A Multi Site, Placebo Controlled, Double Blind Randomised Clinical Trial Evaluating the Effectiveness of Sodium Zirconium Cyclosilicate Versus Placebo to Enable Safe Optimisation of RASi Therapy in Patients With Diabetic Kidney Disease.
Phase: PHASE2
Conditions: CKD, Diabetes Mellitus, Type 2, Hyperkalemia
Sponsor: Barts & The London NHS Trust

        
                
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IRAS: 1003542
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1.1 Title Page
Full / Long Title
A Multi site, placebo controlled, double blind randomised clinical trial evaluating the effectiveness of 
sodium zirconium cyclosilicate versus placebo to enable safe optimisation of RASi therapy in patients 
with diabetic kidney disease. 
Short title and/or Acronym
The ORTIZ Study: Optimising RASi Therapy with SZC
Sponsor Barts Health NHS Trust
Representative of the Sponsor:
Dr Mays Jawad
R&D Operations Manager
Barts Health NHS Trust
Research Services
Dept. W
69-89 Mile End Rd
London
E1 4UJ
Phone: 020 7882 7260
Email: research.governance@qmul.ac.uk
REC Number 21/WS/0082
Sponsor Reference (EDGE): 136721

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2.0 Research Reference Numbers 
 
IRAS Number: 
1003542
EudraCT Number: 
Sponsor ReDA Number:                         
 
2020-002988-62
012668 
ISRCTN Number / Clinical trials.gov 
Number: 
 
NCT04983979
 
 

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3.0 Signature Pages 
 
Chief Investigator Agreement 
 
The study as detailed within this research protocol will be conducted in accordance 
with the principles of Good Clinical Practice, the UK Policy Framework for Health and 
Social Care Research, the Declaration of Helsinki, and the current regulatory 
requirements, including the Medicines for Human Use (Clinical Trials) Regulations 
2004 (UK S.I. 2004/1031) and all subsequent amendments. I delegate responsibility 
for the statistical analysis and oversight to a qualified statistician (see declaration 
below). 
 
Chief Investigator name: _________________ 
 
Signature: 
_________________ 
 
Date: 
_________________ 
 
 
 
The study as detailed within this research protocol plan will be conducted in 
accordance with the principles of Good Clinical Practice, the UK Policy Framework for 
Health and Social Care Research, the Declaration of Helsinki, and the current 
regulatory requirements, including the Medicines for Human Use (Clinical Trials) 
Regulations 2004 (UK S.I. 2004/1031) and all subsequent amendments, and ICH E9 
- Statistical principles for Clinical Trials and ICH E10 - Choice of Control Groups. 
 
I take responsibility for ensuring the statistical work in this protocol is accurate, and for 
the statistical analysis and oversight of this study. 
 
 
_________________ 
 
Signature: 
_________________ 
 
Date: 
_________________ 
 
 
 
 
Thomas Godec
Sep 6, 2022
kieran mccafferty
Sep 6, 2022

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4.0 Principal Investigator Agreement Page 
 
 
Principal Investigator Agreement Page 
The clinical study as detailed within this research protocol (Version 1.1, dated 05 
Jul 2022), or any subsequent amendments, involves the use of an investigational 
medicinal product and will be conducted in accordance with the  UK Policy 
Framework for Health and Social Care Research , the World Medical Association 
Declaration of Helsinki (1996), Principles of ICH-GCP, and the current regulatory 
requirements, as detailed in the Medicines for Human Use (Clinical Trials) 
Regulations 2004 (UK S.I. 2004/1031) and any subsequent amendments of the 
clinical trial regulations. 
Principal Investigator Name: 
Principal Investigator Site: 
Signature and Date: 
4.0 Key Trial Contacts 
 
Chief Investigator 
Kieran McCafferty 
Kieran.mccafferty4@nhs.net  
phone:07980620627 
Trial Co-ordinator/Manager 
Charlie Mizon 
Barts Cardiovascular Clinical Trials Unit (Barts CVCTU) 
William Harvey Heart Centre 
Barts and The London School of Medicine 
Queen Mary University of London 
Charterhouse Square  
London EC1M 6BQ 
a.bellin@qmul.ac.uk  
cvctu@qmul.ac.uk  
Sponsor representative 
Dr Mays Jawad 
R&D Operations Manager 
Barts Health NHS Trust 
Trust headquarters Executive Offices 
Ground Floor Pathology and Pharmacy Building 
The Royal London Hospital 
80 Newark Street 
London, E1 2ES 
Phone: 020 7882 7260 
Email: research.governance@qmul.ac.uk 
 
IMP  manufacturer 
Sharp Packaging Solutions 
7451 Keebler Way 
Allentown, PA 18106, USA 
 

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Funder  and IMP manufacturer 
 
AstraZeneca 
1 Francis Crick Ave, Trumpington, 
Cambridge 
CB2 0AA 
Tamsin Morris  
Tamsin.Luff@astrazeneca.com>
Clinical Trials Unit 
Barts Cardiovascular Clinical Trials Unit (Barts CVCTU) 
William Harvey Heart Centre 
Barts and The London School of Medicine 
Queen Mary University of London 
Charterhouse Square  
London EC1M 6BQ 
cvctu@qmul.ac.uk 
Statistician 
Thomas Godec 
Barts Cardiovascular Clinical Trials Unit (Barts CVCTU) 
William Harvey Heart Centre 
Barts and The London School of Medicine 
Queen Mary University of London 
Charterhouse Square  
London EC1M 6BQ 
t.godec@qmul.ac.uk  
Trial pharmacist 
Rahi Shah Senior Clinical Trials Pharmacist 
Royal London Hospital 
Barts Health NHS trust 
Rahi.shah@nhs.net|rlhpharmacyct.bartshealth@nhs.net
02035946680 
eCRF  
CASTOR EDC 
35 Ludgate Hill 
London 
EC4M7JN 
+44(0)2033184726 
support@castoredc.com 
Randomisation  
Sealed Envelope 
501 Clerkenwell Workshops 
27-31 Clerkenwell Close 
London EC1R 0AT 
+44 (0)2034885064 
Contact@selaedenvelope.com 
IMP secondary packaging,  
labelling and distribution to 
sites 
RenaClinical Ltd 
Unit 11, Gatwick Metro centre 
Horley RH6 9GA 
+44(0)1293368080 
enquiry@renaclinical.com  
Committees  
(TSC/ DMC) 
For membership and contract details please see 
TSC/DMC charter 
 
 

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5.0 Trial Summary 
 
Full title 
A Multi site, placebo controlled, double blind randomised clinical 
trial evaluating the effectiveness of SZC versus placebo to enable 
safe optimisation of RAS therapy in patients with diabetic kidney 
disease.  
 
Short title and/or Acronym 
The ORTIZ Study Optimising RASi Therapy with SZC 
Trial Design 
Methodology 
Multi site, placebo controlled, double blind randomised 
clinical trial. 
Phase of the Trial 
II
Study Duration 
 
18 months, including  14 months recruitment period
Study setting 
 
 
Multi NHS site UK only
Investigational Medicinal Product(s) 
 sodium zirconium cyclosilicate 
Medical condition or disease under 
investigation 
Diabetic Kidney Disease
Planned Sample Size 
116
(Maximum) Treatment duration 
12 weeks 
Follow up duration 
2 weeks
End of Trial definition 
The last visit of the last subject  
 
 

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6.0 Protocol Contributors 
 
Key Protocol Contributors
Full contact details including phone, email and fax numbers
Kieran McCafferty 
Consultant Nephrologist
The Royal London Hospital 
Barts Health NHS Trust 
Kieran.mccafferty4@nhs.net  
phone: 07980620627  
Thomas Godec
Senior Statistician
Cardiovascular Clinical Trials Unit  
Queen Mary University of London 
Charterhouse Square Campus 
02078825673 
t.godec@qmul.ac.uk  
Anna Bellin
Clinical Trials Manager
Cardiovascular Clinical Trials Unit  
Queen Mary University of London 
Charterhouse Square Campus 
02078825673 
a.bellin@qmul.ac.uk  
Robert Hughes
 
GCP and Governance Manager
Joint Research Management Office 
Barts Health NHS Trust and Queen Mary University of London 
 02078827352 research.governance@qmul.ac.uk  
 
 

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7.0 List of Contents 
 
 
1.0 Title Page ........................................................................................................................................... 1 
2.0 Research Reference Numbers ........................................................................................................... 2 
3.0 Signature Pages ................................................................................................................................. 3 
4.0 Principal Investigator Agreement Page............................................................................................. 4 
5.0 Trial Summary ................................................................................................................................... 6 
6.0 Protocol Contributors ....................................................................................................................... 7 
7.0 List of Contents ................................................................................................................................. 8 
8.0 List of Abbreviations / Glossary of Terms ....................................................................................... 12 
9.0 Introduction .................................................................................................................................... 13 
9.1 Background ................................................................................................................................. 13 
9.2 Assessment and management of risk ......................................................................................... 14 
9.3 Rationale for study design .......................................................................................................... 15 
10.0 Trial Flowchart .............................................................................................................................. 16 
11.0 Trial Objectives and Design ........................................................................................................... 17 
11.1 Primary Objective/s .................................................................................................................. 17 
11.2 Secondary Objective/ ................................................................................................................ 17 
11.3 Endpoints .................................................................................................................................. 17 
11.3.1 Primary Endpoint ............................................................................................................... 17 
11.3.2 Safety  Endpoints ............................................................................................................... 17 
11.4 Exploratory endpoints ............................................................................................................... 17 
11.5 Objectives and End Points Summary ........................................................................................ 18 
11.6 Trial Design ................................................................................................................................ 19 
11.7 Study Setting ............................................................................................................................. 19 
12.0 Eligibility Criteria ........................................................................................................................... 20 
12.1 Inclusion Criteria ....................................................................................................................... 20 
12.2 Exclusion Criteria ....................................................................................................................... 20 
13.0 Trial Procedures ............................................................................................................................ 22 
13.1 Recruitment .............................................................................................................................. 22 
13.2 Participant identification .......................................................................................................... 22 
13.3 Informed Consent Procedures .................................................................................................. 22 
13.3.1 Responsibility for obtaining consent ................................................................................. 22 
13.3.2 Consent Considerations ..................................................................................................... 22 
13.3.3 Population .......................................................................................................................... 22 
considerations ............................................................................ 23 
13.3.5 Written/ reading / translation considerations ................................................................... 23 

