## Protocol Section
### Identification Module
**NCT ID:** NCT04983979

**Acronym:** ORTIZ

**Brief Title:** The ORTIZ Study: Optimising RASi Therapy With SZC

**Official 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.

#### Organization Study ID Info
**ID:** 136721
#### Organization
**Class:** OTHER
**Full Name:** Barts & The London NHS Trust
### Status Module
#### Completion Date
**Date:** 2023-05-16

**Type:** ACTUAL

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2023-08-16

**Type:** ACTUAL

**Last Update Submit Date:** 2023-08-15

**Overall Status:** TERMINATED

#### Primary Completion Date
**Date:** 2023-03-16

**Type:** ACTUAL

#### Start Date
**Date:** 2022-06-17

**Type:** ACTUAL

**Status Verified Date:** 2023-06

#### Study First Post Date
**Date:** 2021-07-30
**Type:** ACTUAL
**Study First Submit Date:** 2021-07-09
**Study First Submit QC Date:** 2021-07-21
**Why Stopped:** Lack of recruitment
### Sponsor Collaborators Module

#### Lead Sponsor

**Class:** OTHER

**Name:** Barts & The London NHS Trust

#### Responsible Party

**Type:** SPONSOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** False

**Oversight Has DMC:** True

### Description Module

**Brief Summary:** 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:** 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.

### Conditions Module

**Conditions:**

- CKD

- Diabetes Mellitus, Type 2

- Hyperkalemia

### Design Module

#### Design Info

**Allocation:** RANDOMIZED

**Intervention Model:** PARALLEL

**Intervention Model Description:** A Multi site, placebo controlled, double blind randomised clinical trial.

##### Masking Info

**Masking:** QUADRUPLE

**Masking Description:** double blind randomised clinical trial.

**Who Masked:**

- PARTICIPANT

- CARE_PROVIDER

- INVESTIGATOR

- OUTCOMES_ASSESSOR

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 10

**Type:** ACTUAL

**Phases:**

- PHASE2

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** 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

**Intervention Names:**

- Drug: Sodium Zirconium Cyclosilicate

**Label:** SZC

**Type:** EXPERIMENTAL

#### Arm Group 2

**Description:** 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

**Intervention Names:**

- Drug: Placebo

**Label:** Placebo

**Type:** PLACEBO_COMPARATOR

### Interventions

#### Intervention 1

**Arm Group Labels:**

- SZC

**Description:** sachets of 5g or 10g given OD titrated to serum potassium

**Name:** Sodium Zirconium Cyclosilicate

**Other Names:**

- Lokelma

**Type:** DRUG

#### Intervention 2

**Arm Group Labels:**

- Placebo

**Description:** matched placebo given titrated according to potassium at a dose to 5 or 10g

**Name:** Placebo

**Type:** DRUG

### Outcomes Module

#### Primary Outcomes

**Description:** Proportion of patients on Maximum dose (300mg) Irbesartan therapy at 12 weeks compared to placebo

**Measure:** Proportion of patients on Maximum dose (300mg) Irbesartan therapy at 12 weeks compared to placebo

**Time Frame:** week 12

#### Secondary Outcomes

**Description:** Change in potassium from baseline at each study visit (week 1, week 2, 4,6,8,12)

**Measure:** Change in potassium from baseline at each time point

**Time Frame:** at each study visit (week 1, week 2, 4,6,8,12)

**Description:** Safety

**Measure:** Frequency of adverse events

**Time Frame:** assessed at each study visit (week 1, week 2, 4,6,8,12)

**Description:** Proportion of patients who have a potassium of \>6mmol/l,, or \>6.5mmol/l at any time during the study

**Measure:** Proportion of patients who have a potassium of >6mmol/l, or >6.5mmol/l at any time during the study •

**Time Frame:** Assessed at each study visit (week 1, week 2, 4,6,8,12)

**Description:** Proportion of patients who have a potassium of \<3.5mmol/l, assessed at each study visit (week 1, week 2, 4,6,8,12)

**Measure:** Proportion of patients who have a potassium of <3.5mmol/l •

**Time Frame:** Assessed at each study visit (week 1, week 2, 4,6,8,12)

**Description:** Proportion of patients whose GFR falls by \>30% from the previous visit

**Measure:** Proportion of patients whose Glomerular filtration rate (GFR) falls by >30% from the previous visit •

**Time Frame:** Change in potassium from one visit to the next. Assessed at each study visit (week 1, week 2, 4,6,8,12)

**Description:** Change in GFR at the end of study from baseline

**Measure:** Change in GFR at the end of study from baseline

**Time Frame:** Between baseline and week 12

### Eligibility Module

**Eligibility Criteria:** 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

**Minimum Age:** 18 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Locations

**Location 1:**

**City:** London

**Country:** United Kingdom

**Facility:** Kieran Mccafferty

**State:** Uk

**Zip:** E1 1BB

### IPD Sharing Statement Module

**IPD Sharing:** UNDECIDED

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000003920

- Term: Diabetes Mellitus

- ID: D000044882

- Term: Glucose Metabolism Disorders

- ID: D000008659

- Term: Metabolic Diseases

- ID: D000004700

- Term: Endocrine System Diseases

- ID: D000014883

- Term: Water-Electrolyte Imbalance

### Condition Browse Module - Browse Branches

- Abbrev: BC18

- Name: Nutritional and Metabolic Diseases

- Abbrev: BC19

- Name: Gland and Hormone Related Diseases

- Abbrev: All

- Name: All Conditions

- Abbrev: BXS

- Name: Urinary Tract, Sexual Organs, and Pregnancy Conditions

### Condition Browse Module - Browse Leaves

- ID: M7115

- Name: Diabetes Mellitus

- Relevance: LOW

- As Found: Unknown

- ID: M7119

- Name: Diabetes Mellitus, Type 2

- Relevance: HIGH

- As Found: Diabetes Mellitus, Type 2

- ID: M10698

- Name: Kidney Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M9998

- Name: Hyperkalemia

- Relevance: HIGH

- As Found: Hyperkalemia

- ID: M7123

- Name: Diabetic Nephropathies

- Relevance: LOW

- As Found: Unknown

- ID: M11639

- Name: Metabolic Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M25403

- Name: Glucose Metabolism Disorders

- Relevance: LOW

- As Found: Unknown

- ID: M7862

- Name: Endocrine System Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M17624

- Name: Water-Electrolyte Imbalance

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000003924

- Term: Diabetes Mellitus, Type 2

- ID: D000006947

- Term: Hyperkalemia

### Misc Info Module

- Version Holder: 2024-05-24
