicin, carbamazepine, phenytoin, phenobarbital, St John’s 
Wort) 
 
9.12 
Trial restrictions  
 
Patients should avoid taking potassium supplements (including dietary substitutes such as Lo-Salt) or 
potassium sparing diuretics other than MRA unless required for the management of hypokalaemia. 
 
Use of strong CYP 3A4 inhibitors and combined use of both an ACE inhibitors and ARB should be 
avoided. Most if not all patients will have renal dysfunction and therefore the use of non-steroidal anti-
inflammatory drugs should be avoided where possible. Use of non-evidence based medicines and 
over-the-counter treatments including herbal and other dietary supplements are discouraged. 
 
Patiromer should not be taken within three hours of other oral medications. Patiromer should be mixed 
with water or apple juice, as directed. 
 
9.13 
Assessment of compliance with treatment  
 
Compliance will be estimated at each trial visit by research staff and participants, and documented in 
the eCRF.  For those treated with both patiromer and MRA, research staff must assess compliance 
with both IMPs to ensure that both are taken as intended. For those receiving both patiromer and 
MRA, poor compliance (<80%) should be discussed with the participant, their safety evaluated and 
consideration given to withdrawing patiromer and reverting their management to standard care with 

 
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MRA alone. Poor compliance with MRA should also be discussed with the participant and the benefits 
of MRA emphasised.  
 
Patients must be withdrawn from treatment with IMP(s) if the investigator considers it unsafe for them 
to continue. Safety will be assessed by research nurses and/or investigators at each visit and after the 
occurrence of each SAE/SAR. Participants who have had an SAR (e.g. a hospital admission for the 
management of hyper- or hypo-kalaemia) should be reassessed for their ability to understand and 
comply with IMP dosing instructions.  
• 
If the participant is, in the investigator’s opinion, no longer able or willing to comply with treatment 
instructions, then they should stop one or both IMP and revert to standard-care, even if they have 
not experienced an SAE or SAR.  
• 
Participants who are assigned to patiromer and who have or develop hyperkalaemia (serum 
potassium >5.0mmol/L), even if they have been withdrawn from spironolactone or eplerenone IMP, 
may continue on or restart patiromer.  
• 
For participants with recurrent (two or more within a 6 month period) or life-threatening 
hyperkalaemia, investigators should reduce the dose of spironolactone or eplerenone to a 
maximum of 25mg/day or less (this includes a zero-dose), unless in the opinion of the investigator 
the benefit/risk ratio of receiving higher doses of spironolactone / eplerenone IMPs is still believed 
to be positive (e.g. the participant’s heart failure has responded well to higher doses of 
spironolactone or eplerenone). Participants assigned to patiromer should have the doses adjusted 
to achieve a serum potassium between 4.1 to 4.9mmol/L (inclusive). 
IMP may be re-initiated at any time if the investigator believes it is safe to do so and the participant is 
willing. 
 
Compliance will be encouraged by patient information leaflets and education. However, even if a 
patient is withdrawn from IMP they should be followed according to the protocol. Patients who decline 
to attend trial visits will be unable to obtain trial IMP and therefore will revert to standard care. If the 
participant agrees, they will continue to be contacted by the investigator or followed through their 
medical record even if they decline to attend trial follow-up visits. 
 
 
 

 
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10. SAFETY AND OUTCOME REPORTING 
 
10.1 
Definitions 
 
Term 
Definition 
Adverse Event (AE) 
Any untoward medical occurrence in a participant to whom a 
medicinal product has been administered, including occurrences 
which are not necessarily caused by or related to that product. 
 
Adverse Reaction 
(AR) 
 
An untoward and unintended response in a participant to an 
investigational medicinal product which is related to any dose 
administered to that participant. 
 
The phrase "response to an investigational medicinal product" means 
that a causal relationship between a trial medication and an AE is at 
least a reasonable possibility, i.e. the relationship cannot be ruled out. 
 
All cases judged by either the reporting medically qualified 
professional or the Sponsor as having a reasonable suspected causal 
relationship to the trial medication qualify as adverse reactions. It is 
important to note that this is entirely separate to the known side 
effects listed in the SmPC. It is specifically a temporal relationship 
between taking the drug, the half-life, and the time of the event or any 
valid alternative aetiology that would explain the event. 
 
Serious Adverse 
Event (SAE) 
A serious adverse event is any untoward medical occurrence that: 
• results in death 
• is life-threatening 
• requires inpatient hospitalisation or prolongation of existing 
hospitalisation 
• results in persistent or significant disability/incapacity 
• consists of a congenital anomaly or birth defect 
 
Other ‘important medical events’ may also be considered serious if 
they jeopardise the participant or require an intervention to prevent 
one of the above consequences. 
 
NOTE: The term "life-threatening" in the definition of "serious" refers 
to an event in which the participant 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 were more severe. 
 
Serious Adverse 
Reaction (SAR) 
An adverse event that is both serious and, in the opinion of the 
reporting Investigator, believed with reasonable probability to be due 
to one of the trial treatments, based on the information provided. 
 
Suspected 
Unexpected Serious 
Adverse Reaction 
(SUSAR) 
A serious adverse reaction, the nature and severity of which is not 
consistent with the information about the medicinal product in 
question set out in the reference safety information: 
• in the case of a product with a marketing authorisation, this could be in 
the summary of product characteristics (SmPC) for that product, so 
long as it is being used within its licence. If it is being used off label an 
assessment of the SmPC’s suitability will need to be undertaken. 

 
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• in the case of any other investigational medicinal product, in the 
investigator’s brochure (IB) relating to the trial in question. 
 
NB: “Severe” is often used to describe intensity of a specific event, which may be of relatively minor 
medical significance. “Seriousness” is the regulatory definition as supplied above. 
 
10.2 
Operational reporting for (S)AEs  
 
Adverse events (AEs) will be recorded, notified, assessed, reported, analysed and managed in 
accordance with the Medicines for Human Use (Clinical Trials) Regulations 2004 (as amended) and 
this protocol. All AEs occurring during the trial that are observed by the Investigator or reported by the 
participant will be recorded in the participant’s medical records whether or not attributed to trial 
medication.   
 