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13.3.6 Participants lacking capacity .............................................................................................. 23 
13.3.7 Minors ................................................................................................................................ 23 
13.3.8 Consenting process ............................................................................................................ 23 
13.3.9 Additional consent provisions for collection and use of participant data and biological 
specimens in ancillary studies ....................................................................................................... 23 
13.4 Screening Procedures ............................................................................................................... 24 
13.5 Treatment Allocation ................................................................................................................ 24 
13.5.1 Randomisation Method ..................................................................................................... 24 
13.5.2 Randomisation Procedure ................................................................................................. 24 
13.5.3 Cohort allocation/sequential allocation ............................................................................ 24 
13.6 Blinding ..................................................................................................................................... 24 
13.7 Unblinding ................................................................................................................................. 24 
13.8 Trial Schedule ............................................................................................................................ 26 
13.8.1 Schedule of Treatment for each visit ................................................................................. 26 
13.8.2 Schedule of Assessment (in Diagrammatic Format) and protocolised dosing management 
of IMP ............................................................................................................................................ 26 
13.8.3 Trial assessments ............................................................................................................... 29 
13.8.4 Follow up Procedures ........................................................................................................ 30 
13.9 ................................................................................................................................................... 30 
IMP withholding criteria ................................................................................................................... 30 
13.10 Early withdrawal ..................................................................................................................... 32 
13.11 End of trial (EOT) ..................................................................................................................... 32 
14.0 Laboratories and samples ............................................................................................................. 32 
14.1 Central Laboratories ................................................................................................................. 32 
14.2 Local Laboratories ..................................................................................................................... 32 
14.3 Sample Collection/Labelling/Logging ........................................................................................ 32 
14.4 Sample Receipt/Chain of Custody/Accountability .................................................................... 33 
14.5 Sample Analysis Procedures ..................................................................................................... 33 
14.5.1 The arrangements for sample analysis .............................................................................. 33 
14.5.2 Sample Storage Procedures ............................................................................................... 33 
14.6 Sample and Data Recording/Reporting .................................................................................... 33 
14.7 End of study .............................................................................................................................. 33 
15.1 Name and description of investigational medicinal product (IMP) and non-investigational 
medicinal product (NIMP) ................................................................................................................. 34 
15.2 Legal status of the drug............................................................................................................. 34 
15.3 Summary of Product Characteristics (SmPC) or IB.................................................................... 34 
15.4 Drug storage and supply ........................................................................................................... 34 
15.5 Supplier ..................................................................................................................................... 34 

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15.6 Manufacturer ............................................................................................................................ 35 
15.7 How the drug should be stored ................................................................................................ 35 
15.8 Details of accountability ........................................................................................................... 35 
15.9 Medication destruction/return and Recall ............................................................................... 35 
15.10 Prescription of IMP / Placebo/NIMP ....................................................................................... 35 
15.11 Preparation and labelling of IMP ............................................................................................ 36 
15.12 Preparation and Administration of IMP .................................................................................. 36 
15.13 Dosage schedules .................................................................................................................... 36 
15.14 Dispensing of IMP ................................................................................................................... 36 
15.15 Dosage modifications .............................................................................................................. 36 
15.16 Known drug reactions and interaction with other therapies ................................................. 37 
15.17 Prior and Concomitant medication ......................................................................................... 37 
15.19 Assessment of adherence ....................................................................................................... 37 
15.21 Arrangements for post-trial access to IMP and care .............................................................. 37 
17 Pharmacovigilance ........................................................................................................................... 38 
17.1 General Definitions ................................................................................................................... 38 
17.2 Site Investigators Assessment ................................................................................................... 40 
17.3 Reference Safety information ................................................................................................... 40 
17.4 Notification and reporting Adverse Events or Reactions .......................................................... 40 
17.5 Notification of AEs of special interest ....................................................................................... 41 
17.6 Adverse events that do not require reporting .......................................................................... 41 
17.7 Notification and Reporting of Serious Adverse Events & SUSARs ............................................ 41 
17.8 Sponsor Medical Assessment ................................................................................................... 42 
17.9 Urgent Safety Measures ........................................................................................................... 42 
17.10 Procedures for reporting blinded SUSARs .............................................................................. 42 
17.11 Pregnancy ................................................................................................................................ 43 
18.0 Annual reporting ........................................................................................................................... 44 
19.0 Statistical and Data Analysis ......................................................................................................... 45 
19.0 Statistical and Data Analysis ......................................................................................................... 45 
19.1 Sample size calculation ............................................................................................................. 45 
19.2 Planned recruitment rate.......................................................................................................... 45 
19.3 Statistical analysis plan (SAP) .................................................................................................... 45 
Exploratory endpoints ....................................................................................................................... 46 
19.4 Summary of baseline data and flow of patients ....................................................................... 46 
19.5 Primary outcome analysis ......................................................................................................... 47 
19.7 Subgroup analyses .................................................................................................................... 47 
19.8 Adjusted analysis ...................................................................................................................... 47 

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19.6 Secondary outcome analysis ..................................................................................................... 47 
19.9 Interim analysis and criteria for the premature termination of the trial ................................. 47 
19.10 Subject population .................................................................................................................. 47 
19.11 Procedure(s) to account for missing or spurious data ............................................................ 47 
20.0 Data Handling & Record Keeping .................................................................................................. 48 
20.1 Confidentiality ........................................................................................................................... 48 
20.2 Data Custodian Details .............................................................................................................. 48 
20.3 Psuedononymisation ................................................................................................................ 49 
20.4 Transferring/Transporting Data ................................................................................................ 49 
20.5 Data collection tools and source document identification ....................................................... 49 
20.6 Source Data ............................................................................................................................... 49 
20.7 Case Report Form...................................................................................................................... 49 
20.8 CRFs as Source Documents ....................................................................................................... 50 
20.9 Data handling and record keeping ............................................................................................ 50 
20.10 Access to Data, Source Data and Documents ......................................................................... 50 
21.0 Archiving ....................................................................................................................................... 50 
22.1 Monitoring ................................................................................................................................ 50 
22.2 Auditing ..................................................................................................................................... 51 
22.3 Notification of Serious Breaches to GCP and/or the protocol .................................................. 51 
22.4 Compliance ............................................................................................................................... 51 
22.5 Non-Compliance ....................................................................................................................... 51 
22.6 Regulatory Compliance ............................................................................................................. 52 
23.0 Financial and other competing interests for the chief investigator, PIs at each site and 
committee members for the overall trial management ....................................................................... 52 
24.0 Ethical and Regulatory Considerations ......................................................................................... 52 
25.0 Peer review ................................................................................................................................... 53 
27.1 Amendments ............................................................................................................................. 53 
27.2 Access to the final trial dataset ................................................................................................. 53 
28.0 Trial Committees ........................................................................................................................... 54 
29.0 Publication and Dissemination Policy ........................................................................................... 54 
29.1 Publication ................................................................................................................................ 54 
29.2 Dissemination policy ................................................................................................................. 54 
30.0 References .................................................................................................................................... 55 
 
 
 

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8.0 List of Abbreviations / Glossary of Terms 
 
 
 
 
  
 
 
 
 
 
ACE 
 
 
 
Angiotensin converting enzyme 
ACEi 
 
 
 
Angiotensin converting enzyme inhibitor 
ADR 
 
 
 
Adverse Drug Reaction 
AE 
 
 
 
Adverse event 
ARB 
 
 
 
Angiotensin receptor blocker 
AZ 
 
 
 
AstraZeneca 
BMI 
 
 
 
Body mass index 
BNP    
 
 
Brain-type natriuretic peptide 
BNF 
 
 
 
British National Formulary 
BP 
 
 
 
Blood Pressure 
CI 
 
 
 
Chief investigator 
CKD  
 
 
 
Chronic kidney disease 
ECG 
 
 
 
Electro cardio gram 
CRF 
 
 
 
Case report form 
eCRF  
 
 
Electronic case report form 
eGFR  
 
 
estimated Glomerular Filtration Rate 
HDL  
 
 
 
High-density lipoprotein 
HRA 
 
 
 
Health Research authority 
IRAS 
 
 
 
Integrated Research Approval System 
GI  
 
 
 
Gastrointestinal  
K 
 
 
 
Potassium 
KDOQI  
 
 
Kidney Disease Outcomes Quality Initiative 
MHRA   
 
 
Medicines and Healthcare products Regulatory Agency 
MRA  
 
 
Mineralocorticoid receptor antagonist 
NICE 
 
 
 
The National Institute for Health and Care Excellence 
NIMP  
 
 
Non investigational medicinal product 
 
OD  
 
 
 
Once daily 
PI 
 
 
 
Principal Investigator 
SmPC  
 
 
Summary of product characteristics 
RAS 
 
 
 
Renin angiotensin system 
RASi   
 
 
Renin angiotensin system inhibitor 
REC 
 
 
 
Research Ethics Committee 
SAE 
 
 
 
Serious adverse event 
SAR 
 
 
 
Serious adverse reaction 
SPC 
 
 
 
Summary of product characteristics 
SUB-I  
 
 
Sub investigator 
SUSAR  
 
 
Serious unexpected serious adverse reaction 
uACR  
 
 
Urinary albumin to creatinine ratio  
SZC  
 
 
 
Sodium zirconium cyclosilicate 
WOCBP 
 
 
Woman of child bearing potential 
 

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9.0 Introduction 
 
9.1 Background 
Inhibiting the renin angiotensin (RAS) system has been the cornerstone of therapy for patients 
with proteinuric CKD for almost 2 decades, to slow the decline in renal function, delay the 
presence of dialysis and reduce cardiovascular events and death (Parving et al, Brenner et al,). 
There is evidence in both the cardiac and renal literature that suggests that maximising the 
dose of RAS therapy leads to improved outcomes over smaller doses of RAS therapy (Khan et 
al., Rossing  et al.) 
Indeed, many of the studies on which we base our care use doses which are higher than what 
the majority of our patients are taking. Thus patients are being systemically undertreated by 
therapies which have been shown to have robust reno protection. With up to 80% of patients 
on RASi therapy are not on maximal RASi therapy (Epstein et al, 2015), putting them at risk of 
a more rapid progression and poorer outcomes and increased healthcare costs (Epstein et al, 
2016). 
An important reason for this is the presence or fear around hyperkalaemia. 
With reports of significantly increased rate of hyperkalaemia seen following increases in 
prescribing of RASi therapy (Juurlink  et al.). These concerns have lead NICE to recommend 
not starting patients on RASi therapy if their potassium is >5mmol/l, and KDOQI guidelines 
recommending consideration of stopping RASi therapy if serum potassium is >5.5mmol/l.  
 
