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

• Sponsor: AstraZeneca (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03532009
• Collaborator: (none)
• Enrollment: 182
• Locations: 76
• Arms: 2
• Actual Duration (Months): 22.9
• Patients Per Site: 2.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is an international, multicentre, parallel-group, randomised, double-blind, placebo controlled, phase II study to evaluate the benefits and risks of using sodium zirconium cyclosilicate (ZS) to initiate and intensify renin angiotensin aldosterone system inhibitor (RAASi) therapy in heart failure patients.

Condition or Disease	Intervention/Treatment	Phase
Heart Failure	Drug: Sodium Zirconium Cyclosilicate; Drug: Placebo	Phase 2

Detailed Description

Patients with chronic heart failure (NYHA II-IV) and serum potassium > 5.0 mmol/L or at high risk of developing hyperkalaemia will be enrolled. Patients signing informed consent will be screened for up to 14 days. Patients meeting the inclusion criteria, but not the exclusion criteria, are then randomized in a 1:1 ratio to receive ZS or placebo for 3 months while titrating RAASi therapies. Approximately 280 patients will be randomized in the study. Study treatment in this study refers to ZS or placebo, while RAASi therapies are considered background therapy and will not be provided by the study sponsor. Patients will participate in the study for approximately 16 to 18 weeks in total, depending on the duration of the screening period. A Safety Review Committee will be established to review emerging safety data

Study Design

• Study Type: Interventional
• Actual Enrollment: 182 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase II, Randomised, Double-Blind, Placebo Controlled, Parallel-Group, Multicentre, Three Month Duration Potassium Reduction Initiative to Optimize RAAS Inhibition Therapy With Sodium Zirconium Cyclosilicate in Heart Failure
• Actual Study Start Date: Jun 26, 2018
• Actual Primary Completion Date: May 22, 2020
• Actual Study Completion Date: May 22, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Sodium Zirconium Cyclosilicate (ZS) Powder for oral suspension	Drug: Sodium Zirconium Cyclosilicate; Oral use for approximately 3 months; Other Names: ZS; Lokelma
Placebo Comparator: Placebo Powder for oral suspension	Drug: Placebo; Oral use for approximately 3 months; Other Names: PBO

Outcome Measures

Primary Outcome Measures

1. Percentage of Patients Receiving Different Categories of RAASi Treatments at Month 3 [At the end of the treatment visit (Month 3)]

   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.

Other Outcome Measures

1. Number of Patients Who Experienced Adverse Events (AEs) During the Study [From Day 1 of treatment up to the end of the follow-up period (Week 17)]

   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.

2. Number of Patients Who Experienced Clinically Important Abnormalities in Clinical Laboratory Parameters [From Day 1 of treatment up to the end of the follow-up period (Week 17)]

   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.

3. Number of Patients Who Experienced Clinically Important Abnormalities in Vital Signs Measurements [From Day 1 of treatment up to the end of the follow-up period (Week 17)]

   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.

4. Number of Patients Who Experienced Clinically Significant Changes in Electrocardiogram (ECG) Measurements [From Day 1 of treatment up to the end of the follow-up period (Week 17)]

   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.

5. Number of Patients Who Experienced Low and High S-K Levels [From Day 1 of treatment up to the end of the follow-up period (Week 17)]

   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.

6. Number of Events of Low and High S-K Levels [From Day 1 of treatment up to the end of the follow-up period (Week 17)]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 150 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

2. Provision of signed and dated, written informed consent form prior to any mandatory study specific procedures, sampling, and analyses.

3. Provision of signed and dated written genetic informed consent prior to collection of sample for genetic analysis. Individuals refusing to provide informed consent for genetic testing may still be included in the study, but will not have to provide samples for genetic analysis.

4. Subject must be ≥18 years of age inclusive, at the time of signing the informed consent form.

5. Individuals with established documented diagnosis of symptomatic Heart Failure with Reduced Ejection Fraction (HFrEF, NYHA functional class II-IV), which has been present for at least 3 months.