All adverse reactions must be recorded within the eCRF.  
 
All Serious Adverse Events (SAEs) occurring during the trial must be recorded in the eCRF. 
 
The following are not considered be to be SAEs for the purposes of this trial. 
 
• 
Routine treatment or monitoring of heart failure not associated with deterioration in heart 
failure. 
• 
Treatment which was elective or pre-planned, for a pre-existing non-cardiac condition not 
associated with any deterioration in heart failure, e.g. pre-planned hip replacement operation 
which does not lead to further complications. 
• 
Treatment on an emergency, outpatient basis for an event not fulfilling any of the definitions of 
serious as given above and not resulting in hospital admission.  
• 
Admissions for social reasons not associated with a deterioration of heart failure.  
 
All SAEs will be reported to the IDMC and analysed as part of the final trial results. 
 
Full details of SAEs will be recorded in the electronic Case Report Form. The following information will 
be collected: 
• 
full details in medical terms and a case description 
• 
event duration (start and end dates, if applicable) 
• 
action taken 
• 
outcome 
• 
seriousness criteria 
• 
causality (i.e. relatedness to trial drug / investigation), in the opinion of the investigator 
• 
if related, whether the reaction would be considered expected or unexpected. 
 
Any change of condition or other follow-up information should be added to the eCRF as soon as 
it is available or at least within 24 hours of the information becoming available. Events will be 
followed up until the event has resolved or a final outcome has been reached.  
 
Assessment of Adverse Events 
 
All adverse events must be assessed for seriousness. All SAEs must also be assessed for severity, 
causality and expectedness with reference to this protocol and the Reference Safety Information 
(RSI).  
 
 
 

 
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Assessment of seriousness 
 
An adverse event will be considered serious if it: 
• 
results in death  
• 
is life threatening  
• 
requires hospitalisation or prolongation of existing hospitalisation  
• 
results in persistent or significant disability or incapacity  
• 
consists of a congenital anomaly or birth defect 
• 
requires intervention to prevent one of the above 
• 
Is an event of special interest as defined above  
 
Assessment of causality  
 
i.e. Does the event have a “reasonable causal relationship” with the trial IMPs? The following 
categories are used: 
• 
Yes - the causal and temporal relationship between the event and the absence of a more likely 
explanation suggest that the trial IMP is the most likely cause.  
• 
No - the event is not considered related to the trial IMPs. 
 
Causality will be assigned for each IMP the participant is randomised to receive. 
 
Should an SAE be considered unrelated to the administration of either trial drug then the causality of 
the event will be collected taking into consideration other factors, for example, concomitant 
medications or co-morbidities, etc. 
 
Assessment of causality is the responsibility of the Principal Investigator or medically-qualified 
designee(s) at each site. The CI, their delegate(s), or the Sponsor may provide an opinion regarding 
causality but cannot downgrade the PI’s assessment. 
 
Assessment of expectedness 
 
Should the event be considered to be related to the trial IMP(s), an assessment should be made 
regarding the expectedness of the reaction i.e. whether the reaction is a recognised adverse effect of 
the IMP(s). 
 
Expected - consistent with the relevant product information documented in the RSI(s). 
Unexpected - not consistent with the relevant product information documented in the RSI(s). 
 
The CI, their delegate(s) or the Sponsor have overall responsibility for assigning expectedness as per 
the RSI(s) and providing the final assessment of the event. The reporting investigator may provide an 
opinion on the expectedness of an event and this will be taken into account. 
 
Assessment of severity 
 
This should be assessed and described using the following categories: 
• 
Mild - awareness of event but easily tolerated 
• 
Moderate - discomfort enough to cause some interference with usual activity 
• 
Severe - inability to carry out usual activity. 
 
Recording and reporting of SAEs 
All reportable SAEs (see section 9.3) arising during the clinical trial will be recorded in the eCRF as 
soon as reasonably practicable and in any event within 24 hours of first becoming aware of the event. 
Any follow-up information should also be reported.  

 
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• If recording via the eCRF is not possible, a paper SAE form should be completed. The SAE form is 
downloaded from www.glasgowctu.org, printed, completed and signed. A paper copy of the SAE 
form is filed in the Investigator Site File at each site should this website be unavailable. The 
completed form is faxed to the Glasgow Clinical Trials Unit Pharmacovigilance (PV) Office on +44 
(0)141 357 5588. If fax is not possible, a copy of the SAE form should be scanned and emailed to 
pharmacovig@glasgowctu.org.  
• If necessary a verbal report can be provided by contacting the PV Office on +44 (0)141 330 4744. 
This must be followed up as soon as possible with an electronic or written report. 
 
10.3 Serious Adverse Events (Sponsor reportable events) 
 
Patiromer, spironolactone and eplerenone have well-understood safety profiles. Previous clinical trials 
have shown the combination of drugs to be well-tolerated (12). However, when the IMPs are used in 
combination there remain potential concerns regarding the effects of the IMP(s) on serum potassium. 
 
In addition, participants in this trial are expected to have high rates of hospitalisations, cardiovascular 
events and death due to cardiac disease and related co-morbidities that are unlikely to be attributable 
to treatment with the trial IMP(s). These events will, however, inform the primary and secondary 
endpoints of the trial and will be subject to monitoring by the Data Monitoring Committee. As such 
these event will be recorded within the eCRF as per section 9.2.  
 
Where the medicines are used in combination, the principle concern is changes in serum potassium 
and/or magnesium. For the purposes of pharmacovigilance, safety reporting will focus on the 
occurrence of hypokalaemia, hyperkalaemia, hypomagnesaemia, and events associated with these 
conditions, in particular potentially harmful renal insufficiencies. 
 
Monitoring of non-reportable events 
 
Non-reportable events will be monitored during the study.  If deemed necessary, an initially non-
reportable event may be added to the list of events reported to Sponsor.  The process for this will be 
documented separately. 
 