ACE inhibitors and angiotensin receptor blockers are thought to confer long term renal 
protection through reduction of proteinuria. The reduction in glomerular pressure is a major 
mechanism leading to a reduction in proteinuria, and hence renal protection, however as a 
consequence there will also an acute fall in eGFR. Therefore, when starting/up titrating 
ACEi/ARB it is expected that there will be an acute fall in eGFR, which is expected to be more 
than compensated for due to the subsequent long term renal protection. Indeed, current 
NICE guidelines (NICE 2014) do not suggest any alteration in management until the drop in 
eGFR is >25%.  
 
There is a currently huge unmet need to optimise RASi therapy in those patients with 
hyperkalaemia.  
There have been recent advances in novel therapeutics which can lower potassium in 
patients. One such agent is Sodium zirconium cyclosilicate (SZC). 
 
SZC is a highly selective inorganic cation exchanger designed to entrap potassium in the 
intestine. 
It has been shown to effective in lowering potassium in patients with heart failure, Diabetes, 
CKD and RASi therapy (Anker et al., Packham et al. and Ash et al., Kosiborod et al.). With 
around a 1mmol/l fall in the serum potassium on those treated with SZC, compared to 
placebo. 
In the 5-large clinical trials it appears efficacious, well tolerated and safe. 
 
 

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We propose the following study: the ORTIZ trial will investigate the safety and tolerability of 
SZC compared to placebo to maximise RASi therapy in patients with moderate to advanced 
CKD.  
 
 
9.2 Assessment and management of risk 
 
 and potential risks and benefits to human subjects. 
 
SZC has been shown to be safe and efficacious in several published clinical trials. 
However, in this study we will aim to maximise RASi therapy (Irbesartan) using SZC versus 
placebo.  
ADR from SZC: We foresee very little risk in the use of this agent. See SmPC for SZC 
There is a risk of hypokalaemia in those patients on SZC, however this is rarely at a level with 
is symptomatic or would lead to a discontinuation of therapy. 
 
ADR from the NIMP irbesartan: (see attached SmPC for Irbesartan) 
There are some risks due to the up titration of the RAS therapy, which are well established in 
our current standards of care. 
Hyperkalaemia, in those patients not on SZC. However, we will be monitoring those patients 
very closely during the study (checking their potassium levels following any dose changes 
within 2 weeks. With a pre-specified dose escalation/down escalation/stopping protocol to 
minimise any risk of hyperkalaemia. In addition, all patients will be given advice on a low 
potassium diet. 
 
Hypotension: as we increase the RASi (Irbesartan) therapy, this can lead to hypotension. 
However, these agents will only be increased if the BP is >120/70, so as to minimise the risks, 
and that the vast majority of the patients will be hypertensive as their background 
antihypertensive therapy will have been withheld at the start of the study. 
 
 
Given the frequency of follow up and the conservative nature of the dosing protocol used, 
there is only a very small increased risk above our standard clinical procedures. 
 
treatment period(s). 
Irbesartan is a commonly used RASi: it is being used entirely within its product license and 
dose. 
The dose of SZC is used within its licenced indication and dose.  
 
Preclinical+ clinical Data  
There have been 5 studies published using this agent, 4 of which in populations similar to our 
study population, of patients with CKD, heart failure, and on RASi therapy. 
 
 

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The study protocol of up/down titration is used to minimise any episodes of significant 
hyperkalaemia. 
 
This trial is categorised as: Type A = No higher than the risk of standard medical care 
 
9.3 Rationale for study design 
 
Research Question: Can a 3-month treatment course of  SZC enable safe optimisation of 
RASi therapy. 
This is a double-blind placebo controlled study. The reason for the use of placebo as part of 
the double-blind study is to ensure a lack of bias/confounding.  
 
 
 
 

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10.0 Trial Flowchart 
 
 
 
 
 
 
 
 
 
Patients approached by clinical team
Patient screened+ consented by study team
3 month treatment 
with placebo with 
RAASi Optimisation
Randomised
3 month treatment 
with SZC with 
RAASi Optimisation
End point assessment
SZC/Placebo stops. Back on regular treatment
Final safety visit 

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11.0 Trial Objectives and Design 
 
11.1 Primary Objective/s 
 
Our hypothesis is that 3 
 treatment with SZC versus placebo will enable RASi 
(Irbesartan) maximisation in a cohort of patients with diabetic kidney disease.  
 
 
11.2 Secondary Objective/  
 
The secondary objectives are to look at the effect of SZC on RASi maximisation on change in 
proteinuria, along with safety and tolerability outcomes   
 
11.3 Endpoints 
 
11.3.1 Primary Endpoint 
 
 
Proportion of patients on Maximum dose (300mg) Irbesartan therapy at the end of 12 weeks 
compared to placebo 
  
 
11.3.2 Safety  Endpoints 
 
 
Change in potassium from baseline at each time point 
 
Change in the BP at the end of the study from baseline 
 
Frequency of adverse events 
 
Proportion of patients who have a K of >6, or  >6.5 at any time during the study 
 
Proportion of patients who have a K of <3.5 at any time during the study 
 
Proportion of patients whose GFR falls by >30% from the previous test  
 
Change in (eGFR) renal function at the end of study from baseline 
 
 
 
11.4 Exploratory endpoints 
 
 
Change in pro BNP at the end of study from baseline 
 
Proportion of patients able to remain on 75/150/300mg  dose of irbesartan at the end of the 
study  
 
Ratio of uACR between baseline and 3-month study visit in patients treated with placebo 
versus SZC 
 
Absolute uACR at end of study 
 
Change in Urea levels  
 
Change in Bicarbonate levels  
 

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11.5 Objectives and End Points Summary 
 
 
Objective 
How 
objective 
measured 
outcome of measurement 
Examine the ability of SZC to 
enable RASi (irbesartan) 
maximisation at 12 weeks 
Dose of 
Irbesartan 
therapy at 
12 weeks 
Proportion of patients on Maximum dose 
Irbesartan therapy at the end of 12 weeks 
compared to placebo 
Effect of SZC  enabled RASi 
optimisation on potassium 
lab 
potassium 
Change in potassium from baseline at 
each time point 
Effect of SZC  enabled RASi 
optimisation on BP 
clinic BP 
change in BP between start and end of 
study 
Examine the effect of SZC use 
on patient safety 
SAE/AE 
Frequency of adverse events 
Effect of SZC  enabled RASi 
optimisation on incidence of 
severe hyperkalaemia 
lab 
potassium 
Proportion of patients who have a K of >6, or  
>6.5 at any time during the study 
Effect of SZC  enabled RASi 
optimisation on incidence of 
hypokalaemia  
lab 
potassium 
Proportion of patients who have a K of <3.5 at 
any time during the study 
Effect of SZC  enabled RASi 
optimisation on incidence of 
AKI 
eGFR 
Proportion of patients whose GFR falls by 
>30% from the previous test 
Effect of SZC  enabled RASi 
optimisation on renal function 
eGFR 
Change in (eGFR) renal function at the end of 
treatment from baseline 
Effect of SZC  enabled RASi 
optimisation on markers of 
heart failure 
lab BNP 
change in pro BNP between start and end 
of treatment 
Examine the ability of SZC to 
enable RASi (irbesartan) 
uptitration 
Dose of 
Irbesartan 
therapy at 
each visit 
Proportion of patients able to remain on 
75/150/300mg dose of irbesartan at the end 
of treatment 
Effect of SZC on enabled RASi 
optimisation on proteinuria 
uACR 
Ratio of uACR between baseline and 3-month 
study visit in patients treated with placebo 
versus SZC 
Effect of SZC on enabled RASi 
optimisation on proteinuria 
uACR 
Absolute uACR at end of treatment 
 
 
 

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Effect of SZC on bicarbonate 
levels  
Serum 
Bicarbonate 
Change in serum bicarbonate levels between 
baseline and end of treatment 
Effect of SZC on urea  
Serum urea 
Change in serum urea levels between baseline 
and end of treatment 
 
 
 
  
 
11.6 Trial Design 
 
This is a double-blind placebo controlled pilot study to determine if SZC enables safe dose 
maximisation of RASi therapy (Irbesartan) in patients with diabetic kidney disease.  
 
Patients will be randomised in 1:1 ratio to SZC or placebo. This will be used in addition to 
Irbesartan, the RASi therapy of choice for this study.   
 
ber of study visits will be 8: screening visit, randomisation visit then at 
2,4,6,8,12,14 weeks post randomisation. 
The treatment period will be 12 weeks; the patients will be in the study for 16 weeks. 
 
 
11.7 Study Setting 
 
This is multi centre study (5 sites), with no PIC sites. 
The study will take place in an NHS setting: 
 
Barts Health NHS Trust, with PI Kieran McCafferty 
 
 
 
Imperial College Healthcare NHS Trust, with PI Andrew Frankel 
 
oundation Trust, with PI Richard Hull 
 
Epsom and St Helier University Hospitals NHS Trust, with PI Pauline Swift 
Patients will be recruited from a cohort of patients under the nephrology services in 
secondary care.   
 
 
 

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12.0 Eligibility Criteria 
 
12.1 Inclusion Criteria 
1) Subject must be able and willing to provide written informed consent 
2) Adults  18years old 
3) Type 2 Diabetes  
4) CKD defined as eGFR 25-60ml/min 
5) Albuminuria with uACR measured at >33.9.mg/mmol (300mg/g) 
6) On a stable (>4 weeks) of sub-maximal RASi dose, defined as any ACE or ARB dose up to and 
including  50% of maximum dose as per BNF (see table below) with evidence of hyperkalaemia 
potassium level >5.0mmol/l OR not currently on RASi therapy due to documented issues of 
hyperkalaemia in the past necessitating RASi discontinuation 
 
 
Drug name 
Maximum dose 
Trandrolapril 
4mg 
Captopril 
100mg 
Lisinopril 
10 mg 
Perindropril 
8 mg 
Quinapril 
80 mg 
Ramipril 
10 mg 
Fosinopril 
40 mg 
Imidapril 
20 mg 
Enapril 
40 mg 
Candesartan 
32 mg 
Azilsartan 
80 mg 
Eprosartan 
600 mg 
Irbesartan 
300 mg 
Losartan 
100 mg 
Omlesartan 
40 mg 
Valsartan 
320 mg 
Telmisartan 
80 mg 
 
 
 
12.2 Exclusion Criteria 
 
 
1) Active malignancy 
2) Patients who lack capacity to give informed consent  
3) GI disturbance/chronic diarrhoea/stoma 
4) Subjects with a life expectancy of less than 3 months. 

