Trial Outcomes & Findings for Potassium Reduction Initiative to Optimize RAAS Inhibition Therapy With Sodium Zirconium Cyclosilicate in Heart Failure (NCT NCT03532009)

NCT ID: NCT03532009

Last Updated: 2021-06-15

Results Overview

RAASi treatment categories: * No, or less than target dose, angiotensin converting enzyme inhibitors (ACEi)/ angiotensin receptor blockers (ARB)/ angiotensin receptor/ neprolysin inhibitors (ARNI) and no mineralocorticoid receptor antagonist (MRA); * ACEi/ARB/ARNI at target dose and no MRA; * MRA at less than target dose; * MRA at target dose. Missing values at 3 months were imputed using a multiple imputation approach with 10000 imputations. The imputation model included RAASi category at 3 months as the outcome variable and the following covariates: RAASi category, local lab-K, eGFR and systolic blood pressure measured at the last visit before the 3 months (starting with the randomisation visit) when all the covariates' data were available.

• Recruitment status: TERMINATED
• Study phase: PHASE2
• Target enrollment: 182 participants
• Primary outcome timeframe: At the end of the treatment visit (Month 3)
• Results posted on: 2021-06-15

Participant Flow

This study was performed at 64 sites in 9 countries (Brazil, Bulgaria, Canada, Hungary, Poland, Romania, Russia, Slovakia, and the United States of America) between 26 June 2018 and 22 May 2020.

Patients were randomised in a 1:1 ratio to receive sodium zirconium cyclosilicate (SZC) or placebo for 3 months while titrating renin-angiotensin aldosterone system inhibitor (RAASi) therapies. The study was prematurely terminated due to the COVID-19 pandemic resulting in a reduced sample size (182 randomised patients as opposed to the planned 280 patients).

Participant milestones

Measure	Sodium Zirconium Cyclosilicate Patients with serum potassium (S-K) concentration \> 5.0 millimole/litre (mmol/L) at the last assessment before randomisation received SZC 10 grams (g) orally 3 times daily (tid) for 2 days followed by SZC 5 g once daily (qd) for 3 months. Patients with S-K concentration ≤ 5.0 mmol/L at the last assessment before randomisation received SZC 5 g orally qd for 3 months. SZC was up- or down- titrated depending on local laboratory S-K concentration at every study visit.	Placebo Patients with S-K concentration \> 5.0 mmol/L at the last assessment before randomisation received placebo orally tid for 2 days followed by placebo qd for 3 months. Patients with S-K concentration ≤ 5.0 mmol/L at the last assessment before randomisation received placebo orally qd for 3 months. Placebo was up- or down- titrated depending on local laboratory S-K concentration at every study visit.
Overall Study STARTED	92	90
Overall Study Received Treatment	91	90
Overall Study COMPLETED	90	86
Overall Study NOT COMPLETED	2	4

Reasons for withdrawal

Measure	Sodium Zirconium Cyclosilicate Patients with serum potassium (S-K) concentration \> 5.0 millimole/litre (mmol/L) at the last assessment before randomisation received SZC 10 grams (g) orally 3 times daily (tid) for 2 days followed by SZC 5 g once daily (qd) for 3 months. Patients with S-K concentration ≤ 5.0 mmol/L at the last assessment before randomisation received SZC 5 g orally qd for 3 months. SZC was up- or down- titrated depending on local laboratory S-K concentration at every study visit.	Placebo Patients with S-K concentration \> 5.0 mmol/L at the last assessment before randomisation received placebo orally tid for 2 days followed by placebo qd for 3 months. Patients with S-K concentration ≤ 5.0 mmol/L at the last assessment before randomisation received placebo orally qd for 3 months. Placebo was up- or down- titrated depending on local laboratory S-K concentration at every study visit.
Overall Study Other	1	1
Overall Study Death	1	1
Overall Study Withdrawal by Patient	0	2

Baseline Characteristics

Potassium Reduction Initiative to Optimize RAAS Inhibition Therapy With Sodium Zirconium Cyclosilicate in Heart Failure