The following will be recorded on the eCRF as Serious Adverse Events and will be subject to 
expedited reporting to the sponsor: 
 
• 
Any SAE that is considered, in the Investigator’s opinion, related to the administration of any of the 
IMPs used in the trial, whether individually or in combination. 
• 
Any incidence of an acute kidney injury meeting the criteria of a serious adverse event. 
• 
Renal failure associated with a requirement for renal dialysis/ultrafiltration; and deaths associated 
with renal failure as evidenced by a preceding eGFR of 10ml/min/L/1.73m2 
• 
SAEs associated with one of the following electrolyte disturbances 
o Severe hypokalaemia defined as serum potassium <3.0mmol/L 
o Severe hyperkalaemia defined as a serum potassium> 6.5mmol/L 
o Severe hypomagnesaemia defined by a serum magnesium <0.5mmol/L 
 
Suspected Unexpected Serious Adverse Reactions (SUSARs) 
 
Any SAE assessed as related to trial IMP(s) by the PI or delegate, and unexpected (not documented 
as an expected reaction to the IMP(s) within the RSI(s)) by the CI, their delegate, or the Sponsor will 
be classified as a SUSAR and subject to expedited reporting to the Medicines and Healthcare 
products Regulatory Agency (MHRA) and the Research Ethics Committee (REC). Should the CI 
disagree with the PI’s assessment of causality, both opinions will be provided on the report. 
 

 
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The Sponsor will inform the MHRA and the REC of SUSARs within the required expedited reporting 
timescales: 
• 
Fatal or life threatening SUSARs - not later than 7 days of Sponsor awareness that the case 
fulfils the criteria for a fatal or life threatening SUSAR, and any follow up information within a 
further 8 days.  
• 
All other SUSARs - not later than 15 days of Sponsor awareness that the case fulfils the 
criteria for a SUSAR. 
 
The Sponsor will report SUSARs to the MHRA via the MHRA eSUSAR reporting system and to REC 
by email with accompanying CTIMP Safety Report Form. 
 
10.4 
Responsibilities 
 
Principal Investigator (PI):  
 
• 
Attendance at the initiation meeting/teleconference. 
• 
Training of new members of the trial team in the protocol and its procedures. 
• 
Ensuring that the ISF is accurately maintained.  
• 
Dissemination of important safety or trial-related information to all stakeholders at their site. 
• 
Checking for AEs and ARs when participants attend for treatment / follow-up. 
• 
Ensuring that AEs are recorded and reported in line with the requirements of the protocol.  
• 
Ensuring that all SAEs are recorded and reported to the Sponsor within 24 hours of becoming 
aware of the event, and providing further follow-up information as soon as available.  
• 
Using medical judgement in assigning seriousness, causality, and severity of SAEs. 
• 
Providing an opinion on the expectedness of an SAE with reference to the trial protocol and 
Reference Safety Information. 
• 
Using definitions in this protocol, flagging events of special interest or potential endpoints. 
 
Chief Investigator (CI)  
 
• 
Providing clinical oversight of the safety of patients participating in the trial, including an 
ongoing review of the risk/benefit. 
• 
Providing clinical review of section 4.8 of the representative SmPCs on an annual basis to 
define the Reference Safety Information for the trial. 
• 
Using medical judgement to confirm seriousness and causality of all SAEs. 
• 
Reviewing expectedness of related SAEs with reference to the trial protocol and Reference 
Safety Information. 
• 
Preparing the clinical sections and final sign-off of the Development Safety Update Report 
(DSUR). 
• 
Using definitions in this protocol, confirming events of special interest or potential endpoints. 
 
Sponsor: 
 
• 
Central data collection and verification of AEs, SAEs, SARs and SUSARs according to the trial 
protocol. 
• 
Maintaining the Reference Safety Information for the trial and ensuring it is complies with 
regulatory guidance. 
• 
In the absence of the CI and their delegates, reviewing expectedness of SAEs against the 
Reference Safety Information. 
• 
Reporting safety information to the CI or delegate for the ongoing assessment of risk/benefit.  
• 
Reporting safety information to the independent oversight committees identified for the trial 
(Independent Data Monitoring Committee (IDMC) and/or Trial Steering Committee (TSC)) 
according to the Trial Monitoring Plan. 

 
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• 
Expedited reporting of SUSARs to the Competent Authority (MHRA in UK) and REC within 
required timelines. 
• 
Notifying Investigators of SUSARs that occur within the trial. 
• 
Annual checking for updates to the Reference Safety Information for the trial, and notifying PIs 
of any changes. 
• 
Preparing standard tables and other relevant information for the DSUR in collaboration with the 
CI and ensuring timely submission to the MHRA and REC. 
 
Trial Steering Committee:  
 
Periodically reviewing recruitment and the overall progress of the trial and liaising with the IDMC 
and sponsor regarding safety issues. Reporting the results of the trial to the investigators and 
wider public and writing primary and secondary papers. 
 
Trial Management Group: 
 
They will be responsible for day to day running of the trial. 
 
Independent Data Monitoring Committee: 
 
In accordance with the Charter for the IDMC, periodically reviewing unblinded safety data in 
individual cases and to determine patterns and trends of events, or to identify safety issues, 
which would not be apparent on an individual case basis, reporting concerns to the TSC and 
sponsor.  
 
Clinical Endpoint Committee (CEC):  
 
In accordance with the Charter for the CEC, review and classify all potential clinical endpoints in 
the trial. 
 
10.5 
Notification of deaths  
 
All deaths occurring within the trial will be reported within the eCRF as an SAE.  
 
10.6 
Pregnancy reporting  
 
Women at risk of pregnancy are excluded from this trial. Patiromer is not absorbed and therefore is 
not considered a risk to female partners of male participants. MRA are guideline-recommended 
therapy and are not known to pose a risk to female partners of men who take MRA. 
 
10.7 
Overdose 
 
Patients may take an overdose of patiromer or MRA deliberately or inadvertently. 
 
Definition: An overdose is defined as a patient who has taken substantially more of the IMP than 
intended, either in a single large dose (usually this will be a deliberate act of self-harm) or a smaller 
deviation but over a longer period of time. For this protocol, the latter will be defined as taking a dose-
level higher than intended that either persists for more than one month or results in hospitalisation or 
death. 
 