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5) Women who are pregnant, lactating, planning to become pregnant. 
6) Women of childbearing potential who are unwilling to use effective methods of 
contraception  during the study. 
7) Presence of any condition which, in the opinion of the investigator, places the subject 
at undue risk or potentially jeopardizes the quality of the data to be generated 
including NYHA class III/IV. 
8) History of acute eGFR fall with RASi therapy (>30% in eGFR on initiation of RASi 
therapy) 
9) Known hypersensitivity or previous anaphylaxis to SZC or Irbesartan  
10) Hypotension: BP <120/70mm/hg at screening despite no antihypertensive agent use 
11) Uncontrolled Blood pressure: BP >170/110 at screening 
12) Evidence of prolonged QT on ECG QTc(f)>550msec 
13) History of QT prolongation associated with other medications that required 
discontinuation of that medication 
14) Treatment with lithium, or dual blockade with ACEi and ARB or mineralocorticoid 
inhibitor 
15) History of congenital long QT syndrome 
16)  Symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic 
sustained ventricular tachycardia. Subjects with atrial fibrillation controlled by 
medication are permitted 
17) Current or recent (within 3 months) participation in a clinical trial involving an 
investigational medicinal product. 
18) Current treatment with a potassium binder medication 
19) Potassium value > 6mmol/l at Randomisation 
 
 Effective contraception defined as oral contraceptive pill, Intra-Uterine Device, double 
barrier methods or abstinence as a clearly defined lifestyle choice for the whole duration 
of the study.  
 
 
 

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13.0 Trial Procedures 
 
13.1 Recruitment 
 
13.2 Participant identification 
 
Participants will be identified by their regular clinical team. Eligibility decision will be made 
by the CI/PI. 
 
 
13.3 Informed Consent Procedures 
 
Informed consent will be obtained prior to the participant undergoing procedures that are 
specific to the trial and are outside standard routine care at the participating site (including 
the collection of identifiable participant data or entering data into the study case report 
form). 
 
13.3.1 Responsibility for obtaining consent 
 
The Chief Investigator (CI)/ local PI retains overall responsibility for the informed consent of 
participants at their site and must ensure that any person delegated responsibility to 
participate in the informed consent process is duly authorised, trained and competent to 
participate according to the ethically approved protocol, principles of Good Clinical Practice 
(GCP) and Declaration of Helsinki. If delegation of consent occurs then details should be 
provided in the Site Delegation Log. 
 
Consent can only be taken by the CI/PI or a medical practitioner trained in the study and 
delegated on the study log. 
 
13.3.2 Consent Considerations 
 
The right of a patient to refuse participation without giving reasons will be respected. 
 
The participant must remain free to withdraw from the trial at any time without giving 
reasons and without this compromising his/her further treatment and must be provided with 
a contact point where he/she may obtain further information about the trial. Where a 
participant is required to re-consent, for example if during the trial new Reference Safety 
Information becomes available, or following an amendment that affects the patient, or new 
information needs to be provided to a participant, it is the responsibility of the CI to ensure 
this is done in a timely manner. 
 
13.3.3 Population 
 
The patient population is adult patients under the care of the Nephrology departments in 
secondary care 

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 The CI or delegated local PIs take responsibility for ensuring that all vulnerable subjects are 
protected and participate voluntarily in an environment free from coercion or undue 
influence.  
 
 
13.3.5 Written/ reading / translation considerations 
 
For patients who do not speak English, we will make every effort to offer independent advocates or 
standard clinical translation services (eg Language line) to enable informed consent to take place and 
for subsequent study visits. 
 
 
13.3.6 Participants lacking capacity 
 
We will not approach any patient who is felt not to have capacity to take part in the study.  
 
13.3.7 Minors 
 
Patients under 18 are not eligible to participate in the study. 
 
13.3.8 Consenting process 
 
Patients will be approached by a member of the clinical team and asked if they would like to 
know more about the study. If the patient is interested, the research team will contact the 
patient to discuss the trial. They will inform the potential participant or his/her legal 
representative about the nature and objectives of the trial and possible risks associated with 
their participation. 
 
In addition, they will receive the PIS and have a minimum of 24 hours to read it and have all 
their queries satisfactorily answered.  
 
 
 
13.3.9 Additional consent provisions for collection and use of participant data and 
biological specimens in ancillary studies 
 
Patient samples will be stored and destroyed as per standard practice. Samples will not be 
not be used for future research. 

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13.4 Screening Procedures  
 
All participants that undergo screening will be logged into a study specific screening log. 
 
Following consent, and before randomisation takes place procedures will be performed see 
section 13.8.3 for details. 
 
 
13.5 Treatment Allocation 
 
13.5.1 Randomisation Method 
The method of randomisation will be a simple 1:1 randomisation using a computer based 
randomisation sequence (sealed envelope). 
details and study number will be documented in the Investigator site file. 
 
13.5.2 Randomisation Procedure 
 
An online Randomisation tool (sealed envelope) will be used and recorded as part of the 
eCRF/Study database. Please see the ORTIZ Randomisation and Unblinding procedure for full 
details.  
 
13.5.3 Cohort allocation/sequential allocation 
n/a 
 
13.6 Blinding 
 
This is a double-blind placebo study: both the patient and the study team will be blinded to 
the treatment intervention.  
 
 
13.7 Unblinding 
will be the responsibility of the CI. 
 
o be broken if possible a formal request for unblinding 
must be made by the Investigator or treating health care professional or sponsor (following 
a SUSAR or SAE), however in the case of an emergency the PI or CI can unblind a participant 
via the unblinding software (sealed envelope). 
 
 PI/CI or their team then that health care 
professional will notify the Investigator team that an unblinding is required for a trial subject 
and an assessment to unblind should be made in consultation with the clinical and research 
teams and CI. 
 
atment allocation details the CI or treating health care professional 
riate. 

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 must document the breaking of the code and the reasons for doing so on the 
eCRF/data collection tool, in the site file and medical notes. The CI/PI will ensure it is also 
documented  in the final study report and/or statistical report at the end of the study. 
 
PI or delegate will notify the CI in writing as soon as possible following the code break 
detailing the necessity of the code break. 
 
Trial Steering Committee/Drug 
Monitoring Committee for review. 
 
Upon receipt of a SUSAR notification, the JRMO GCP team will log in to Sealed Envelope to 
confirm the treatment allocation of the patient and to make an unblinded SUSAR report to 
the MHRA. The JRMO will not share the treatment allocation information with any blinded 
study team members. 
 
 
 
 
 
 

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13.8 Trial Schedule 
 
13.8.1 Schedule of Treatment for each visit 
See study schedule table below 
13.8.2 Schedule of Assessment (in Diagrammatic Format) and protocolised dosing 
management of IMP 
Schedule of visits 
Screen
ing 
Visit 
1 
Visit 
2 
Visit 
3 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
follow up 
visit 
Unsched
uled 
Early 
terminati
on visit 
Day 
Day -
14 to -
7 
Day 
0 
Day 7
(+/-2)
Day 
14 
(+/-4)
Day 
28(+/
-4) 
Day 
42 
(+/-4)
Day 
56(+/
-4) 
Day 
84(+/
-4) 
Day 98 
(+/-4) 
  
 
Informed 
Consent 
X 
  
  
  
  
  
  
  
  
  
 
Eligibility criteria 
X 
X 
  
  
  
  
  
  
  
  
 
Demographic 
data 
X 
  
  
  
  
  
  
  
  
  
 
Medical history 
X 
  
  
  
  
  
  
  
  
  
 
Pregnancy test if 
WOCBP 
X 
  
  
  
  
  
  
  
  
  
 
Concomitant 
medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
if needed
X 
Randomisation 
  
X 
  
  
  
  
  
  
  
  
 
Stop background 
antihypertensives 
X 
 
 
 
 
 
 
 
 
 
 
First IMP dose at 
site 
 
X 
 
 
 
 
 
 
 
 
 
Drug 
accountability 
(IRB and SZC) 
  
  
X 
X 
X 
X 
X 
X 
  
If needed
 
IMP and NIMP 
drug dispense 
  
X 
  
  
X 
  
X 
  
  
If 
needed  
 
Physical 
examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 If 
needed 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
If needed
X 
FBC 
  
X 
  
  
  
  
  
X 
  
If 
needed  
 
U+E  
(+bicarbonate) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
If needed
X 
Pro NT BNP 
  
X 
  
  
  
  
  
X 
  
  
 
Optional POC 
potassium 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
ECG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
If needed 
X 
Urine collection 
(uACR) 
  
X 
  
  
  
  
  
X 
  
If needed 
 
AE assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Uptitration of 
RASi 
  
X 
X 
X 
X 
X 
  
  
If needed
 

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 RASi dose back 
to baseline  
  
  
  
  
  
  
  
X 
  
  
X 

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13.8.3 Trial assessments 
Screening visit 
 
 
a. Informed consent 
b. Inclusion/Exclusion criteria 
c. Demographic data 
d. Concomitant Medication 
e. Physical examination 
f. Medical history 
g. ECG with QTc (f) measured 
h. Vital signs (weight/height/BP/pulse) 
i. 
Laboratory investigations: U+E 
j. 
Pregnancy test for women of childbearing potential 
k. Stop all antihypertensive medications (unless judged by PI as fulfilling other purpose 
eg: beta blockers may continue in patients with angina/arrhythmia or as judged by PI 
as a risk to health to stop all antihypertensives.) 
Rescreening: If patient does not meet the inclusion/exclusion criteria patients, but PI feels 
there is a likelihood of subsequently meeting criteria then the patient may be rescreened (up 
to a maximum of 3 times)  
 
Within 7-14 days of screening visit 
Randomisation visit 1 
a. Concomitant Medication  
b. ECG with QTc (f) measured 
c. Confirmation of meeting Inclusion and no Exclusion criteria 
d. Physical examination 
e. Vital signs (weight/BP/Pulse) 
f. Urine ACR 
g. Lab bloods: U+E (including bicarbonate) , FBC, NT pro BNP 
h. Point of care potassium (optional)_  
i. 
Adverse event assessment (AE and SAE) 
j. 
Randomisation 
k. Study drug dispense and irbesartan dose chosen as per K value** 
l. 
Patient shown how to take IMP and given first dose in clinic. 
 
Visit 2,3,4,5,6: see protocolised  
a. Concomitant Medication:  
b. IMP accountability* 
c. Physical examination 
d. Vital signs (weight/BP/Pulse) 
e. ECG with QTc(f) measured 
f. Lab bloods: U+E (including bicarbonate) 
g. Point of care potassium (optional)  
h. Adverse event assessment (AE and SAE) 
i. 
Up titration assessment using BP/K**/GFR : see protocol figure 13.8.2  
j. 
Dispense IMP: visit 4 +6 only. At visits 2,3 and 5 unused IMP and nIMP are returned 
to the patient after accountability. 