Baseline characteristics by cohort

Measure	Sodium Zirconium Cyclosilicate n=92 Participants Patients with S-K concentration \> 5.0 mmol/L at the last assessment before randomisation received SZC 10 g orally tid for 2 days followed by SZC 5 g qd for 3 months. Patients with S-K concentration ≤ 5.0 mmol/L at the last assessment before randomisation received SZC 5 g orally qd for 3 months. SZC was up- or down- titrated depending on local laboratory S-K concentration at every study visit.	Placebo n=90 Participants Patients with S-K concentration \> 5.0 mmol/L at the last assessment before randomisation received placebo orally tid for 2 days followed by placebo qd for 3 months. Patients with S-K concentration ≤ 5.0 mmol/L at the last assessment before randomisation received placebo orally qd for 3 months. Placebo was up- or down- titrated depending on local laboratory S-K concentration at every study visit.	Total n=182 Participants Total of all reporting groups
Age, Continuous	72.9 years STANDARD_DEVIATION 8.8 • n=5 Participants	71.0 years STANDARD_DEVIATION 8.1 • n=7 Participants	71.9 years STANDARD_DEVIATION 8.5 • n=5 Participants
Age, Customized ≤ 17 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Customized 18 - 64 years	17 Participants n=5 Participants	16 Participants n=7 Participants	33 Participants n=5 Participants
Age, Customized 65 - 84 years	65 Participants n=5 Participants	69 Participants n=7 Participants	134 Participants n=5 Participants
Age, Customized ≥ 85 years	10 Participants n=5 Participants	5 Participants n=7 Participants	15 Participants n=5 Participants
Sex: Female, Male Female	41 Participants n=5 Participants	33 Participants n=7 Participants	74 Participants n=5 Participants
Sex: Female, Male Male	51 Participants n=5 Participants	57 Participants n=7 Participants	108 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	15 Participants n=5 Participants	14 Participants n=7 Participants	29 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	77 Participants n=5 Participants	76 Participants n=7 Participants	153 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) White	90 Participants n=5 Participants	89 Participants n=7 Participants	179 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
S-K Concentration ≤ 5.0 mmol/L	65 Participants n=5 Participants	67 Participants n=7 Participants	132 Participants n=5 Participants
S-K Concentration > 5.0 mmol/L	27 Participants n=5 Participants	23 Participants n=7 Participants	50 Participants n=5 Participants
New York Heart Association (NYHA) Functional Classification Class I	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
New York Heart Association (NYHA) Functional Classification Class II	61 Participants n=5 Participants	57 Participants n=7 Participants	118 Participants n=5 Participants
New York Heart Association (NYHA) Functional Classification Class III	31 Participants n=5 Participants	33 Participants n=7 Participants	64 Participants n=5 Participants
New York Heart Association (NYHA) Functional Classification Class IV	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Left Ventricular Ejection Fraction (LVEF)	33.8 LVEF Percentage STANDARD_DEVIATION 5.8 • n=5 Participants	33.9 LVEF Percentage STANDARD_DEVIATION 6.1 • n=7 Participants	33.8 LVEF Percentage STANDARD_DEVIATION 6.0 • n=5 Participants
Estimated Glomerular Filtration Rate (eGFR)	40.0 Millilitre/minute/1.73 metre^2 STANDARD_DEVIATION 11.0 • n=5 Participants	42.7 Millilitre/minute/1.73 metre^2 STANDARD_DEVIATION 11.5 • n=7 Participants	41.3 Millilitre/minute/1.73 metre^2 STANDARD_DEVIATION 11.3 • n=5 Participants

PRIMARY outcome

Timeframe: At the end of the treatment visit (Month 3)

Population: All randomised patients with a non-missing value for the RAASi treatment category (after imputation) were included.

RAASi treatment categories:

• No, or less than target dose, angiotensin converting enzyme inhibitors (ACEi)/ angiotensin receptor blockers (ARB)/ angiotensin receptor/ neprolysin inhibitors (ARNI) and no mineralocorticoid receptor antagonist (MRA);
• ACEi/ARB/ARNI at target dose and no MRA;
• MRA at less than target dose;
• MRA at target dose.

