The ORTIZ Study: Optimising RASi Therapy With SZC (ORTIZ)

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.

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.

Study Overview

• Status: Terminated
• Conditions: Diabetes Mellitus, Type 2; CKD; Hyperkalemia
• Intervention / Treatment: Drug: Sodium Zirconium Cyclosilicate; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • Uk
    • London, Uk, United Kingdom, E1 1BB
      • Kieran Mccafferty

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. 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 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:

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.
5. Women who are pregnant, lactating, planning to become pregnant or unwilling to use effective methods of contraception during the study.
6. 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.
7. History of acute eGFR fall with RASi therapy (>30% in eGFR on initiation of RASi therapy)
8. Known hypersensitivity or previous anaphylaxis to SZC or Irbesartan
9. Hypotension: BP <120/70mm/hg at screening despite no antihypertensive agent use
10. Uncontrolled Blood pressure: BP >170/110 at screening
11. Evidence of prolonged QT on ECG QTc(f)>550msec
12. History of QT prolongation associated with other medications that required discontinuation of that medication
13. Treatment with lithium, or dual blockade with ACEi and ARB or mineralocorticoid inhibitor
14. History of congenital long QT syndrome
15. Symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Subjects with atrial fibrillation controlled by medication are permitted
16. Current or recent (within 3 months) participation in a clinical trial involving an investigational medicinal product.
17. Current treatment with a potassium binder medication

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: SZC; 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; sachets of 5g or 10g given OD titrated to serum potassium; Other Names: Lokelma
Placebo Comparator: Placebo; 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; matched placebo given titrated according to potassium at a dose to 5 or 10g

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Patients on Maximum Dose (300mg) Irbesartan Therapy at 12 Weeks Compared to Placebo	Difference in proportion of patients on maximum dose (300mg) Irbesartan therapy at the end of 12 weeks compared to placebo. Proportion is calculated per arm as number of individuals on maximum dose Irbesatan therapy divided by the number of individuals in the study arm. The difference in proportion is calculated as experimental arm - placebo comparator arm.	Study end (week 12)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Potassium From Baseline at Each Time Point	Difference in potassium from baseline at each study visit (weeks 1, 2, 4, 6, 8,12) calculated as a mean for each study visit.	At each study visit (weeks 1, 2, 4, 6, 8,12)
Change in the BP at the End of the Study From Baseline	Difference in systolic and diastolic BP from baseline to end of study follow-up (week 12) calculated as a mean for each study visit.	Study end (week 12)
Proportion of Patients Who Have a Potassium of >6mmol/l, or >6.5mmol/l at Any Time During the Study	Difference in proportion of patients who have a potassium of >6mmol/l,, or >6.5mmol/l at any time during the study. Proportion is calculated per arm as number of individuals with a maximum potassium across study follow-up of >6mmol/l or >6.5mmol/l divided by the number of individuals in the study arm. The difference in proportion is calculated as experimental arm - placebo comparator arm.	Cumulative across study follow-up, assessed at study end (week 12)
Proportion of Patients Who Have a Potassium of <3.5mmol/l •	Difference in proportion of patients who have a potassium of <3.5mmol/l at any time during the study. Proportion is calculated per arm as number of individuals with a minimum potassium of <3.5mmol/l across study follow-up divided by the number of individuals in the study arm. The difference in proportion is calculated as experimental arm - placebo comparator arm.	Cumulative across study follow-up, assessed at study end (week 12)
Proportion of Patients Whose Glomerular Filtration Rate (GFR) Falls by >30% From the Previous Visit •	Difference in proportion of patients with a sudden drop in GFR defined as >30% decreased between study visits. Proportion is calculated per arm as number of individuals experiencing a sudden drop of GFR divided by the number of individuals in the study arm. The difference in proportion is calculated as experimental arm - placebo comparator arm.	Cumulative. Calculated at each study visit. Assessed at study end (week 12).
Change in GFR at the End of Study From Baseline	Difference in GFR from baseline to end of study follow-up (week 12) calculated as a mean for each study visit.	Study end (week 12)
Frequency of Adverse Events	A count of the number of adverse events reported in each study arm	Study end (week 12)

Collaborators and Investigators

• Sponsor: Barts & The London NHS Trust
• Investigators: Study Chair: Keiran McCafferty, Barts & The London NHS Trust

Study record dates

Study Major Dates

• Study Start (Actual): June 17, 2022
• Primary Completion (Actual): March 16, 2023
• Study Completion (Actual): May 16, 2023

Study Registration Dates

• First Submitted: July 9, 2021
• First Submitted That Met QC Criteria: July 21, 2021
• First Posted (Actual): July 30, 2021

Study Record Updates

• Last Update Posted (Actual): June 8, 2025
• Last Update Submitted That Met QC Criteria: June 6, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Glucose Metabolism Disorders; Diabetes Mellitus; Water-Electrolyte Imbalance; Diabetes Mellitus, Type 2; Hyperkalemia
• Other Study ID Numbers: 136721

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No