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Visit 7 
a. Concomitant Medication review 
b. IMP and RASI accountability* 
c. Physical examination 
d. Vital signs (weight/BP/Pulse) 
e. ECG with QTc (f) measured 
f. Lab bloods: FBC, U+E (including bicarbonate), Pro NT BNP 
g. Point of care potassium (optional) 
h. uACR 
i. 
Adverse event assessment (AE and SAE) 
j. 
IMP stopped 
k. Irbesartan stopped and patient returned to their original dose of ACE/ARB  
 
 
13.8.4 Follow up Procedures 
 
Visit 8 
a. Concomitant Medication review 
b. Vital signs (weight/BP/Pulse) 
c. Lab bloods: U+E 
d. Physical examination 
e. ECG with QTc(f) measured 
f. Adverse event assessment 
 
 
 
BP/pulse to be recorded after resting seated for minimum of 5 minutes: performed in 
triplicate with the average rate, systolic and diastolic values taken from the second 
and third readings. 
 
*IMP accountability includes SZC/placebo and the NIMP: Irbesartan. The patient will 
be asked to bring back the IMP and Irbesartan to each clinic visit for accountability. 
The IMP/NIMP will then be given back to the patient, except for visit 4 and 6 where 
new IMP will be dispensed. 
 
** K value measured using local labs on the day of clinic (an optional point of care 
potassium can be used to determine the potassium for dispensing purposes if sites use 
this routinely. Note if there is a discrepancy between point of care potassium and local 
lab potassium then local lab potassium will be taken as the correct value for protocol 
decisions) 
  
If K>6 at clinic visit, patient should have repeat K check as an unscheduled visit and 
management as per local guidelines. 
 
13.9  
 
IMP withholding criteria 
The IMP will be withheld immediately and the patient will receive appropriate medical 
intervention, but continue in the study  if: 

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 Potassium < 3.5 mmol/L, at any time during the study* 
 Potassium is found to be  >6.5 despite not being on ARB any time during the study. 
 If an absolute QTc(f) >550ms, or an increase in QTc interval > 60ms from baseline to 
more than 500ms is reached . All patients meeting the QTc(f)>500ms criterion should 
immediately have potassium assessed, if not already done within 1 hour of 
performing the ECG. 
 
 
 if the investigator feels that individual adverse events  or IMP related side effects 
 for example if the investigator feels 
that hyperkalaemia is a safety risk, then the IMP/or NIMP may be stopped and the 
patient treated as per local standard of care.  
 In addition the patient may be brought up for an unscheduled visit to recheck 
potassium if felt to be clinically needed as per local practice  
 The investigator feels that individual adverse events or new information gained 
mean that it is not safe to continue the study 
 If the patient becomes pregnant. 
 If the patient is found to be non-adherent to the study medication (see section 
15.19) 
 
If at a subsequent visit(s), and after appropriate management and if the withholding criteria 
are no longer present the PI may elect to reintroduce the IMP.  
*If a patient develops hypokalaemia (<3.5mmol/l) the IMP will be withheld and the patient 
will be manged as standard of care. The IMP can only be restarted if hypokalaemia has 
resolved and the serum potassium has risen to >5mmol/l. If hypokalaemia (serum K 
<3.5mmol/l) recurs on reintroducing IMP then IMP is permanently withdrawn.  
** If a patient develops severe hyperkalaemia with a serum K of >6.5mmol/l despite not 
being on an ARB. The patient will be withdrawn from the IMP permanently and receive 
standard of care as per local policies/national guidelines (Alfonzo et al 2019), which may 
include but are not limited to: admission to hospital for cardiac monitoring, cardiac 
stabilisation with IV calcium,  insulin/dextrose, nebulised salbutamol, bicarbonate treatment 
if acidotic, addition of loop or thiazide diuretics or potassium binders/resins cessation of 
NSAIDS, non selective beta blockers,  mineralocorticoid receptor antagonists, trimethoprim, 
reinforcement of dietary restrictions or dialysis.  
Patients will remain on the study and continue with the study visits, but will stop the IMP 
and may need to reduce their RASi back to their original dose. 
Patients would be encouraged to continue with the study visits for safety, however should 
they not want to take part in any further study visits, they can withdraw from the study and 
continue to be followed up by their clinical care team as standard.  
 
Routine clinical data collection will continue for patients who have withdrawn from the 
study unless they specifically opt out of using routine clinical data collection. 

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Should a patient withdraw from the study this will be documented on the CRF using a study 
termination form which including recording reasons for withdrawal and consent for any 
follow-up information being collected. 
 
 
13.10 Early withdrawal 
 
If a patient is withdrawn from the IMP early they will continue with their standard care at 
the unit. 
It will be documented in the CRF and medical notes if the patient is happy to continue on 
with study visit schedule and assessments (without the IMP) or continue to have their 
clinical data collected or no further data collected. 
 
 
13.11 End of trial (EOT) 
 
sponsor approval. The EOT notification must be received by REC and MHRA within 90 days of 
the end of the trial. 
If the study is ended prematurely, the Chief Investigator will notify the Sponsor, REC & MHRA 
including the reasons for the premature termination (within 15 days). 
 
End of Trial definition: is after the last patient has completed their last visit. 
14.0 Laboratories and samples 
 
14.1 Central Laboratories 
 
No central labs will be used. 
 
14.2 Local Laboratories  
 
Biochemistry and haematology samples will be sent to the local site Laboratory. Lab tests 
performed are: renal function (U+E), NT pro BNP, uACR FBC. 
 
14.3 Sample Collection/Labelling/Logging 
 
Samples will be collected by the research nurse or trained phlebotomist as per standard of 
care. 
Samples will be labelled with patient identification and sent to the local labs as per routine 
care and the results logged on the eCRF. 
 
) to be collected: 
The total volume of bloods which will be taken on top of routine care is: 

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2 tea-spoons (3-5ml) of blood per clinic visit (7x5ml samples of blood) in a lithium heparin 
tube provided locally. 
 
or blood will be stored as part of the study 
 
 
14.4 Sample Receipt/Chain of Custody/Accountability 
 
Samples will be sent to the lab by the research nurse, where they will be processed per the 
responsibility for the custody of the samples until they are handed over the lab technicians 
at the sample collection point. 
 
 
14.5 Sample Analysis Procedures 
 
14.5.1 The arrangements for sample analysis 
 
Samples will be taken to the local lab by the research nurse/team after being taken. All 
samples will be processed in accordance with local procedures. 
No samples will be shipped to external labs/sites. No samples will be retained. 
 
 
 
14.5.2 Sample Storage Procedures 
 
n/a 
 
14.6 Sample and Data Recording/Reporting  
 
Data will be recorded on the source data worksheets and eCRF. 
The eCRF will be completed by a member of the study team delegated by the PI at each of the 
participating sites.  
 
14.7 End of study 
 
No material will be kept in the department. All biological samples will have been sent to the lab and 
disposed of as per their routine SOP. 
 
 

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15.0 Trial Medication 
 
15.1 Name and description of investigational medicinal product (IMP) and non-
investigational medicinal product (NIMP) 
 
IMP:  5g/10g sodium zirconium cyclosilicate (SZC) or placebo powder for oral suspension 
sachets.  
 
SZC/placebo will be provided free of charge to hospital sites for use in patients being 
treated within the ORTIZ clinical trial. 
SZC/placebo will be packaged in two types of IMP kits: 
 Induction kit: carton containing 6 sachets of 10g SZC/placebo  
 Maintenance kit: carton containing 30 sachets of 5g SZC/placebo 
 
NIMP: Irbesartan 75mg/150mg/300mg tablets (see product SMPC for full details).  
Irbesartan will be supplied from the local hospital stock as per standard of care.  
 
 
Refer to the ORTIZ Pharmacy Manual for further information regarding the IMP and NIMP 
 
15.2 Legal status of the drug 
 
SZC is currently licensed in the UK for the treatment of hyperkalaemia in adult patients 
 
 
15.3 Summary of Product Characteristics (SmPC) or IB 
 
Refer to the current SMPC for the products SZC and Irbesartan for further information.  
 
15.4 Drug storage and supply 
 
  
The IMP/placebo will be shipped securely to the clinical trials pharmacy from the supplier, 
where it will be stored until needed. The research nurse will collect the IMP/placebo from the 
clinical trials pharmacy and give this to the study patients. All medicinal products left over 
after study completion will be destroyed. 
 
15.5 Supplier 
 
The final drug product (carton containing sachets of SZC/placebo) will be packaged, labelled 
and sent to site pharmacy by RenaClinical Ltd.  
 
RenaClinical  
Horley,  
United Kingdom 

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15.6 Manufacturer 
The sachets of SZC/placebo were manufactured by Sharp Packaging Solutions on behalf of 
AstraZeneca. 
Sharp Packaging Solutions 
7451 Keebler Way 
Allentown, PA 18106, USA 
AstraZeneca, Cambridge, UK 
ThermoFisher is responsible for the distribution of the drug product on behalf of 
AstraZeneca, from Sharp Packaging Solutions to RenaClinical Ltd.  
Depot in USA: Fisher Clinical Services, 700A Nestle Way Breinigsville, PA, 18031, USA 
Depot in UK: Fisher Clinical Services, Langhurstwood Road, Horsham, West Sussex, RH12 
4QD, UK 
 
15.7 How the drug should be stored 
SZC/placebo must be stored at room temperature, between 15 - 
  
  
 
15.8 Details of accountability 
 
 SZC/placebo will be dispensed from pharmacy and given to the patient by a member of the 
research team on the delegation log.  
The details of study medication received, dispensed, and returned should be recorded on 
the study accountability logs.  
Accountability logs should be maintained by the clinical trial pharmacy. 
 
 
15.9 Medication destruction/return and Recall 
 
At visits 4, 6 and 7 any unused, used or partially used IMP and nIMP will be returned and 
counted. After the monitor has verified the accountability, the sponsor and CI will authorise 
destruction as per local policy. 
 
15.10 Prescription of IMP / Placebo/NIMP 
 
The IMP, (SZC/Placebo) will be prescribed by the PI or one of the sub-investigators using the 
study prescription template.  
The NIMP, Irbesartan, will be prescribed by the PI or one of the sub-investigators  as per 
standard of care, and it will be dispensed from local hospital stock.  
 

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15.11 Preparation and labelling of IMP 
 
The active treatment is SZC 5g/10g. The placebo contains no active ingredient and is a visual match to 
the active.  
The final drug product (cartons containing sachets of SZC/placebo) will be packaged, 
labelled and sent to site pharmacy by RenaClinical Ltd.  
 
15.12 Preparation and Administration of IMP 
 
For SZC/placebo, the contents of the sachet(s) should be stirred well in approximately 45ml 
water before ingestion.  
Patients will be counselled on how to take the study medication during visit 1. 
 