Missing values at 3 months were imputed using a multiple imputation approach with 10000 imputations. The imputation model included RAASi category at 3 months as the outcome variable and the following covariates: RAASi category, local lab-K, eGFR and systolic blood pressure measured at the last visit before the 3 months (starting with the randomisation visit) when all the covariates' data were available.

Outcome measures

Measure	Sodium Zirconium Cyclosilicate n=89 Participants Patients with S-K concentration \> 5.0 mmol/L at the last assessment before randomisation received SZC 10 g orally tid for 2 days followed by SZC 5 g qd for 3 months. Patients with S-K concentration ≤ 5.0 mmol/L at the last assessment before randomisation received SZC 5 g orally qd for 3 months. SZC was up- or down- titrated depending on local laboratory S-K concentration at every study visit.	Placebo n=87 Participants Patients with S-K concentration \> 5.0 mmol/L at the last assessment before randomisation received placebo orally tid for 2 days followed by placebo qd for 3 months. Patients with S-K concentration ≤ 5.0 mmol/L at the last assessment before randomisation received placebo orally qd for 3 months. Placebo was up- or down- titrated depending on local laboratory S-K concentration at every study visit.
Percentage of Patients Receiving Different Categories of RAASi Treatments at Month 3 No, or less than target dose ACEi/ARB/ARNI, no MRA	14.7 Percentage of Patients	13.5 Percentage of Patients
Percentage of Patients Receiving Different Categories of RAASi Treatments at Month 3 ACEi/ARB/ARNI at target dose and no MRA	14.7 Percentage of Patients	15.1 Percentage of Patients
Percentage of Patients Receiving Different Categories of RAASi Treatments at Month 3 MRA at less than target dose	14.2 Percentage of Patients	24.5 Percentage of Patients
Percentage of Patients Receiving Different Categories of RAASi Treatments at Month 3 MRA at target dose	56.4 Percentage of Patients	47.0 Percentage of Patients

OTHER_PRE_SPECIFIED outcome

Timeframe: From Day 1 of treatment up to the end of the follow-up period (Week 17)

Population: The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.

An AE is the development of any untoward medical occurrence in a patient or clinical study patient administered an investigational product (IP) and which does not necessarily have a causal relationship with the IP. An AE can be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of an IP.

A serious adverse event (SAE) is an AE occurring during any study phase, that fulfils one or more of the following criteria:

• Results in death;
• Is immediately life-threatening;
• Requires in-patient hospitalisation or prolongation of existing hospitalisation;
• Results in persistent or significant disability or incapacity;
• Is a congenital abnormality or birth defect;
• Is an important medical event that may jeopardise the patient or may require medical treatment to prevent one of the outcomes listed above.

Outcome measures

Measure	Sodium Zirconium Cyclosilicate n=91 Participants Patients with S-K concentration \> 5.0 mmol/L at the last assessment before randomisation received SZC 10 g orally tid for 2 days followed by SZC 5 g qd for 3 months. Patients with S-K concentration ≤ 5.0 mmol/L at the last assessment before randomisation received SZC 5 g orally qd for 3 months. SZC was up- or down- titrated depending on local laboratory S-K concentration at every study visit.	Placebo n=90 Participants Patients with S-K concentration \> 5.0 mmol/L at the last assessment before randomisation received placebo orally tid for 2 days followed by placebo qd for 3 months. Patients with S-K concentration ≤ 5.0 mmol/L at the last assessment before randomisation received placebo orally qd for 3 months. Placebo was up- or down- titrated depending on local laboratory S-K concentration at every study visit.
Number of Patients Who Experienced Adverse Events (AEs) During the Study Any SAE	14 Participants	10 Participants
Number of Patients Who Experienced Adverse Events (AEs) During the Study Any AE leading to discontinuation of IP	5 Participants	2 Participants
Number of Patients Who Experienced Adverse Events (AEs) During the Study Any AE	43 Participants	47 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: From Day 1 of treatment up to the end of the follow-up period (Week 17)

Population: The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.

The number of patients who experienced clinically important abnormalities in clinical laboratory assessments as assessed by the Investigator are presented. Clinically important abnormalities in clinical laboratory parameters were reported as AEs. Clinical laboratory assessments included clinical chemistry, haematology and urinalysis performed at the central laboratory.