Overdoses resulting in an SAE will be recorded on the SAE eCRF.  
 
Investigators will evaluate whether it is safe for the patient to continue on IMP and if not they will revert 
to standard care. They will continue to be followed-up as intended in all other respects.  

 
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Psychiatric advice will be sought for patients who have attempted self-harm. 
 
10.8 
Reporting urgent safety measures  
 
If any urgent safety measures are taken the CI/Sponsor will phone the MHRA’s Clinical Trial Unit on 
020 3080 6456, ideally within 24 hours. This will be followed up no later than 3 days from the date the 
measures are taken, giving written notice to the MHRA (who will advise the format required) and the 
relevant REC of the measures taken and the circumstances giving rise to those measures. A 
substantial amendment must also be submitted to the MHRA. 
 
10.9 
The type and duration of the follow-up of participants after adverse reactions. 
 
Adverse events and reactions will be recorded, reported and followed to completion in line with this 
protocol until 30 days after participant’s last dose of the IMP.  
Any SUSAR identified will be reported to the Sponsor and to the Regulatory Authorities irrespective of 
how long after IMP administration the reaction has occurred. 
 
10.10 
Development safety update reports (DSURs) 
 
DSURs will be submitted within 60 days of the anniversary of the issue of the Clinical Trials 
Authorisation for the trial. DSURs will be prepared and submitted by the sponsor (PV Office) in liaison 
with the CI. 
 
11. STATISTICS AND DATA ANALYSIS 
 
11.1 
Sample size calculation 
 
The anticipated primary endpoint rate in the control group is 40%.  We estimate that 999 subjects per 
group (yielding 719 first-events) will provide >90% power to detect a hazard ratio of 0.75 (25% reduction) 
at the 1% significance level and >80% power to detect a hazard ratio of 0.80 at the 5% significance level, 
which we believe reflect clinically meaningful benefit.  This is based on a time to first event analysis using 
the Wald statistic in a Cox proportional hazards model. To allow for some uncertainty the trial will be 
stopped once 750 patients have experienced a primary endpoint. As the primary endpoint is a recurrent-
event analysis, the trial should have additional power. 
 
The primary endpoint at 60 days is a novel scoring system and therefore there are no prior data upon 
which to base assumptions. Assuming a normal distribution of “Congestion Index” scores, 400 patients 
provides >90% power to demonstrate a difference between strategies of 0.325 of a standard deviation in 
the effect size for the change in score between baseline and follow-up.  
 
11.2 
Anticipated recruitment rate 
 
On average, the 100 sites participating in this trial will care for about 20,000 patients with advanced 
heart failure per year, of which we estimate 25% would be suitable and 10% would be both suitable 
and willing to participate in this trial. Accordingly, we anticipate that each site should be able to enrol 
20 patients per year. We anticipate it will take 12-18 months to initiate all 100 sites and that not all 
sites will perform to target. Therefore, we assume that enrolment will take two to three years.  
 
 
 

 
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11.3 
Statistical analysis  
 
The primary analysis will be done on the intention-to-treat population. The primary endpoint is the 
composite of time to need for IV diuretics (subsequent to initial discharge) for worsening or recalcitrant 
heart failure, hospitalisation for worsening heart failure or non-cancer deaths analysed as a recurrent 
event.  This is a novel trial endpoint and methodology for analysing such outcomes is evolving. 
Therefore the methods used to analyse the recurrent events will be updated based on this evolving 
area of research and will be finalized prior to database lock. 
 
Time to first event outcomes will be analysed using Cox proportional hazards models with randomised 
treatment as a covariate.  Statistical significance will be assessed using the Walk statistic and 
estimated hazard ratios for the treatment effect and their 95% confidence intervals calculated.   
 
Time to event curves will be constructed using cumulative incidence functions adjusting for competing 
risks where appropriate.  Outcomes from the Quality of Life and congestion scores will be analysed at 
the specified time points using t-tests with no imputation for missing data.  Days dead or hospitalised 
and quality-adjusted days alive and out of hospital will be analysed using re-randomisation tests 
adjusting for potential length of follow-up.  Serious adverse events will be tabulated by system organ 
class and preferred term. A complete statistical analysis plan will be completed and signed off before 
database lock. 
 
11.4 
Subgroup analyses 
 
The primary outcome will be analysed in the following sub-groups: 
• 
Age (by tertile) 
• 
Sex (categorical) 
• 
Recruitment as an in-patient or out-patient (categorical) 
• 
MRA dose prior to inclusion (<25mg, 25mg, >25mg of spironolactone or eplerenone) 
• 
Systolic blood pressure (by tertile) 
• 
eGFR (by tertile) 
• 
LVEF (<40%, 40-49%, >49%) 
• 
COPD (categorical) 
• 
Diabetes mellitus (categorical) 
 
Results will be presented within each subgroup along with a test for treatment by subgroup interaction. 
 
11.5 
Interim analysis and criteria for the premature termination of the trial 
 
Unblinded trial data will be reviewed on an ongoing basis by the IDMC.  The primary role of the IDMC 
will be to protect the interests of the patients.  The IDMC may recommend to the TSC and Co-
Sponsors that the trial should be stopped prematurely because of concerns about patient safety of 
conclusive evidence of overwhelming benefit. The IDMC will meet after 100, 200, 400, 1,000, 1,500 
and 2,000 patients have completed 60-day follow-up. 
 
The IDMC may recommend stopping the study for safety at any time. At each meeting, the IDMC will 
review the overall rate of serious adverse events and serious adverse events of special interest 
(hypokalaemia, hyperkalaemia, hypotension, renal failure, arrhythmias and heart failure) that may be 
influenced (favourably or unfavourably) by intervention. 
 
The IDMC will take into account all results and the consistency and biological plausibility of the 
findings in making any recommendation.  The final decision on continuing or stopping the trial will lie 
with the TSC/Co-Sponsors. The pre-specified stopping guidelines below will be detailed in the IDMC 
Charter and statistical analysis plan.   
 

