The ORTIZ Study: Optimising RASi Therapy With SZC

Study Overview
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Brief Summary
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The hypothesis is that 3 months' treatment with SZC versus placebo will enable RASi (Irbesartan) maximisation in a cohort of patients with diabetic kidney disease.

Detailed Description
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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. 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. 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 , putting them at risk of a more rapid progression and poorer outcomes and increased healthcare costs. 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. 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 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. 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.

Official Title
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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.

Conditions
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CKD, Diabetes Mellitus, Type 2, Hyperkalemia

Intervention / Treatment
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* Drug: Sodium Zirconium Cyclosilicate
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able and willing to provide written informed consent Adults ≥ 18years old Type 2 Diabetes CKD defined as eGFR 25-60ml/min Albuminuria with uACR measured at >33.9.mg/mmol (300mg/g) 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 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 Exclusion Criteria: Active malignancy Patients who lack capacity to give informed consent GI disturbance/chronic diarrhoea/stoma Subjects with a life expectancy of less than 3 months. Women who are pregnant, lactating, planning to become pregnant or unwilling to use effective methods of contraception during the study. 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. History of acute eGFR fall with RASi therapy (>30% in eGFR on initiation of RASi therapy) Known hypersensitivity or previous anaphylaxis to SZC or Irbesartan Hypotension: BP <120/70mm/hg at screening despite no antihypertensive agent use Uncontrolled Blood pressure: BP >170/110 at screening Evidence of prolonged QT on ECG QTc(f)>550msec History of QT prolongation associated with other medications that required discontinuation of that medication Treatment with lithium, or dual blockade with ACEi and ARB or mineralocorticoid inhibitor History of congenital long QT syndrome Symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Subjects with atrial fibrillation controlled by medication are permitted Current or recent (within 3 months) participation in a clinical trial involving an investigational medicinal product. Current treatment with a potassium binder medication

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A Multi site, placebo controlled, double blind randomised clinical trial.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SZC<br>3 month treatment using Sodium zirconium cyclocilicate. Doses of 5 or 10g once daily will be used. The dose will be titrated according to potassium levels performed at clinic visits | Drug: Sodium Zirconium Cyclosilicate<br>* sachets of 5g or 10g given OD titrated to serum potassium<br>* Other names: Lokelma;|
| Placebo Comparator: Placebo<br>3 month treatment using matched placebo. Doses of 5 or 10g once daily will be used. The dose will be titrated according to potassium levels performed at clinic visits | Drug: Placebo<br>* matched placebo given titrated according to potassium at a dose to 5 or 10g<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients on Maximum dose (300mg) Irbesartan therapy at 12 weeks compared to placebo | Proportion of patients on Maximum dose (300mg) Irbesartan therapy at 12 weeks compared to placebo | week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in potassium from baseline at each time point | Change in potassium from baseline at each study visit (week 1, week 2, 4,6,8,12) | at each study visit (week 1, week 2, 4,6,8,12) | 
| Frequency of adverse events | Safety | assessed at each study visit (week 1, week 2, 4,6,8,12) | 
| Proportion of patients who have a potassium of >6mmol/l, or >6.5mmol/l at any time during the study • | Proportion of patients who have a potassium of >6mmol/l,, or >6.5mmol/l at any time during the study | Assessed at each study visit (week 1, week 2, 4,6,8,12) | 
| Proportion of patients who have a potassium of <3.5mmol/l • | Proportion of patients who have a potassium of <3.5mmol/l, assessed at each study visit (week 1, week 2, 4,6,8,12) | Assessed at each study visit (week 1, week 2, 4,6,8,12) | 
| Proportion of patients whose Glomerular filtration rate (GFR) falls by >30% from the previous visit • | Proportion of patients whose GFR falls by >30% from the previous visit | Change in potassium from one visit to the next. Assessed at each study visit (week 1, week 2, 4,6,8,12) | 
| Change in GFR at the end of study from baseline | Change in GFR at the end of study from baseline | Between baseline and week 12 |