Outcome measures

Measure	Sodium Zirconium Cyclosilicate n=91 Participants Patients with S-K concentration \> 5.0 mmol/L at the last assessment before randomisation received SZC 10 g orally tid for 2 days followed by SZC 5 g qd for 3 months. Patients with S-K concentration ≤ 5.0 mmol/L at the last assessment before randomisation received SZC 5 g orally qd for 3 months. SZC was up- or down- titrated depending on local laboratory S-K concentration at every study visit.	Placebo n=90 Participants Patients with S-K concentration \> 5.0 mmol/L at the last assessment before randomisation received placebo orally tid for 2 days followed by placebo qd for 3 months. Patients with S-K concentration ≤ 5.0 mmol/L at the last assessment before randomisation received placebo orally qd for 3 months. Placebo was up- or down- titrated depending on local laboratory S-K concentration at every study visit.
Number of Patients Who Experienced Clinically Important Abnormalities in Clinical Laboratory Parameters Anaemia	1 Participants	1 Participants
Number of Patients Who Experienced Clinically Important Abnormalities in Clinical Laboratory Parameters Iron deficiency anaemia	1 Participants	0 Participants
Number of Patients Who Experienced Clinically Important Abnormalities in Clinical Laboratory Parameters Hypoglycaemia	1 Participants	1 Participants
Number of Patients Who Experienced Clinically Important Abnormalities in Clinical Laboratory Parameters Hypertriglyceridaemia	0 Participants	1 Participants
Number of Patients Who Experienced Clinically Important Abnormalities in Clinical Laboratory Parameters Hyponatraemia	0 Participants	1 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: From Day 1 of treatment up to the end of the follow-up period (Week 17)

Population: The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.

The number of patients who experienced clinically important abnormalities in vital signs assessments as assessed by the Investigator are presented. Clinically important abnormalities in vital signs measurements were reported as AEs. Vital signs assessments included weight, pulse, and systolic and diastolic blood pressure measurements.

Outcome measures

Measure	Sodium Zirconium Cyclosilicate n=91 Participants Patients with S-K concentration \> 5.0 mmol/L at the last assessment before randomisation received SZC 10 g orally tid for 2 days followed by SZC 5 g qd for 3 months. Patients with S-K concentration ≤ 5.0 mmol/L at the last assessment before randomisation received SZC 5 g orally qd for 3 months. SZC was up- or down- titrated depending on local laboratory S-K concentration at every study visit.	Placebo n=90 Participants Patients with S-K concentration \> 5.0 mmol/L at the last assessment before randomisation received placebo orally tid for 2 days followed by placebo qd for 3 months. Patients with S-K concentration ≤ 5.0 mmol/L at the last assessment before randomisation received placebo orally qd for 3 months. Placebo was up- or down- titrated depending on local laboratory S-K concentration at every study visit.
Number of Patients Who Experienced Clinically Important Abnormalities in Vital Signs Measurements Hypotension	4 Participants	1 Participants
Number of Patients Who Experienced Clinically Important Abnormalities in Vital Signs Measurements Hypertension	2 Participants	0 Participants
Number of Patients Who Experienced Clinically Important Abnormalities in Vital Signs Measurements Hypertensive crisis	1 Participants	1 Participants
Number of Patients Who Experienced Clinically Important Abnormalities in Vital Signs Measurements Blood pressure inadequately controlled	0 Participants	1 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: From Day 1 of treatment up to the end of the follow-up period (Week 17)

Population: The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.

The number of patients who experienced clinically significant changes in ECG measurements as assessed by the Investigator are presented. Clinically important abnormalities in ECG measurements were reported as AEs. 12-lead ECGs were obtained using a digital ECG machine that automatically calculates the heart rate and measures PR, QRS, and QT (using QT interval corrected by Fredericia's algorithm) intervals.