 
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Interim analysis 
If the analysis of 60-day outcome for the first 400 patients evaluated at 60 days suggests a potential 
failure of the treatment strategy [either similar doses of MRA amongst patients assigned to patiromer 
and standard care or a lack of improvement in congestion by Day-60] then the IDMC will be asked to 
consider stopping the trial unless the conditional power of the trial to show benefit on the primary 
endpoint exceeds 70%. 
 
• 
In order for the dose of MRA to be considered dissimilar for participants assigned to patiromer 
compared to standard care the following criteria should be met:- 
o The mean dose of MRA of those assigned to patiromer should be >50% higher (i.e. 
25mg/day versus >37.5mg/day) than for those assigned to standard care. 
o This difference should be statistically significant 
• 
If there is no significant difference in either the overall congestion index or in plasma 
concentration of NT-proBNP at 60-days, then this will be considered a lack of improvement in 
congestion. 
 
If patiromer fails by either or both criteria, the trial may be terminated unless a strong trend to benefit 
on morbidity and mortality is observed in the overall trial data. At the time of this evaluation, we 
anticipate that >100 patients will have been followed for at least one year, up to 800 patients may 
have been randomised altogether and >200 primary endpoints will have occurred. 
 
11.6 
Participant population 
 
Analyses will be carried out on an intention to treat basis according to randomised treatment. 
 
11.7 
Procedure(s) to account for missing or spurious data  
 
The main analyses will be based on morbidity/mortality data for which imputation is not necessary.  
For quality of life outcomes, laboratory results or other continuous variables results will be analysed 
with and without imputation.  Multiple imputation procedures will be used.  Full details will be provided 
in the statistical analysis plan. 
 
11.8 
Other statistical considerations 
 
A Statistical Analysis Plan (SAP) for each phase of the trial will be maintained and approved as a 
version controlled document prior to each formal statistical analysis.  The SAP will contain full details 
of all analyses along with assumptions and procedures for handling problematic or incomplete data 
(e.g. incomplete dates). 
 
11.9 
Economic evaluation 
 
No formal economic evaluation will be included in the statistical analysis plan, however quality of life 
and hospitalisation data will be collected and may be utilised in a separate economic analysis at a 
later date if required. 
 
 
 

 
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12. DATA MANAGEMENT 
 
12.1  
Source Documentation 
 
ICH GCP defines source data as: ‘All information in original records and certified copies of original 
records of clinical findings, observations or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial’. In this trial, the location of the majority of the source data will 
be the hospital's medical records including subject case notes, laboratory records and ECGs. The 
source data transcribed into the eCRF from the medical records must be accurate and verifiable. For 
questionnaires completed by trial subjects, the completed questionnaires will be regarded as the 
source data location. In cases where data is transcribed directly into the eCRF and no other paper or 
electronic source exists, then the eCRF will be considered the source record.  In these cases, these 
data should be prospectively documented in the medical records to ensure a full record of the trial is 
available at site. 
 
12.2 
Data collection  
 
An eCRF, developed by the Robertson Centre for Biostatistics, will capture all data required to meet 
this protocol’s requirements. Access to the eCRF will be restricted, via a trial-specific web portal, and 
only authorised site-specific personnel will be able to make entries to their patients’ data via the web 
portal. The Investigator or his /her designee will be responsible for all entries into the eCRF and will 
confirm that the data are accurate, complete and verifiable.  Data will be stored in a MS SQL Server 
database.   
 
Direct access to the web portal will be granted, on request, to authorised representatives from the 
Sponsor, host institution and the regulatory authorities to permit trial-related monitoring, audits and 
inspections. 
 
12.3  
Data Validation 
 
Where it is practical, data will be validated at the point of entry into the eCRF. Any additional data 
discrepancies will be flagged to the investigator and any data changes will be recorded to maintain a 
complete audit trail (reason for change, date change made and who made the change). 
 
12.4  
Data Security 
 
The Robertson Centre for Biostatistics systems are fully validated in accordance with industry and 
regulatory standards, and incorporate controlled access security. High volume servers are firewall 
protected and preventative system maintenance policies are in place to ensure no loss of service or 
data. Web servers are secured by digital certificates. Data integrity is assured by strictly controlled 
procedures, including secure data transfer procedures.  Data are backed up on-site nightly and off-site 
to a commercial data vault weekly. The Robertson Centre for Biostatistics has an ISO 9001:2008 
quality management system and ISO 27001:2013 for Information Security, and is regularly inspected 
against the standards by the British Standards Institution. 
 
12.5 
Archiving 
 
The Trial Master File will be archived by the Sponsor at the end of the trial for a minimum period of 25 
years.  
 
Archiving of Site Files will also be for a minimum of 25 years from completion of the trial, and this 
action will be delegated to the sites in the Clinical Trial Site Agreement that will be put in place 
between Sponsor and Sites. Sites will be notified by the Sponsor when Site files can be archived. 
Destruction of site files can only take place with the approval of the Sponsor. 

 
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13. MONITORING, AUDIT & INSPECTION 
 
Trial monitoring visits will be conducted by NHS GG&C monitor(s).  Prior to starting the trial, a trial-
specific Monitoring Plan will be developed by the monitor(s).  The level of monitoring, on-site and 
remote, will be based on the outcome of the completed monitoring risk assessment, and will be clearly 
documented in the monitoring plan which will be approved by the NHS GG&C Research Governance 
Manager / Academic Lead Clinical Trial Monitor. As standard, monitoring visit(s) will cover site file 
review, review of Informed Consent Forms (ICFs), Source Data Verification (SDV) and Serious 
Adverse Event (SAE) review as per monitoring plan objectives.  
 
Central monitoring objectives will be documented in the monitoring plan upon agreement between the 
RCB and the Sponsor. 
 
The CI and other investigators shall be accessible for monitoring visits.  Direct access to patient 
records for source data verification will need to be granted and prepared prior to any monitoring visits. 
 
 

 
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14. ETHICAL AND REGULATORY CONSIDERATIONS 
 
14.1  
Research Ethics Committee (REC) review and reports 
 
Before the start of the trial, approval will be sought from a REC for the trial protocol, informed consent 
forms and other relevant documents e.g. advertisements and GP information letters. 
 