15.13 Dosage schedules 
 
At visit 1  (randomisation visit) the patient will be dispensed IMP according to the potassium 
level.   
 
If serum potassium level is 5mmol/L or less the patient will receive SZC/placebo 5g OD.  
 
If the serum potassium level is 5.1-5.5 mmol/L the patient will receive SZC/placebo 10g TDS for 
48h followed by SZC/placebo 5g OD.   
 
If the serum potassium level is 5.5-6 mmol/L the patient will receive SZC/placebo 10g TDS for 
48h followed by SZC/placebo 10g OD. 
 
SZC/placebo should be taken once a day with or without food.  
 
Drug accountability will be assessed at visits 2-7 and finally at month 3 where patients will 
bring back their remaining unused supply. Non-adherence is defined as less than 70 % of 
medications taken.  
 
15.14 Dispensing of IMP 
 
There will be a dispensing guideline in place within pharmacy. Each member of staff who 
dispenses the IMP should sign the local/pharmacy dispensing log to document appropriate 
IMP tracking. Any members of the trial team should ensure that they have had study specific 
training and their involvement should be demonstrated by the study specific trial delegation 
log.  
 
Refer to the ORTIZ Pharmacy Manual for the type and number of SZC/placebo kits to be 
dispensed at study visit.  
 
15.15 Dosage modifications 
 
 
 

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The dose of SZC/placebo and irbesartan will be adjusted at each of the subsequent protocol 
visits (2, 3, 4, 5 and 6) following the baseline visit, depending on results from the safety 
assessments (eGFR change from previous test, blood pressure, and potassium level 
according to the protocolled SZC/placebo and irbesartan dosing schedule. These changes 
are described in figure in 13.8.2. 
 
The max dose of SZC/placebo will be 10g (2 sachets) OD. The max dose of irbesartan will be 
300mg OD. 
 
 
 
15.16 Known drug reactions and interaction with other therapies 
As SZC is not absorbed or metabolised by the body, and does not meaningfully bind other 
medicinal products, there are limited effects on other medicinal products. 
SZC can transiently increase gastric pH by absorbing hydrogen ions and can lead to changes 
in solubility and absorption kinetics for co-administered medicinal products with pH-
dependent bioavailability.  
Therefore SZC should be administered at least 2 hours before or 2 hours after oral 
medications with clinically meaningful gastric pH dependent bioavailability.   
Examples of medicinal products that should be administered 2 hours before or after SZC to 
avoid possible raised gastric pH drug interaction are:                                                           
 
azole antifungals (ketoconazole, itraconazole and posaconazole),          anti-HIV drugs  
(atazanavir, nelfinavir, indinavir, ritonavir, saquinavir, raltegravir, ledipasvir and rilpivirine) and 
 
tyrosine kinase inhibitors  (erlotinib, dasatinib and nilotinib) 
 
15.17 Prior and Concomitant medication 
 
Prohibited medications:  
No other potassium binder medications are permitted (Patiromer/Calcium resonium) 
During the study treatment period when patients are on irbesartan, they should not be 
commenced on any ACEi/ARB/MRA or direct renin inhibitors (eg aliskiren) 
 
 
15.19 Assessment of adherence 
 
IMP adherence will be assessed at each visit, when the research team will count the number 
of doses used and consider less than 70% adherence or >120% to be non-adherent. If the 
patient fails compliance on consecutive 2 visits they will be withdrawn from the study 
medication and returned to standard of care.  
Overdose: if in the unlikely event the patient is found to have taken overdose of IMP (>150% 
of IMP taken), then IMP will be withheld and patient will be managed as per standard of 
care. 
 
 
15.21 Arrangements for post-trial access to IMP and care 
 

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No arrangements have been made for post-trial access to IMP, however this drug is approved for 
treating hyperkalaemia in those patients with a potassium of >6. As such patients who have a 
potassium of >6 may receive this drug as per standard of care after the study. 
 
17 Pharmacovigilance 
 
17.1 General 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 Event of 
Special interest (AESI) 
An adverse event of special interest (serious or non-serious) is one of 
programme, for which ongoing monitoring and rapid communication by the 
investigator to the sponsor could be appropriate. Such an event might 
require further investigation in order to characterise and understand it. 
Depending on the nature of the event, rapid communication by the trial 
sponsor to other parties (e.g., regulators) might also be warranted.  
 
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. 
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. 
SAEs will be collected from the time the patient signs the consent from until 
their last study visit.  
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. 

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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 (RSI): 
 In the case of a product with a marketing authorisation, in the summary of 
product characteristics (SmPC) for that product. 
 In the case of any other investigational medicinal product, i
brochure (IB) relating to the trial in question. 
 
 

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17.2 Site Investigators Assessment 
 
The Chief Investigator is responsible for the care of the participant, or in his/her absence a 
delegated medical practitioner  and  is responsible for assessment of any event for: 
 
 
Seriousness 
Assessing whether the event is serious according to the definitions given in section 17.1. 
 
 
Causality 
Assessing the causality of all serious adverse events/reactions in relation to the trial treatment 
according to the definition given. If the SAE is assessed as having a reasonable causal 
relationship, then it is defined as a SAR. 
 
 
Expectedness 
Assessing the expectedness of all SAEs according to the definition given.  If the SAE is 
unexpected, then it is a SUSAR. 
 
 
Severity 
Assessing the severity of the event according to the following terms and assessments. The 
definition based on patient/event outcome criteria. 
 
o Mild: Some discomfort noted but without disruption of daily life 
o Moderate: Discomfort enough to affect/reduce normal activity 
o Severe: Complete inability to perform daily activities and lead a normal life 
 
17.3 Reference Safety information 
 
Reference Safety Information (RSI) is the information used for assessing whether an adverse 
reaction is expected. 
 
 See attached SZC Summary of Product Characteristics | AstraZeneca UK Limited  
For the nIMP Irbesartan we will use the SMPC for Irbesartan (Sanofi) as an example of the 
SMPC to be used when deciding expectedness, though multiple brand of irbesartan may be 
used. 
 
 
17.4 Notification and reporting Adverse Events or Reactions 
 
If the AE is not defined as SERIOUS, the AE is recorded in the study file and the participant is 
(where appropriate) and the CRF. 

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All AEs will be sent to AZ quarterly: AE report and accompanying cover page by way of fax to 
 fax line: +1 302 886 4114 or email if a secure is set up: 
AEMailboxClinicalTrialTCS@astrazeneca.com 
This will be completed by the trial manager. 
 
 
17.5 Notification of AEs of special interest 
 
Potassium levels at any point >6.5mmol/l 
Any potassium level <3.5mmol/l 
 
17.6 Adverse events that do not require reporting 
 
Specific biochemical and physiological parameters (potassium, BP, creatinine) will be 
expected to be altered as part of the predefined protocol and would not be expected to be 
reported as AEs: with the exception of those associated with an SAE or an AE of special 
interest (as above) 
 
 
 
17.7 Notification and Reporting of Serious Adverse Events & SUSARs  
 
sponsor SAE form and reported to the sponsor (Barts Health NHS Trust Joint Research 
Management Office at research.safety@qmul.ac.uk) and to the cardiovascular clinical trials 
unit at cvctusafetyreporting@qmul.ac.uk within 24 hours of the CI or the PI or co-
investigators becoming aware of the event. Nominated co-investigators (as listed in the 
delegation log) will sign the SAE forms in the absence of the  PI at the participating sites.  
 
Suspected Unexpected Serious Adverse Reactions (SUSARs) that occur during the trial will 
be reported to the JRMO within 24 hours of the CI or co-investigator becoming aware of the 
event. SUSARs should be reported to the sponsor (Barts Health JMRO at 
research.safety@qmul.ac.uk) and to the cardiovascular clinical trials unit at 
cvctusafetyreporting@qmul.ac.uk within 24 hours. The sponsor will then report this to the 
MHRA. 
 
SAEs that do not require expedited reporting to the local authorities need to be reported to 
AstraZeneca at least quarterly, preferably as they occur, either as individual case reports or 
as line-listings. This will be done by the central trial manager. 
When reporting to AstraZeneca, a cover page should accompany the SAE form indicating the 
following: 
-External Sponsored Research (ESR) 
 -
 

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-The trial name/title and AstraZeneca  ESR reference number 
Investigative site must indicate, either in the SAE report or the cover page, the causality of 
events in relation to all study medications.  
Send SAE report and accompanying cover page 
 
SAE 
to 
be 
reported 
to 
the 
AstraZeneca 
Safety 
mailbox  
(AEMailboxclinicaltrialTCS@astrazeneca.com) or 
302 886 4114 
 
 
17.8 Sponsor Medical Assessment 
 
The CI retains overall responsibility for oversight of IMP safety profile and medical assessment 
of SAEs and SUSARs. The CI must review all SAEs within 48 hours of receipt. This review should 
encompass seriousness, relatedness and expectedness. Day 0 for all SUSARs is when the 
SAE/SUSAR is received by the CI and /or coordinating team and /or sponsor whichever is first. 
 
It is expected that the CI will achieve oversight of IMP safety profile through trial 
committees as per section 28.0. 
 
 
17.9 Urgent Safety Measures 
 
The CI may take urgent safety measures to ensure the safety and protection of the clinical 
trial subjects from any immediate hazard to their health and safety. The measures should be 
taken immediately. In this instance, approval from the Competent Authority prior to 
implementing these safety measures is not required. However, it is the responsibility of the 
CI to attempt, where possible, to discuss the proposed measures with the Sponsor and 
Medical Advisor at the MHRA (via telephone) prior to implementing them if possible. 
 
The CI has an obligation to inform both the MHRA and Research Ethics Committee in writing 
within 3 days, in the form of a substantial amendment along with Astra Zeneca. The sponsor 
(JRMO) must be sent a copy of the correspondence with regards to this matter as soon as it 
is sent. 
 
17.10 Procedures for reporting blinded SUSARs 
 
The CI as sponsor medical assessor will assess the event blinded, and will assess for active 
IMP and Placebo. For SUSARS the CI will remain blinded, however the Barts Health NHS 
Trust Joint Research Management Office will be unblinded in order to report unblinded 
SUSARs to the MHRA. 
 
 

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17.11 Pregnancy 
If a patient becomes pregnant while on the IMP the study medication and the Irbesartan will 
be withdrawn but the patient will continue in the study. RASi therapy should be avoided in 
pregnancy as recommended by BNF. Should pregnancy occur, the 
 antihypertensive 
medication will be altered to those what are safe in pregnancy. 
 