Outcome measures

Measure	Sodium Zirconium Cyclosilicate n=91 Participants Patients with S-K concentration \> 5.0 mmol/L at the last assessment before randomisation received SZC 10 g orally tid for 2 days followed by SZC 5 g qd for 3 months. Patients with S-K concentration ≤ 5.0 mmol/L at the last assessment before randomisation received SZC 5 g orally qd for 3 months. SZC was up- or down- titrated depending on local laboratory S-K concentration at every study visit.	Placebo n=90 Participants Patients with S-K concentration \> 5.0 mmol/L at the last assessment before randomisation received placebo orally tid for 2 days followed by placebo qd for 3 months. Patients with S-K concentration ≤ 5.0 mmol/L at the last assessment before randomisation received placebo orally qd for 3 months. Placebo was up- or down- titrated depending on local laboratory S-K concentration at every study visit.
Number of Patients Who Experienced Clinically Significant Changes in Electrocardiogram (ECG) Measurements	0 Participants	0 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: From Day 1 of treatment up to the end of the follow-up period (Week 17)

Population: The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.

The S-K levels used for this analysis were based on the measurements obtained by the central laboratory. Patients with S-K levels < 3.5 mmol/L were considered to have low S-K levels. Patients with S-K levels > 5.0 mmol/L were considered to have high S-K levels.

Outcome measures

Measure	Sodium Zirconium Cyclosilicate n=91 Participants Patients with S-K concentration \> 5.0 mmol/L at the last assessment before randomisation received SZC 10 g orally tid for 2 days followed by SZC 5 g qd for 3 months. Patients with S-K concentration ≤ 5.0 mmol/L at the last assessment before randomisation received SZC 5 g orally qd for 3 months. SZC was up- or down- titrated depending on local laboratory S-K concentration at every study visit.	Placebo n=90 Participants Patients with S-K concentration \> 5.0 mmol/L at the last assessment before randomisation received placebo orally tid for 2 days followed by placebo qd for 3 months. Patients with S-K concentration ≤ 5.0 mmol/L at the last assessment before randomisation received placebo orally qd for 3 months. Placebo was up- or down- titrated depending on local laboratory S-K concentration at every study visit.
Number of Patients Who Experienced Low and High S-K Levels S-K < 3.0 mmol/L	0 Participants	0 Participants
Number of Patients Who Experienced Low and High S-K Levels S-K < 3.5 mmol/L	7 Participants	0 Participants
Number of Patients Who Experienced Low and High S-K Levels S-K > 5.5 mmol/L	23 Participants	32 Participants
Number of Patients Who Experienced Low and High S-K Levels S-K > 6.0 mmol/L	3 Participants	4 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: From Day 1 of treatment up to the end of the follow-up period (Week 17)

Population: The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.

The S-K levels used for this analysis were based on the measurements obtained by the central laboratory. Patients with S-K levels < 3.5 mmol/L were considered to have had an event of low S-K levels. Patients with S-K levels > 5.0 mmol/L were considered to have had an event of high S-K levels.

Outcome measures

Measure	Sodium Zirconium Cyclosilicate n=91 Participants Patients with S-K concentration \> 5.0 mmol/L at the last assessment before randomisation received SZC 10 g orally tid for 2 days followed by SZC 5 g qd for 3 months. Patients with S-K concentration ≤ 5.0 mmol/L at the last assessment before randomisation received SZC 5 g orally qd for 3 months. SZC was up- or down- titrated depending on local laboratory S-K concentration at every study visit.	Placebo n=90 Participants Patients with S-K concentration \> 5.0 mmol/L at the last assessment before randomisation received placebo orally tid for 2 days followed by placebo qd for 3 months. Patients with S-K concentration ≤ 5.0 mmol/L at the last assessment before randomisation received placebo orally qd for 3 months. Placebo was up- or down- titrated depending on local laboratory S-K concentration at every study visit.
Number of Events of Low and High S-K Levels S-K < 3.0 mmol/L	0 Events	0 Events
Number of Events of Low and High S-K Levels S-K < 3.5 mmol/L	12 Events	0 Events
Number of Events of Low and High S-K Levels S-K > 5.5 mmol/L	37 Events	59 Events
Number of Events of Low and High S-K Levels S-K > 6.0 mmol/L	3 Events	4 Events