Substantial amendments that require review by REC will not be implemented until the REC grants a 
favourable opinion for the trial (it is noted that amendments may also need to be reviewed and 
accepted by the MHRA and/or NHS R&D departments before they can be implemented in practice at 
sites). 
 
All correspondence with the REC will be retained in the Trial Master File/Investigator Site File.  
 
An annual progress report (APR) will be submitted to the REC within 30 days of the anniversary date 
on which the favourable opinion was given, and annually until the trial is declared ended (this is the 
Chief Investigator’s responsibility). 
 
The Chief Investigator will notify the REC of the end of the trial. 
 
If the trial is ended prematurely, the Chief Investigator will notify the REC, including the reasons for the 
premature termination 
 
Within one year after the end of the trial, the Chief Investigator will submit a final report with the 
results, including any publications/abstracts, to the REC. 
 
14.2  
Peer review 
 
The trial protocol was reviewed by the British Society for Heart Failure sub-committee and at two UK 
Heart Failure Investigators Research Network meetings during 2018. Members have expertise in the 
care of patients with heart failure and/or the conduct of clinical trials in the relevant population. The 
protocol has also been reviewed by representatives of the funder (Vifor) and of the sponsor.  
 
14.3  
Public and Patient Involvement 
 
The trial was designed by physicians with expertise in managing heart failure supported by the Robertson 
Centre for Biostatistics research design service. 
 
A patient panel was convened to review the trial design and protocol. The design and protocol were 
revised in the light of their comments. 
 
Patients will advise on the patient information sheet and enrolment strategy. 
 
Patient organisations will disseminate information about the ongoing trial and, in due course, its results. 
 
Guidance on involving patients and the public in research can be found on the INVOLVE website. 
http://www.invo.org.uk/ 
 
14.4  
Regulatory Compliance  
 
• 
The trial will not commence until a Clinical Trial Authorisation (CTA) and a favourable opinion is 
obtained from the MHRA and REC, respectively.  

 
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• 
The protocol and trial conduct will comply with the Medicines for Human Use (Clinical Trials) 
Regulations 2004 and any relevant amendments. 
 
14.5  
Protocol compliance  
 
Prospective, planned deviations or waivers to the protocol are not allowed under the UK regulations 
on Clinical Trials and must not be used e.g. it is not acceptable to enrol a participant if they do not 
meet the eligibility criteria or restrictions specified in the trial protocol. Accidental protocol deviations 
can happen at any time. They will be adequately documented on the relevant forms and reported to 
the Chief Investigator and Sponsor immediately. Deviations from the protocol that frequently recur are 
not acceptable and will trigger immediate action and could potentially be classified as a serious 
breach. 
 
14.6  
Notification of Serious Breaches to GCP and/or the protocol  
 
A “serious breach” is a breach which is likely to affect to a significant degree: 
1. the safety or physical or mental integrity of  trial participants; or 
2. the scientific value of the trial 
 
If any of the above occurs then the CI and Sponsor will be notified. The sponsor will notify the 
appropriate authorities in writing of any serious breach in accordance with their standard operating 
procedures. 
 
14.7  
Data protection and patient confidentiality  
 
All investigators and trial site staff must comply with the requirements of the Data Protection Act 2018 
with regards to the collection, storage, processing and disclosure of personal information and will 
uphold the Act’s core principles.  
 
• 
Personal information will be collected via the eCRF to enable record linkage to be carried out 
and to provide electronic access to trial monitors to a copy of the signed informed consent 
document. These data items will be encrypted and only those individuals who require to see 
these data i.e. the person performing the record linkage and site research team staff or the trial 
monitor, as appropriate, will be able to view them.  All electronic data will be held securely in 
accordance with ISO 27001:2013 at the Robertson Centre for Biostatistics, part of the Glasgow 
Clinical Trials Unit. All Centre staff are required to sign confidentiality agreements and to follow 
Standard Operating Procedures in accordance with Good Clinical Practice and ISO 
certification. 
• 
Only those that have been trained and approved will be able to enter or view any data via the 
web portal.  Each site can only see their own patients’ data.  
 
14.8  
Financial and other competing interests for the chief investigator, PIs at each site and 
committee members for the overall trial management  
 
Professor John Cleland and Professor Martin Cowie have received honoraria from Vifor Pharma for 
advisory boards and speaking at meetings.  
 
Vifor are funding the trial and supplying patiromer. 
 
If new competing interests develop, either due to changes in the status of existing trial personnel or to 
the inclusion of new personnel, this will be documented in the trial master file. 
 
 

 
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14.9  
Indemnity 
 
The Co-Sponsors (University of Glasgow and Greater Glasgow Health Board) will ensure that 
provision has been made for insurance or indemnity to cover the liability of the investigator and 
sponsor which may arise in relation to the clinical trial in accordance with Part 2 (14) of Schedule 1 to 
SI 2004/1031. 
 
Clinical negligence will be covered by the Clinical Negligence and Other Risks Indemnity Scheme in 
Scotland, and the equivalent schemes in other UK countries. 
 
The Insurance cover will be subject to the appropriate authorisations being received from the MHRA, 
Ethics, and the NHS. 
 
14.10  
Amendments  
 
Any change in the trial protocol will require an amendment.  Any proposed substantial protocol 
amendments which may impact on the safety of patients or integrity of the trial will be initiated by the 
CI following discussion with the Sponsor and TSC and any required amendment forms will be 
submitted to the regulatory authority, ethics committee and Sponsor. The Sponsor will determine 
whether an amendment is non-substantial or substantial. All amended versions of the protocol will be 
signed by the CI and Sponsor representative.  Following a substantial amendment, favourable 
opinion/approval must be sought from the original reviewing REC, MHRA (where appropriate) and 
Research and Development (R&D) office prior to implementation. The Chief Investigator will be 
responsible for informing the Trial Management Group of all protocol amendments. 
 
14.11  
Post trial care 
 
Patiromer and both MRA are already licensed for use in the UK. 
 