If a patient on the IMP gets pregnant the CI has the responsibility to ensure that the 
pregnancy form is completed and sent to the sponsor within the agreed timelines.  The 
initial report should be sent within 24 hours and follow up information submitted as and 
when it becomes available up to agreed follow up time after birth.  
All pregnancies and outcomes of pregnancy should be reported to to the sponsor (Barts 
Health JMRO at research.safety@qmul.ac.uk) and to the cardiovascular clinical trials unit at 
cvctusafetyreporting@qmul.ac.uk  
email: AEMailboxClinicalTrialTCS@astrazeneca.com if a secure line is set up 
 
 

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18.0 Annual reporting 
 
Development Annual Safety Update (DSUR) 
The DSUR will be written by the 
sponsor for review prior to submission to the MHRA. The DSUR is due for submission within 
60 days of the end of the reporting period. The reporting period is annually from the date on 
CI will carry out a risk benefit analysis of the IMPs encompassing all events having arisen on 
the trial. REC will be sent a copy of the DSUR. 
 
Annual Progress Report (APR) 
The APR will be written by the CI (using HRA template) and submitted to the sponsor for 
review prior to submission to the REC. The APR is due within 30 days of the anniversary date 
 
 
 

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19.0 Statistical and Data Analysis 
 
19.0 Statistical and Data Analysis 
 
19.1 Sample size calculation 
 
From published data, reduction in serum potassium with SZC is between 0.7-1mmol/l.  From 
this data we hypothesise that 60% of patients on the IMP will get to maximum dose of irbesartan 
(300mg), the drop outs being either change in eGFR or for hypotension, and 30% of patients will get 
to the top dose in the placebo arm. The sample size calculation using a 2-sided Chi-square test at the 
2 sided 5% level of significance, with a 80% power to detect a difference, would indicate that the total 
sample size should be 98. With a 15% drop out rate, we would expect to randomize 116 patients. 
 
 
19.2 Planned recruitment rate 
 
Based on previous experience with trials in diabetic kidney disease It is expected that the 
recruitment will be complete within 14 months. 
 
19.3 Statistical analysis plan (SAP) 
 
Please refer to SAP for full details 
 
Primary endpoint 
Whether a patient is on Maximum dose Irbesartan therapy (300mg) at the end of 12 weeks 
treatment period 
 
Null hypothesis 
No difference in the likelihood that a patient is a success with respect to the primary endpoint 
between the SZC and the placebo groups 
 
Analysis of the primary endpoint 
 
The primary endpoint will be analysed using the ITT principle, i.e. all randomized patients will be 
included. The analysis itself will be performed by means of a 2-sided chi-squared test, with a p-value 
< 0.05 indicating that the null hypothesis of no difference can be rejected. Patients with missing 
primary endpoint will be excluded from the analysis. However, the impact of such an exclusion on 
the results will be evaluated by considering different hypothetical scenarios where e.g. all patients in 
  
 
Sub-group analyses for primary endpoint per e.g. S-K at screening might be performed in order to 
explore consistency of effect. 
 
 

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Safety endpoints 
 
 
Change in potassium from baseline at each time point 
Change in the BP at the end of the study from baseline 
Adverse events 
Whether a patient has a K of > 6 at any time during the study 
Whether a patient has a K of > 6.5 at any time during the study 
Whether a patient has a K of < 3.5 at any time during the study 
Whether a patient  GFR falls by > 30% from the previous test  
Change in (eGFR) renal function at the end of study from baseline 
 
Analysis of the safety endpoints 
 
The safety endpoints will be evaluated using all patients who received at least one dose of 
investigational product. For discrete endpoints, such as whether a patient has K > 6 at any 
point during the study, the number and percentage of such patients will be presented. In 
addition, for illustrative purposes, a 2-sided Chi-square test will be performed. For 
continuous endpoints, such as change from baseline of a safety lab, summary statistics such 
as mean, standard deviation, median, minimum and maximum, both for the absolute values 
and for changes from baseline, will be provided. In addition, an analysis of covariance will be 
conducted, with treatment and the baseline value included as covariates. 
 
Adverse events will be tabulated by system organ class and preferred term, as well as by 
severity and causality as judged by the investigator. A more formal comparison between the 
adverse event rates in the respective treatment arms will also be performed by means of 
Poisson regression. 
 
It should be noted that no multiplicity correction will be applied. Thus, the p-values obtained 
from the testing of the safety endpoints are to be regarded as possibly indicative rather than 
confirmatory and will be interpreted with caution. 
 
 
Exploratory endpoints 
 
1. Change in pro BNP at the end of study from baseline 
2. Dose of irbesartan (75/150/300 mg)  at the end of the study  
3. Ratio of uACR between baseline and 3-month study visit 
4. Change in absolute uACR at end of study from baseine 
 
 
 
19.4 Summary of baseline data and flow of patients 
 
Baseline data used: 
Demographic data 
Medical history 
Vital signs 

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Baseline data will be presented overall and by treatment group. Continuous data will be 
reported as mean (SD) and median (IQR) and categorical data as number (%).  
 
We plan to produce a consort flow diagram.  
 
19.5 Primary outcome analysis 
 
Analysis of the primary endpoint
 
 
19.7 Subgroup analyses 
 
No sub groups will be studied 
 
19.8 Adjusted analysis 
 
The primary  analysis will be unadjusted.  
 
19.6 Secondary outcome analysis 
 
See section 19.3 for secondary outcome (safety/exploratory) end points. 
 
 
19.9 Interim analysis and criteria for the premature termination of the trial 
 
No interim analysis is planned. 
 
19.10 Subject population 
 
The study population will be those patients with diabetic kidney disease who satisfy the 
inclusion criteria and do not meet any of the exclusion criteria. 
 
19.11 Procedure(s) to account for missing or spurious data  
 
This is a short study; therefore, we do not expect dropout rates to be significant. In the consent form 
we will gain consent to access their GP records to allow us to follow the patients if they do drop out 
for outcome events.  
We plan to minimise dropout rates as we are experience at delivering clinical trials, we have a good 
patient network and will not enrol patients who we feel are unlikely to complete the study. 
If there is missing outcome data, sensitivity analysis will be undertaken to examine the impact.. 
 

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20.0 Data Handling & Record Keeping 
 
20.1 Confidentiality 
 
The Principal Investigator has the responsibility to ensure that participant anonymity is 
protected and maintained. They must also ensure that their identities are protected from any 
unauthorized parties. Information with regards to study participants will be kept confidential 
and managed in accordance with the Data Protection Act 2018, NHS Caldicott Guardian, The 
Research Governance Framework for Health and Social Care and Research Ethics Committee 
Approval. All trial data will be stored in line with the Medicines for Human Use (Clinical Trials) 
Amended Regulations 2006 and the Data Protection Act and archived in line with the 
Medicines for Human Use (Clinical Trials) and all subsequent amendments as defined in the 
JRMO SOP 20 Archiving. 
 
The Chief Investigator and the study team will adhere to these regulations to ensure that the 
ensure this is done accordingly, at time of consent each participant will be allocated a unique 
screening number by either the CI or a member of the study team before undergoing any 
screening procedures. 
 
Participant confidentiality will be maintained using study identification numbers to ensure 
compliance with the requirements of the Data Protection Act 2018. 
 
All investigators and trial site staff will 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 
 
 
 
20.2 Data Custodian Details  
 
of the research data;  
Identifiable information including name, address, phone number, hospital number and DOB 
will be collected at site. Only members of the study team who are on the delegation log will 
have access to this data along with the sponsor or delegates for audit purposes. 
 
relating to this 
study. 
 
 
information is replaced by an unrelated sequence of characters. 
Secure maintenance of the data and the linking code in separate locations using 
encrypted digital files within password protected folders and storage media. 

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Limiting access to the minimum number of individuals necessary for quality control, 
audit, and analysis.  
 
 
20.3 Psuedononymisation  
 
Data will be in the form of linked anonymised data. Unique study numbers will be used, 
which are linked to a treatment code. This will be contained in the ISF on the enrolment log. 
 
 
20.4 Transferring/Transporting Data 
 
All patient-identifiable information will be stored in a locked environment, or on password 
protected NHS computers or on a secure ECRF. 
No data will be transferred out of this environment 
 
 
20.5 Data collection tools and source document identification 
The source document will be the electronic patient  record. Data from the paper source 
data worksheets will be uploaded to an eCRF. 
 
20.6 Source Data 
 
The source documents will comprise the site medical notes and health records (paper and 
electronic), including laboratory and pharmacy records. 
 
 
20.7 Case Report Form 
 
 
Data will be recorded directly to a database using electronic Case Report Forms. The eCRFs 
will be managed by a secure web application, accessible via HTTPS/SSL. Users will be issued 
with a username and password and will be required to login for web application access; 
their activity will be tracked using unique user identities and their access to data controlled 
by defined access roles. Patient Identifiable Data will be encrypted in the database and kept 
separately from the clinical data. Direct access to the database will be restricted to named 
users only. 
A paper backup system will be established in case of technical failure or for local 
convenience. Where paper CRFs are used, they should be kept in the investigator file and 
they will be reviewed as part of source data verification during site monitoring. Patients will 
be identified only by initials, trial number. 
The eCRFs will be completed by the Investigator or suitably trained research staff, as 
designated in the site delegation log, as accurately and completely as possible throughout 
the study. 
 
 

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20.8 CRFs as Source Documents 
 
The source documents will be paper source document worksheets 
 
      
 
20.9 Data handling and record keeping 
 
Data will be recorded from study visits in the   source data and transcribed to the eCRF. All 
documents (source data worksheets, signed consent forms etc. will be kept according to the 
 the use the database and CRF. 
 
 
20.10 Access to Data, Source Data and Documents 
 
Direct access will be granted to authorised representatives from the Sponsor or delegate, host 
institution and the regulatory authorities to permit trial-related monitoring, audits and 
inspections. 
 
Only people who have a 'legitimate relationship' with the patient (i.e. are members of the 
health care team) are entitled to have access to medical records. 
 
 
 
21.0 Archiving 
 
During the course of research and for archiving period, all records are the responsibility of the 
Chief Investigator and must be kept in secure conditions. When the research trial is complete, 
it is a requirement of the Research Governance Framework and Trust Policy that the records 
are kept for a further 25 years. 
Destruction of essential documents will require authorisation from the Sponsor. 
report. 
 
22.0 Monitoring, Audit and Inspection 
 
22.1 Monitoring 
 
A Trial Monitoring Plan will be developed and signed by the Sponsor and Chief investigator 
procedures are detailed in the Trial Monitoring Plan. A sponsor monitor will monitor the trial 
on a regular basis. 

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22.2 Auditing 
 
The sponsor retains the right to audit the trial, trial site. In addition, any part of the trial may 
be inspected by the regulatory bodies and funders where applicable. 
 