6. Individuals with left ventricular ejection fraction ≤ 40% (any measurement made within the past 12 months using echocardiography, multiple gate acquisition scan, computer tomography scanning, magnetic resonance imaging or ventricular angiography is acceptable, provided no subsequent measurement above 40%).

7. Individuals receiving background standard of care for HFrEF and treated according to locally recognized guidelines with both drugs and devices, as appropriate. Therapy with ACEi/ARB/ARNI, MRA and beta blocker should have been stable for ≥4 weeks. Subjects who are not being treated with beta blockers because of a contraindication are eligible. Subjects should be taking no MRA or a low dose of MRA (spironolactone, eplerenone, or canrenone) defined as less than or equal to 12.5 mg once a day (QD) or 25 mg every other day (QOD). If patients are taking a low dose MRA, the rationale for the low dose must be the patient could not tolerate a higher dose due to documented hyperkalemia observed at higher doses.

8. Individuals with mild hyperkalaemia or at risk of developing hyperkalaemia during the study, as defined by meeting all of the criteria in any one of the 3 categories listed below:

9. eGFR 20-44 ml/min/1.73m2 by CKD-EPI and local lab-K 4.0-5.5 mmol/L inclusive, or

10. eGFR 45-59 ml/min/1.73m2 by CKD-EPI and local lab-K 5.1-5.5 mmol/L inclusive, or

11. eGFR 45-59 ml/min/1.73m2 by CKD-EPI and local lab-K 4.0-5.0 mmol/L inclusive and a documented history of S-K > 5.0 mmol/L due to RAASi.

12. Women of childbearing potential must have a negative pregnancy test during screening (before first dose of IP) performed locally.

Exclusion Criteria:

1. HF due to restrictive cardiomyopathy, active myocarditis, constrictive pericarditis, hypertrophic (obstructive) cardiomyopathy or uncorrected primary valvular disease.

2. Current acute decompensated HF, hospitalization due to decompensated HF within 4 weeks prior to enrolment, or Myocardial infarction (MI), unstable angina, stroke or transient ischemic attack (TIA) within 12 weeks prior to enrolment.

3. Coronary revascularization (percutaneous coronary intervention [PCI] or coronary artery bypass grafting [CABG]) or valvular repair/replacement within 12 weeks prior to enrolment or planned to undergo any of these operations after randomization.

4. Implantation of a Cardiac Resynchronization Therapy (CRT) device or Implantable Cardioverter Defibrillator (ICD) within 12 weeks prior to enrolment or intent to perform atrial fibrillation ablation or to implant a CRT device.

5. Previous cardiac transplantation or implantation of a ventricular assistance device (VAD) or similar device, or transplantation or implantation expected after randomization.

6. Symptomatic bradycardia or second (Mobitz type 2) or third-degree heart block without a pacemaker.

7. Symptomatic hypotension or systolic blood pressure (BP) <95 mmHg on 2 consecutive measurements.

8. Receiving dialysis or anticipated by the investigator to require dialysis therapy within 3 months.

9. Prior history of hypersensitivity to a RAASi drug, including but not limited to development of angioedema, icterus, hepatitis, or neutropenia or thrombocytopenia requiring treatment modification.

10. Addison's disease or other causes of hypoaldosteronism.

11. Known hypersensitivity to ZS.

12. Any condition outside the cardiovascular (CV) and renal disease area, such as but not limited to malignancy, with a life expectancy of less than 2 years based on investigator´s clinical judgement.

13. Active malignancy requiring treatment.

14. MRA therapies that are mainly investigational and/or are not widely available as an oral dosing formulation (eg, canrenoate and finerenone) are excluded.

15. Treated with potassium binding resins such as sodium polystyrene sulfonate (SPS;e.g. Kayexalate®) or calcium polystyrene sulfonate (CPS; e.g. Resonium®) or the cation exchange polymer, patiromer sorbitex calcium (Veltassa®) within 7 days prior to the first dose of study drug.