Adverse Events

Sodium Zirconium Cyclosilicate

Serious events: 14 serious events

Other events: 16 other events

Deaths: 1 deaths

Placebo

Serious events: 10 serious events

Other events: 7 other events

Deaths: 1 deaths

Serious adverse events

Measure	Sodium Zirconium Cyclosilicate n=91 participants at risk Patients with S-K concentration \> 5.0 mmol/L at the last assessment before randomisation received SZC 10 g orally tid for 2 days followed by SZC 5 g qd for 3 months. Patients with S-K concentration ≤ 5.0 mmol/L at the last assessment before randomisation received SZC 5 g orally qd for 3 months. SZC was up- or down- titrated depending on local laboratory S-K concentration at every study visit.	Placebo n=90 participants at risk Patients with S-K concentration \> 5.0 mmol/L at the last assessment before randomisation received placebo orally tid for 2 days followed by placebo qd for 3 months. Patients with S-K concentration ≤ 5.0 mmol/L at the last assessment before randomisation received placebo orally qd for 3 months. Placebo was up- or down- titrated depending on local laboratory S-K concentration at every study visit.
Infections and infestations Bronchitis	0.00% 0/91 • From Day 1 of treatment up to the end of the follow-up period (Week 17) The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.	1.1% 1/90 • Number of events 1 • From Day 1 of treatment up to the end of the follow-up period (Week 17) The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.
Infections and infestations Diverticulitis	1.1% 1/91 • Number of events 1 • From Day 1 of treatment up to the end of the follow-up period (Week 17) The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.	0.00% 0/90 • From Day 1 of treatment up to the end of the follow-up period (Week 17) The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.
Infections and infestations Osteomyelitis	0.00% 0/91 • From Day 1 of treatment up to the end of the follow-up period (Week 17) The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.	1.1% 1/90 • Number of events 1 • From Day 1 of treatment up to the end of the follow-up period (Week 17) The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.
Infections and infestations Pneumonia	1.1% 1/91 • Number of events 2 • From Day 1 of treatment up to the end of the follow-up period (Week 17) The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.	1.1% 1/90 • Number of events 1 • From Day 1 of treatment up to the end of the follow-up period (Week 17) The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.
Blood and lymphatic system disorders Iron deficiency anaemia	1.1% 1/91 • Number of events 1 • From Day 1 of treatment up to the end of the follow-up period (Week 17) The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.	0.00% 0/90 • From Day 1 of treatment up to the end of the follow-up period (Week 17) The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.
Metabolism and nutrition disorders Diabetes mellitus inadequate control	0.00% 0/91 • From Day 1 of treatment up to the end of the follow-up period (Week 17) The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.	1.1% 1/90 • Number of events 1 • From Day 1 of treatment up to the end of the follow-up period (Week 17) The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.
Metabolism and nutrition disorders Hyponatraemia	0.00% 0/91 • From Day 1 of treatment up to the end of the follow-up period (Week 17) The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.	1.1% 1/90 • Number of events 1 • From Day 1 of treatment up to the end of the follow-up period (Week 17) The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.
Nervous system disorders Syncope	0.00% 0/91 • From Day 1 of treatment up to the end of the follow-up period (Week 17) The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.	1.1% 1/90 • Number of events 1 • From Day 1 of treatment up to the end of the follow-up period (Week 17) The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.
Cardiac disorders Acute myocardial infarction	2.2% 2/91 • Number of events 3 • From Day 1 of treatment up to the end of the follow-up period (Week 17) The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.	1.1% 1/90 • Number of events 1 • From Day 1 of treatment up to the end of the follow-up period (Week 17) The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.
Cardiac disorders Angina unstable	0.00% 0/91 • From Day 1 of treatment up to the end of the follow-up period (Week 17) The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.	1.1% 1/90 • Number of events 1 • From Day 1 of treatment up to the end of the follow-up period (Week 17) The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.
Cardiac disorders Atrial fibrillation	1.1% 1/91 • Number of events 1 • From Day 1 of treatment up to the end of the follow-up period (Week 17) The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.	0.00% 0/90 • From Day 1 of treatment up to the end of the follow-up period (Week 17) The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.
Cardiac disorders Cardiac failure acute	2.2% 2/91 • Number of events 2 • From Day 1 of treatment up to the end of the follow-up period (Week 17) The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.	1.1% 1/90 • Number of events 1 • From Day 1 of treatment up to the end of the follow-up period (Week 17) The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.
Cardiac disorders Cardiac failure chronic	2.2% 2/91 • Number of events 2 • From Day 1 of treatment up to the end of the follow-up period (Week 17) The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.	2.2% 2/90 • Number of events 2 • From Day 1 of treatment up to the end of the follow-up period (Week 17) The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.
Cardiac disorders Myocardial fibrosis	1.1% 1/91 • Number of events 1 • From Day 1 of treatment up to the end of the follow-up period (Week 17) The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.	0.00% 0/90 • From Day 1 of treatment up to the end of the follow-up period (Week 17) The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.
Vascular disorders Hypertension	1.1% 1/91 • Number of events 1 • From Day 1 of treatment up to the end of the follow-up period (Week 17) The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.	0.00% 0/90 • From Day 1 of treatment up to the end of the follow-up period (Week 17) The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	1.1% 1/91 • Number of events 1 • From Day 1 of treatment up to the end of the follow-up period (Week 17) The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.	0.00% 0/90 • From Day 1 of treatment up to the end of the follow-up period (Week 17) The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.
Gastrointestinal disorders Gastrointestinal polyp haemorrhage	0.00% 0/91 • From Day 1 of treatment up to the end of the follow-up period (Week 17) The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.	1.1% 1/90 • Number of events 1 • From Day 1 of treatment up to the end of the follow-up period (Week 17) The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.
Skin and subcutaneous tissue disorders Dermatitis allergic	0.00% 0/91 • From Day 1 of treatment up to the end of the follow-up period (Week 17) The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.	1.1% 1/90 • Number of events 1 • From Day 1 of treatment up to the end of the follow-up period (Week 17) The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.
Renal and urinary disorders Chronic kidney disease	1.1% 1/91 • Number of events 1 • From Day 1 of treatment up to the end of the follow-up period (Week 17) The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.	1.1% 1/90 • Number of events 1 • From Day 1 of treatment up to the end of the follow-up period (Week 17) The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.
General disorders Generalised oedema	1.1% 1/91 • Number of events 1 • From Day 1 of treatment up to the end of the follow-up period (Week 17) The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.	0.00% 0/90 • From Day 1 of treatment up to the end of the follow-up period (Week 17) The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.