At the end of the trial, participants will be returned to usual care as defined by local and national 
guidelines at that time. The results of the trial may of course have an impact on these guidelines and 
the future care of patients with heart failure.’ 
 
Spironolactone and eplerenone are generic medicines that are already widely prescribed. 
 
14.12  
Access to the final trial dataset 
 
The data will be held securely at the Robertson Centre for Biostatistics at the University of Glasgow 
where it may be accessed by approved data-managers, statisticians and the Chief Investigator. 
 
A full data-set may be shared with the funder after the trial is complete.  
 
After the primary results have been published, data-sets may also be shared with co-investigators and 
others working in this field. This is subject to submission of a detailed statistical analysis plan, 
evidence of appropriate clinical and statistical expertise to support the analysis and its interpretation. 
Submissions must be approved by the TSC. Where data are shared, a data sharing agreement will be 
required which will detail requirements to ensure secure disposal after the analysis is complete. 
The TSC will oversee and coordinate manuscript proposals. 
 
 
 

 
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15. DISSEMINATION POLICY 
 
15.1  
Dissemination policy 
 
The University of Glasgow will own the data arising from the trial. 
 
On completion of the trial, the data will be analysed and tabulated. The Steering Committee will publish 
the primary manuscript and review proposals for further analyses. Participating investigators will be 
invited to propose secondary manuscripts, with priority given to those who have enrolled many patients. 
Colleagues who have not participated should seek ‘sponsorship’ from a participating investigator in order 
to submit a proposal. Timelines for analyses, manuscript writing and review will be agreed on a case-by-
case basis subject to available resources. The sponsor and funder should be acknowledged in all 
publications. 
 
Participants will be informed of results by a newsletter and may request information about the trial results 
after publication. 
 
The trial protocol will be made publicly available prior to publication on a clinical trials website.  
 
15.2  
Authorship eligibility guidelines and any intended use of professional writers 
 
The primary manuscript will be authored by the Steering Committee and the Principal Investigators 
from sites providing high quality data on a substantial number of patients. 
 
The Steering Committee will delegate authorship to investigators and other colleagues after 
considering their proposals.  
 
We do not intend to use professional writers for the peer-reviewed manuscripts describing the results. 
The funder may wish to employ professional writers for the ‘commercial’ press and will acknowledge 
any services paid for. 
 
 

 
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16.  APPENDICES 
 
Appendix 1: Risk 
 
 LOW ≡ Comparable to the risk of standard medical care 
 MODERATE ≡ Somewhat higher than the risk of standard medical care 
 HIGH ≡ Markedly higher than the risk of standard medical care 
Justification:  
MRA are already recommended and widely used for patients with heart failure and are an effective 
treatment for congestion. Patiromer reduces serum potassium, allowing higher doses of MRA to be 
used 
.  
There are risks (hyperkalaemia, hypotension and renal dysfunction) and benefits (relief of congestion, 
improvement in symptoms, reduction in mortality) to use of higher doses of MRA. 
 
Patiromer might cause hypokalaemia, although this is unlikely in a population highly prone to 
hyperkalaemia. 
 
What are the key risks related to 
therapeutic interventions you plan to 
monitor in this trial? 
How will these risks be minimised? 
IMP/Intervention  
Body 
system/Hazard 
Activity 
Frequency 
Comments 
Patiromer 
Hypokalaemia 
Monitoring serum 
potassium 
See 
schedule 
 
MRA 
Hyperkalaemia 
 
MRA 
Symptomatic 
hypotension 
Monitoring 
symptoms 
 
MRA 
Renal dysfunction 
Monitoring serum 
creatinine 
 
An IDMC will monitor patient-safety. 
 
Treatment is not blinded and therefore investigators may identify safety issues. 
Outline any processes that have been simplified based on the risk adapted approach.  
 
All IMP will be labelled for trial use only, including the nature of the IMP, its dose and the number of 
sachets/pills. 
 
The trial is not blinded. Patients and investigators will know what is prescribed. 
 
Patients in the control group will receive MRA only. Patients in the intervention group will receive 
patiromer and MRA. 

 
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Appendix 2: Symptom Questionnaire 
 
Patient ID                                                                Today’s Date 
Symptoms                                                  Score using any number between 0 and 9 
With 0 meaning no problem or none, 5 meaning troublesome and 9 being severe 
Breathlessness 
 
Running (score 9 if you don’t run because it makes you very breathless) 
 
On moderate exertion (e.g. walking quickly, climbing 2-3 flights of  stairs) 
 
On mild exertion (e.g. walking slowly or doing light housework) 
 
On slight exertion (washing or dressing) 
 
Sitting at rest 
 
Do you get breathless lying flat? 
 
Other Symptoms 
 
Swelling of Ankles 
 
Swelling of Legs Above Ankles 
 
Are you troubled by tiredness during the day? 
 
Do you suffer much from anxiety? 
 
Do you feel depressed? 
 
Chest Pain on Exertion 
 
Dizziness 
 
Palpitations 
 
Muscle Aches & Pains 
 
Cough and/or Wheeze 
 
Other Symptom or Problem (Name) 
 
Other Symptom or Problem (Name) 
 
Quality of Life (with 1 = very good, 5 = average, 9 = very bad) 
 
How do you rate your health? 
 
How do you rate your overall quality of life? 
 
Please also answer these questions “Yes” or “No” or Give a Number 
How many pillows do you sleep with? 
 
Do you sometimes wake in the night fighting for breath? 
 
If so, how many nights in the last two months? 
 
Have you had any falls?  
 
If so, how many in the last two months? 
 
Have you had any blackouts? 
 
If so, how many in the last two months? 
 
 
 

 
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Appendix 3: Managing Discontinuation of Patiromer or MRA 
 
Patients who stop patiromer should have the dose of MRA adjusted to prevent hyperkalaemia. If 
serum potassium is in the normal range, the dose of MRA should be halved or reduced to 25mg/day, 
whichever is higher. Serum potassium should be re-checked in 7-12 days. 
 