16. Treated with potassium supplements within 7 days prior to randomization.

17. Participation in another clinical study with ZS at any time or treatment with any investigational product (IP) during the last 3 months.

18. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff, AstraZeneca representatives, and/or staff at the study site).

19. Judgment by the investigator that the subject should not participate in the study if the subject is unlikely to comply with study procedures, restrictions and requirements.

20. Previous randomisation in the present study.

21. Subjects with a family history of long QT syndrome, presence of cardiac arrhythmias or conduction defects that require immediate treatment, or a QTc (corrected QT interval) of ≥550 msec.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	National City	California	United States	91950
2	Research Site	Stanford	California	United States	94305
3	Research Site	Waterbury	Connecticut	United States	06708
4	Research Site	Miami	Florida	United States	33133
5	Research Site	New Smyrna Beach	Florida	United States	32169
6	Research Site	Port Charlotte	Florida	United States	33952
7	Research Site	Indianapolis	Indiana	United States	46260
8	Research Site	Alexandria	Louisiana	United States	71301
9	Research Site	Boston	Massachusetts	United States	02115
10	Research Site	Flint	Michigan	United States	48504
11	Research Site	Brooklyn	New York	United States	11204
12	Research Site	Wyomissing	Pennsylvania	United States	19610
13	Research Site	Rapid City	South Dakota	United States	57701
14	Research Site	El Paso	Texas	United States	79935
15	Research Site	Belo Horizonte		Brazil	30140 062
16	Research Site	Belo Horizonte		Brazil	30150-240
17	Research Site	Brasillia		Brazil	70200-730
18	Research Site	Campina Grande do Sul		Brazil	83430000
19	Research Site	Campinas		Brazil	13060-080
20	Research Site	Curitiba		Brazil	80010-030
21	Research Site	Marília		Brazil	17515000
22	Research Site	Porto Alegre		Brazil	90020090
23	Research Site	Rio de Janeiro		Brazil	20241-180
24	Research Site	Santo Andre		Brazil	09090-790
25	Research Site	Sao Paulo		Brazil	05403-000
26	Research Site	São José do Rio Preto		Brazil	15090-000
27	Research Site	Uberlandia		Brazil	38411-186
28	Research Site	Votuporanga		Brazil	15500-003
29	Research Site	Plovdiv		Bulgaria	4003
30	Research Site	Shumen		Bulgaria	9700
31	Research Site	Sofia		Bulgaria	1202
32	Research Site	Sofia		Bulgaria	1407
33	Research Site	Sofia		Bulgaria	1527
34	Research Site	Vancouver	British Columbia	Canada	V5Z 1M9
35	Research Site	Montreal	Quebec	Canada	H1T 1C8
36	Research Site	Saint-Charles-Borromee	Quebec	Canada	J6E 6J2
37	Research Site	Trois-Rivieres	Quebec	Canada	G8Z 3R9
38	Research Site	Quebec		Canada	G1V 4G5
39	Research Site	Baja		Hungary	6500
40	Research Site	Budapest		Hungary	1051
41	Research Site	Budapest		Hungary	1096
42	Research Site	Budapest		Hungary	1106
43	Research Site	Budapest		Hungary	1122
44	Research Site	Budapest		Hungary	1204
45	Research Site	Hatvan		Hungary	3000
46	Research Site	Kecskemét		Hungary	6000
47	Research Site	Miskolc		Hungary	3529
48	Research Site	Nyíregyháza		Hungary	4400
49	Research Site	Pécs		Hungary	7623
50	Research Site	Szentes		Hungary	6600
51	Research Site	Chorzów		Poland	41-500
52	Research Site	Gdańsk		Poland	80-952
53	Research Site	Legnica		Poland	59-220
54	Research Site	Poznań		Poland	60-848
55	Research Site	Rzeszów		Poland	35-055
56	Research Site	Tczew		Poland	83-110
57	Research Site	Brasov		Romania	500283
58	Research Site	Bucuresti		Romania	042122
59	Research Site	Cluj Napoca		Romania	400001
60	Research Site	Craiova		Romania	200642
61	Research Site	Sibiu		Romania	550245
62	Research Site	Tg Mures		Romania	540143
63	Research Site	Aramil		Russian Federation	624002
64	Research Site	Ekaterinburg		Russian Federation	620039
65	Research Site	Krasnoyarsk		Russian Federation	660062
66	Research Site	Moscow		Russian Federation	121552
67	Research Site	Novosibirsk		Russian Federation	630055
68	Research Site	Perm		Russian Federation	614000
69	Research Site	Ryazan		Russian Federation	390039
70	Research Site	Saint Petersburg		Russian Federation	191015
71	Research Site	Tver		Russian Federation	170036
72	Research Site	Yaroslavl		Russian Federation	150062
73	Research Site	Brezno		Slovakia	97742
74	Research Site	Lucenec		Slovakia	984 01
75	Research Site	Presov		Slovakia	080 01
76	Research Site	Svidnik		Slovakia	08901