Other adverse events

Measure	Sodium Zirconium Cyclosilicate n=91 participants at risk Patients with S-K concentration \> 5.0 mmol/L at the last assessment before randomisation received SZC 10 g orally tid for 2 days followed by SZC 5 g qd for 3 months. Patients with S-K concentration ≤ 5.0 mmol/L at the last assessment before randomisation received SZC 5 g orally qd for 3 months. SZC was up- or down- titrated depending on local laboratory S-K concentration at every study visit.	Placebo n=90 participants at risk Patients with S-K concentration \> 5.0 mmol/L at the last assessment before randomisation received placebo orally tid for 2 days followed by placebo qd for 3 months. Patients with S-K concentration ≤ 5.0 mmol/L at the last assessment before randomisation received placebo orally qd for 3 months. Placebo was up- or down- titrated depending on local laboratory S-K concentration at every study visit.
Infections and infestations Viral upper respiratory tract infection	6.6% 6/91 • Number of events 7 • From Day 1 of treatment up to the end of the follow-up period (Week 17) The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.	3.3% 3/90 • Number of events 3 • From Day 1 of treatment up to the end of the follow-up period (Week 17) The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.
Cardiac disorders Cardiac failure chronic	7.7% 7/91 • Number of events 7 • From Day 1 of treatment up to the end of the follow-up period (Week 17) The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.	2.2% 2/90 • Number of events 2 • From Day 1 of treatment up to the end of the follow-up period (Week 17) The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.
Renal and urinary disorders Chronic kidney disease	5.5% 5/91 • Number of events 5 • From Day 1 of treatment up to the end of the follow-up period (Week 17) The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.	3.3% 3/90 • Number of events 3 • From Day 1 of treatment up to the end of the follow-up period (Week 17) The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.

Additional Information

Global Clinical Lead

Study Information Center

Phone: 1-877-240-9479

Email: information.center@astrazeneca.com

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place