Patients who stop their MRA should have the dose of patiromer adjusted to prevent hypokalaemia.  
Many patients will be on other potassium retaining treatments and may still benefit from patiromer. 
If serum potassium is in the normal range, stop patiromer and re-check serum potassium in 7-12 days. 
If serum potassium exceeds 5.0mmol/L, patiromer should be re-started.  
 
 

 
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Appendix 4: Safety Reporting Flow Chart 
 
 

 
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Appendix 5: EQ-5D 
 
 

 
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Appendix 6: KCCQ-12  
 
 
 
 

 
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Appendix 7: Patient Global Assessment 
 
The patient global assessment should be completed by the patient after having been asked by 
either the Investigator or the Study Nurse: “Compared to before starting the trial, are you better or 
worse?”  
 
Patients should be provided with the following options: 
 
□ Markedly improved 
□ Moderately improved 
□ Slightly improved 
□ Unchanged 
□ Slightly worsened 
□ Moderately worsened 
□ Markedly worsened 
 
Please note that it should ideally always be the same person who asks the question to the patient 
during the entire duration of the study. 
 
 

 
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Appendix 8: Frailty Scale 
 
 
 
 
 

 
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Appendix 9: Key Protocol Contributors 
 
Prof John GF Cleland 
Chief Investigator, University of Glasgow 
Liz Anderson 
Director Projects Administration, University of Glasgow 
Sharon Kean 
Director Information Systems, University of Glasgow 
Michele Robertson 
Assistant Director Biostatistics, University of Glasgow 
Ammani Brown 
Patient / Public Involvement, NHS Greater Glasgow and Clyde 
Dr Elizabeth Douglas 
Senior Clinical Trials Pharmacist, NHS Greater Glasgow and Clyde 
Dr Jane Hair 
Deputy Director Biorepository, NHS Greater Glasgow and Clyde 
Dr Marc Jones 
Pharmacovigilance Officer, NHS Greater Glasgow and Clyde 
Dr Abdallah Al-Mohammed 
Sheffield Teaching Hospitals NHS Foundation Trust 
Dr Lisa Anderson 
St George's University Hospital NHS Foundation Trust 
Dr Ameet Bakhai 
Royal Free London NHS Foundation Trust 
Prof Prithwish Banerjee 
University Hospitals Coventry and Warwickshire 
Dr Craig Barr 
Dudley Group NHS Foundation Trust 
Prof Andrew Clark 
University of Hull 
Dr Justin Cooke 
Chesterfield Royal Hospital NHS Foundation Trust 
Dr Peter Cowburn 
University Hospital Southampton NHS Foundation Trust 
Dr Martin Cowie 
Imperial College Healthcare NHS Trust 
Dr Gershan Davis 
North Cumbria University Hospitals NHS Trust 
Dr Fozia Ahmed 
Manchester University NHS Foundation Trust 
Dr Karen Hogg 
NHS Greater Glasgow and Clyde 
Dr Alan Japp 
NHS Lothian 
Dr Paul Kalra 
Portsmouth NHS Trust 
Prof Phil Kalra 
Salford Royal NHS Foundation Trust 
Dr Phil Keeling 
Torbay and South Devon NHS Foundation Trust 
Dr Rebecca Lane 
Royal Brompton and Harefield NHS Foundation Trust 
Prof Chim Lang 
NHS Tayside 
Dr Ninian Lang 
NHS Greater Glasgow and Clyde 
Dr Stephen Leslie 
NHS Highlands and Islands 
Dr Andrew Ludman 
Royal Devon and Exeter NHS Foundation Trust 
Dr Theresa McDonagh 
King's College Hospital NHS Foundation Trust 
Prof Mark Petrie 
NHS Greater Glasgow and Clyde 
Dr Alison Seed 
Blackpool Teaching Hospitals NHS Foundation Trust 
Prof Iain Squire 
University Hospitals of Leicester 
Dr Ali Vazir 
Royal Brompton and Harefield NHS Foundation Trust 
Dr Robin Weir 
NHS Lanarkshire 
Dr Jay Wright 
Liverpool Heart and Chest Hospital 
Dr Zaheer Yousef 
Cardiff and Vale University Health Board 
 

 
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Appendix 10: Amendment History 
 
Amendment 
No. 
Protocol 
version 
no. 
Date issued 
Author(s) of 
changes 
Details of changes made 
01 
3.0 
04 October 2019 
Prof John 
Cleland 
Main changes: 
Updated exclusion criteria; changes 
in line with revised SmPC; updates 
to Section 10 ‘Safety and Outcome 
Reporting’ to clarify responsibilities; 
clarification relating to use of non-
labelled MRA during run-in phase, 
and for reimbursement; inclusion of 
patient questionnaires (EQ5D, 
KCCQ, PGA, and frailty scale) in 
appendices. 
03 
4.0 
 
Prof John 
Cleland 
Main changes: 
Clarification of new information 
relating to drug interactions; 
simplification of the process for 
assessing IMP compliance. 
06 
5.0 
 
Prof John 
Cleland 
Main changes: 
Clarification of process for 
monitoring non-reportable events; 
reference to AE changed to AR for 
consistency; screening log inclusion 
criteria amendment; clarification 
regarding co-enrolment; removal of 
spirometry test; capture of COVID 
history and vaccination details; 
addition of subcutaneous loop 
diuretics to primary endpoint 
definition to adapt to changes in 
clinical practice; update of 2014 
guidelines on management of 
severe hyperkalaemia to the 2020 
version. 
 
 

 
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17. REFERENCE LIST 
 
 
1.  Shoaib A, Waleed M, Khan S, Raza A, Zuhair M, Kassianides X, Djahit A, Goode K, Wong K, 
Rigby A, Clark A, Cleland J. Breathlessness at rest is not the dominant presentation of patients 
admitted with heart failure. Eur J Heart Fail 2014;16(12):1283-1291. 
     2.  Shoaib A, Mamas MA, Ahmad QS, McDonagh TM, Hardman SMC, Rashid M, Butler 
R, Duckett S, Satchithananda D, Nolan J, Dargie HJ, Clark AL, Cleland JGF. Characteristics 
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