Sponsors and Collaborators

• AstraZeneca

Investigators

• Principal Investigator: Jean-Claude Tardif, Montreal Heart Institute 5000 Belanger Street, Montreal, PQ Canada H1T1C8

Study Documents (Full-Text)

• Study Protocol - May 26, 2020
• Statistical Analysis Plan - Aug 21, 2020

More Information

Additional Information:

• redacted CSR synopsis
• redacted SAP
• redacted CSP

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT03532009
• Other Study ID Numbers: D9484C00001
• First Posted: May 22, 2018
• Last Update Posted: Jun 15, 2021
• Last Verified: May 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by AstraZeneca: Heart Failure; Chronic Heart Failure; Hyperkalaemia
• Additional relevant MeSH terms: Heart Failure

Study Results

Participant Flow

Recruitment Details	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.
Pre-assignment Detail	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).

Arm/Group Title	Sodium Zirconium Cyclosilicate	Placebo
Arm/Group Description	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.	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.
Period Title: Overall Study
STARTED	92	90
Received Treatment	91	90
COMPLETED	90	86
NOT COMPLETED	2	4

Baseline Characteristics

Arm/Group Title	Sodium Zirconium Cyclosilicate	Placebo	Total
Arm/Group Description	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.	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 of all reporting groups
Overall Participants	92	90	182
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	72.9 (8.8)	71.0 (8.1)	71.9 (8.5)
Age, Customized (Count of Participants)
≤ 17 years	0 0%	0 0%	0 0%
18 - 64 years	17 18.5%	16 17.8%	33 18.1%
65 - 84 years	65 70.7%	69 76.7%	134 73.6%
≥ 85 years	10 10.9%	5 5.6%	15 8.2%
Sex: Female, Male (Count of Participants)
Female	41 44.6%	33 36.7%	74 40.7%
Male	51 55.4%	57 63.3%	108 59.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	15 16.3%	14 15.6%	29 15.9%
Not Hispanic or Latino	77 83.7%	76 84.4%	153 84.1%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 1.1%	0 0%	1 0.5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 1.1%	1 1.1%	2 1.1%
White	90 97.8%	89 98.9%	179 98.4%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
S-K Concentration (Count of Participants)
≤ 5.0 mmol/L	65 70.7%	67 74.4%	132 72.5%
> 5.0 mmol/L	27 29.3%	23 25.6%	50 27.5%
New York Heart Association (NYHA) Functional Classification (Count of Participants)
Class I	0 0%	0 0%	0 0%
Class II	61 66.3%	57 63.3%	118 64.8%
Class III	31 33.7%	33 36.7%	64 35.2%
Class IV	0 0%	0 0%	0 0%
Left Ventricular Ejection Fraction (LVEF) (LVEF Percentage) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [LVEF Percentage]	33.8 (5.8)	33.9 (6.1)	33.8 (6.0)
Estimated Glomerular Filtration Rate (eGFR) (Millilitre/minute/1.73 metre^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Millilitre/minute/1.73 metre^2]	40.0 (11.0)	42.7 (11.5)	41.3 (11.3)