22.3 Notification of Serious Breaches to GCP and/or the protocol 
 
The CI  (as single site this is also CI) is responsible for reporting any serious breaches to the 
sponsor (JRMO) within 24 hours of becoming aware of the breach. 
 
 
The sponsor will work with the CI to investigate any potential breach. The sponsor will notify 
the MHRA, and the CI will notify the REC, within 7 working days of becoming aware of the 
serious breach. 
 
 
 
22.4 Compliance 
 
The CI will ensure that the trial is conducted in compliance with the principles outlined in the 
Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 2004/1031), and any 
subsequent amendments of the clinical trial regulations, current UK Policy Framework for 
Health and Social Care Research, GCP guidelines, the World Medical Association Declaration 
 
The trial will not commence until a Clinical Trial Authorisation (CTA) is obtained from the 
MHRA. 
The protocol and trial conduct will comply with the Medicines for Human Use (Clinical Trials) 
Regulations 2004 and any relevant amendments. 
 
 
22.5 Non-Compliance 
the eligibility criteria are not 
allowed  
at any time. They must be adequately 
documented on the relevant forms and reported to the Chief Investigator and Sponsor 
immediately. 
 
 All deviations will be documented in the patient records, deviation log and CRF. 
 
The CI and the coordinating team should assess the non-compliances and agree on a 
timeframe in which they need to be dealt with. This assessment should include the need to 
escalate to the sponsor. Any event with the potential to affect participant safety or data 
integrity should be reported to the sponsor within 24 hours of the Coordinating team 
becoming aware. 
 

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Where applicable corrective and preventative actions (CAPA) should be taken. Each action 
will be given a different timeframe dependent on the severity. If the actions are not dealt with 
accordingly, the Sponsor will agree an appropriate action, which could include an on-site 
audit. 
 
22.6 Regulatory Compliance 
 
 Participants will not be recruited into the trial until permission has been granted by the 
sponsor. 
The trial will not commence until a Clinical Trial Authorisation (CTA) is obtained from the 
MHRA. 
The protocol and trial conduct will comply with the Medicines for Human Use (Clinical Trials) 
Regulations 2004 and any relevant amendments 
Before any site can enrol participants into the trial, the Principal Investigator or designee will 
 
Investigator or designee will confir
ongoing (note that both substantial amendments, and amendments considered to be non-
substantial for the purposes of REC and/or MHRA may still need to be notified to NHS R&D). 
 
This study does not involve ionising radiation 
  
23.0 Financial and other competing interests for the chief investigator, PIs at 
each site and committee members for the overall trial management 
All members of committee will sign a competing interests form 
 
 
 
24.0 Ethical and Regulatory Considerations 
 
Before the start of the trial, approval will be sought from the Research Ethics Committee (REC) 
and MHRA for the trial protocol, informed consent forms and other relevant documents e.g. 
advertisements and GP information letters. 
Decision whether an amendment constitutes a minor or substantial amendment lies with the 
sponsor. 
Substantial amendments that require review by the Sponsor and REC and MHRA (where 
relevant) will not be implemented until the REC and or MHRA grants a favourable opinion for 
the study (note 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 Sponsor, REC and MHRA will be retained in the Trial Master File 
at the lead site and Investigator Site File at each site. 

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The Chief Investigator will notify the REC, MHRA and Sponsor of the end of the study. 
 
25.0 Peer review 
 
This protocol has undergone extensive peer review by the funder AstraZeneca. 
 
26.0 Public and Participant Involvement 
 
We will engage with our patient group (The Renal patient forum) to invite them to consider 
nominating one or more patients to sit on the Trial Steering Committee.  
 
27.0 Indemnity 
NHS Indemnity will apply to the Sponsor and host sites as all are NHS Trusts.  
 
27.1 Amendments 
Under the Medicines for Human Use (Clinical Trials) Regulations 2004, the sponsor may make a 
non-substantial amendment at any time during a trial. If the sponsor wishes to make a 
substantial amendment to the CTA or the documents that supported the original application for 
the CTA, the sponsor must submit a valid notice of amendment to the licencing authority (MHRA) 
and to the HRA and REC for consideration. The MHRA,REC and HRA will provide a response 
to decide whether an amendment is substantial or non-substantial for the purposes of 
submission to the MHRA,REC and HRA. 
If applicable, other specialist review bodies (e.g. CAG) need to be notified about substantial 
amendments in case the amendment affects their opinion of the study. 
Amendments will also  be notified to NHS R&D departments of participating sites to assess 
whether the amendment affects the NHS capability and capacity for that site.  
The CI along with the steering committee will be responsible for making the decision to amend 
the protocol. Amendments will be submitted by the CI to the MHRA, HRA and REC and will 
inform the Trial registries and local R&D departments.  Any changes to study documents will be 
subject to version control and amendment history. 
 
 
27.2 Access to the final trial dataset 
 
The steering committee will have access to the final dataset along with the CI. 
 
 

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28.0 Trial Committees 
 
The Trial steering committee/Data monitoring committee will be set up in accordance with 
the sponsor s standard operating procedure for Trial Committees: JMRO SOP 47. 
 
29.0 Publication and Dissemination Policy 
 
29.1 Publication 
 
 Publications will occur at the end of the study. 
 
The sponsor retains the right to review all publications prior to submission or publication. 
 
Responsibility for ensuring accuracy of any publication from this study is delegated to the 
Chief Investigator. 
 
All publications should acknowledge the Sponsor. The correct designation for the sponsor is 
Barts Health NHS Trust 
Publication authorship will be decided by the TSC 
 
The full study report will be accessible via Eudra CT.  
 
29.2 Dissemination policy 
 
Data arising from the trial is owned by the sponsor. 
The DKC will be acknowledged in any publications arising from the study. 
Participants will be notified of the outcome of the trial in writing.  
Their non-blinded treatment allocation will be made available to patients on request 
following publication. 
 
The trial protocol and the full study report, will be made publicly available via EudraCT 
 
 
 

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30.0 References 
 
Alfonzo A, Harrison A, Baines R, Chu A, Mann S MacRury M; Clinical Practice Guidelines 
Treatment of Acute Hyperkalaemia in Adults. https://renal.org/wp-
content/uploads/2020/02/DRAFT-RENAL-ASSOCIATION-HYPERKALAEMIA-GUIDELINE-2019-
for-review.pdf (accessed 28.5.20) 
Anker SD, Kosiborod M, Zannad F, Piña IL, McCullough PA, Filippatos G, van der Meer P, 
Ponikowski P, Rasmussen HS, Lavin PT, Singh B, Yang A, Deedwania P; Maintenance of serum 
potassium with sodium zirconium cyclosilicate (ZS-9) in heart failure patients: results from a 
phase 3 randomized, double-blind, placebo-controlled trial. Eur J Heart Fail. 2015 
Oct;17(10):1050-6 
Ash SR, Singh B, Lavin PT, Stavros F, Rasmussen HS; A phase 2 study on the treatment of 
hyperkalemia in patients with chronic kidney disease suggests that the selective potassium 
trap, ZS-9, is safe and efficient. Kidney Int. 2015 Aug;88(2):404-11.  
Atkins RC, MD, Briganti EM, MD, Lewis JB, Hunsicker LG, Braden G, Champion de 
Crespigny PJ, DeFerrari G, Drury P, Locatelli F, Wiegmann TB, and Lewis EJ, for the 
Collaborative Study Group; Proteinuria Reduction and Progression to Renal Failure in 
Patients With Type 2 Diabetes Mellitus and Overt Nephropathy. American Journal of 
Kidney Diseases, Vol 45, No 2 (February), 2005: pp 281-287 
Bakris G, Agarwal R, MD; Chan JC, Cooper ME, Gansevoort RT, Haller H, Remuzzi G, Peter 
Rossing P,  Schmieder RE, Nowack C, Kolkhof P, Joseph A, Pieper A, Kimmeskamp-
Kirschbaum N, Ruilope LM, MD, for the Mineralocorticoid Receptor Antagonist Tolerability 
Study Diabetic Nephropathy (ARTS-DN) Study Group. JAMA. 2015;314(9):884-894.  
 
Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn 
SM, Zhang Z, Shahinfar S; RENAAL Study Investigators. Effects of losartan on renal and 
cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 
2001 Sep 20;345(12):861-9. 
Epstein M, Reaven NL, Funk SE, McGaughey KJ, Oestreicher N, Knispel J. Evaluation of the 
treatment gap between clinical guidelines and the utilization of renin-angiotensin-
aldosterone system inhibitors. Am J Manag Care. 2015 Sep;21(11 Suppl):S212-20. 
Epstein M, Alvarez PJ, Reaven NL, Funk SE, McGaughey KJ, Brenner MS, Benton W, 
Golestaneh L. Evaluation of clinical outcomes and costs based on prescribed dose level of 
renin-angiotensin-aldosterone system inhibitors. Am J Manag Care. 2016 Aug;22(11 
Suppl):s311-s324. 
Juurlink DN, Mamdani MM, Lee DS, Kopp A, Austin PC, Laupacis A, Redelmeier DA; Rates of 
hyperkalemia after publication of the Randomized Aldactone Evaluation Study. New Engl J 
Med2004;351:543 551. 

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Khan MS, Fonarow GC, Ahmed A, Greene SJ, Vaduganathan M, Khan H, Marti C, 
Gheorghiade M, Butler J; Dose of Angiotensin-Converting Enzyme Inhibitors and Angiotensin 
Receptor Blockers and Outcomes in Heart Failure: A Meta-Analysis. Circ Heart Fail. 2017 
Aug;10(8). 
Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz 
I; Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with 
nephropathy due to type 2 diabetes. N Engl J Med. 2001 Sep 20;345(12):851-60. 
National Institute for Health and Care Excellence Chronic kidney disease in adults: 
assessment and management (2014)  
Packham DK, Rasmussen HS, Lavin PT, El-Shahawy MA, Roger SD, Block G, Qunibi W, Pergola 
P, Singh B; Sodium zirconium cyclosilicate in hyperkalemia. N Engl J Med. 2015 Jan 
15;372(3):222-31. 
Parving HH, Lehnert H, Bröchner-Mortensen J, Gomis R, Andersen S, Arner P; Irbesartan in 
Patients with Type 2 Diabetes and Microalbuminuria Study Group. 
The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 
diabetes. N Engl J Med. 2001 Sep 20;345(12):870-8. 
Rossing K, Christensen PK, Hansen BV, Carstensen B, Parving HH; 
Optimal dose of candesartan for renoprotection in type 2 diabetic patients with 
nephropathy: a double-blind randomized cross-over study. Diabetes Care 2003, 26:150 155. 
 
This protocol is based on JRMO CTIMP Protocol Template June 2015 version 4.0.