Outcome Measures

1. Primary Outcome

Title	Percentage of Patients Receiving Different Categories of RAASi Treatments at Month 3
Description	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.
Time Frame	At the end of the treatment visit (Month 3)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Sodium Zirconium Cyclosilicate	Placebo
Arm/Group Description	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.	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.
Measure Participants	89	87
No, or less than target dose ACEi/ARB/ARNI, no MRA	14.7	13.5
ACEi/ARB/ARNI at target dose and no MRA	14.7	15.1
MRA at less than target dose	14.2	24.5
MRA at target dose	56.4	47.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sodium Zirconium Cyclosilicate, Placebo
	Comments	The p-value was obtained by pooling the p-values from Chi-square tests performed on individual data sets using the F-distribution and reflects a global test of no difference in distribution of patients in the respective categories between SZC and placebo groups. The null hypothesis was that there is no difference between SZC and placebo in the distribution of percentage of patients in the 4 RAASi treatment categories. The hypothesis was tested at a significance level of 5%.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.426
	Comments
	Method	F-test
	Comments

2. Other Pre-specified Outcome

Title	Number of Patients Who Experienced Adverse Events (AEs) During the Study
Description	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.
Time Frame	From Day 1 of treatment up to the end of the follow-up period (Week 17)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Sodium Zirconium Cyclosilicate	Placebo
Arm/Group Description	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.	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.
Measure Participants	91	90
Any SAE	14 15.2%	10 11.1%
Any AE leading to discontinuation of IP	5 5.4%	2 2.2%
Any AE	43 46.7%	47 52.2%

3. Other Pre-specified Outcome

Title	Number of Patients Who Experienced Clinically Important Abnormalities in Clinical Laboratory Parameters
Description	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.
Time Frame	From Day 1 of treatment up to the end of the follow-up period (Week 17)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Sodium Zirconium Cyclosilicate	Placebo
Arm/Group Description	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.	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.
Measure Participants	91	90
Anaemia	1 1.1%	1 1.1%
Iron deficiency anaemia	1 1.1%	0 0%
Hypoglycaemia	1 1.1%	1 1.1%
Hypertriglyceridaemia	0 0%	1 1.1%
Hyponatraemia	0 0%	1 1.1%

4. Other Pre-specified Outcome

Title	Number of Patients Who Experienced Clinically Important Abnormalities in Vital Signs Measurements
Description	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.
Time Frame	From Day 1 of treatment up to the end of the follow-up period (Week 17)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Sodium Zirconium Cyclosilicate	Placebo
Arm/Group Description	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.	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.
Measure Participants	91	90
Hypotension	4 4.3%	1 1.1%
Hypertension	2 2.2%	0 0%
Hypertensive crisis	1 1.1%	1 1.1%
Blood pressure inadequately controlled	0 0%	1 1.1%

5. Other Pre-specified Outcome

Title	Number of Patients Who Experienced Clinically Significant Changes in Electrocardiogram (ECG) Measurements
Description	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.
Time Frame	From Day 1 of treatment up to the end of the follow-up period (Week 17)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Sodium Zirconium Cyclosilicate	Placebo
Arm/Group Description	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.	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.
Measure Participants	91	90
Count of Participants [Participants]	0 0%	0 0%

6. Other Pre-specified Outcome

Title	Number of Patients Who Experienced Low and High S-K Levels
Description	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.
Time Frame	From Day 1 of treatment up to the end of the follow-up period (Week 17)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Sodium Zirconium Cyclosilicate	Placebo
Arm/Group Description	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.	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.
Measure Participants	91	90
S-K < 3.0 mmol/L	0 0%	0 0%
S-K < 3.5 mmol/L	7 7.6%	0 0%
S-K > 5.5 mmol/L	23 25%	32 35.6%
S-K > 6.0 mmol/L	3 3.3%	4 4.4%

7. Other Pre-specified Outcome

Title	Number of Events of Low and High S-K Levels
Description	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.
Time Frame	From Day 1 of treatment up to the end of the follow-up period (Week 17)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Sodium Zirconium Cyclosilicate	Placebo
Arm/Group Description	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.	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.
Measure Participants	91	90
S-K < 3.0 mmol/L	0	0
S-K < 3.5 mmol/L	12	0
S-K > 5.5 mmol/L	37	59
S-K > 6.0 mmol/L	3	4

Adverse Events

Time Frame	From Day 1 of treatment up to the end of the follow-up period (Week 17)
Adverse Event Reporting Description	The Safety analysis set included all patients randomly assigned to study treatment and who took at least one dose of study drug.
Arm/Group Title	Sodium Zirconium Cyclosilicate		Placebo
Arm/Group Description	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.		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.
All Cause Mortality
	Sodium Zirconium Cyclosilicate		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/91 (1.1%)		1/90 (1.1%)
Serious Adverse Events
	Sodium Zirconium Cyclosilicate		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/91 (15.4%)		10/90 (11.1%)
Blood and lymphatic system disorders
Iron deficiency anaemia	1/91 (1.1%)	1	0/90 (0%)	0
Cardiac disorders
Acute myocardial infarction	2/91 (2.2%)	3	1/90 (1.1%)	1
Angina unstable	0/91 (0%)	0	1/90 (1.1%)	1
Atrial fibrillation	1/91 (1.1%)	1	0/90 (0%)	0
Cardiac failure acute	2/91 (2.2%)	2	1/90 (1.1%)	1
Cardiac failure chronic	2/91 (2.2%)	2	2/90 (2.2%)	2
Myocardial fibrosis	1/91 (1.1%)	1	0/90 (0%)	0
Gastrointestinal disorders
Gastrointestinal polyp haemorrhage	0/91 (0%)	0	1/90 (1.1%)	1
General disorders
Generalised oedema	1/91 (1.1%)	1	0/90 (0%)	0
Infections and infestations
Bronchitis	0/91 (0%)	0	1/90 (1.1%)	1
Diverticulitis	1/91 (1.1%)	1	0/90 (0%)	0
Osteomyelitis	0/91 (0%)	0	1/90 (1.1%)	1
Pneumonia	1/91 (1.1%)	2	1/90 (1.1%)	1
Metabolism and nutrition disorders
Diabetes mellitus inadequate control	0/91 (0%)	0	1/90 (1.1%)	1
Hyponatraemia	0/91 (0%)	0	1/90 (1.1%)	1
Nervous system disorders
Syncope	0/91 (0%)	0	1/90 (1.1%)	1
Renal and urinary disorders
Chronic kidney disease	1/91 (1.1%)	1	1/90 (1.1%)	1
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/91 (1.1%)	1	0/90 (0%)	0
Skin and subcutaneous tissue disorders
Dermatitis allergic	0/91 (0%)	0	1/90 (1.1%)	1
Vascular disorders
Hypertension	1/91 (1.1%)	1	0/90 (0%)	0
Other (Not Including Serious) Adverse Events
	Sodium Zirconium Cyclosilicate		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/91 (17.6%)		7/90 (7.8%)
Cardiac disorders
Cardiac failure chronic	7/91 (7.7%)	7	2/90 (2.2%)	2
Infections and infestations
Viral upper respiratory tract infection	6/91 (6.6%)	7	3/90 (3.3%)	3
Renal and urinary disorders
Chronic kidney disease	5/91 (5.5%)	5	3/90 (3.3%)	3

Limitations/Caveats

The study was paused from May to October 2019 to undergo a major protocol amendment. The study was also prematurely terminated due to the COVID-19 pandemic resulting in a reduced sample size and a high premature treatment discontinuation rate.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.