NCT04727528: NEUTRALIZE

Study of the Effect of SZC on Serum Potassium and Serum Bicarbonate in Patients With Hyperkalemia and Metabolic Acidosis Associated With Chronic Kidney Disease

Terminated Phase 3 Results posted Last updated 6 October 2023

What this trial tests

Phase 3 trial testing Sodium zirconium cyclosilicate in Hyperkalaemia in 39 participants. Terminated before completion.

Timeline

22 March 2021

Primary endpoint
14 September 2022

14 September 2022

Quick facts

Lead sponsor	AstraZeneca
Phase	Phase 3
Status	Terminated
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	double
Primary purpose	treatment
Enrollment	39
Start date	22 March 2021
Primary completion	14 September 2022
Estimated completion	14 September 2022
Sites	30 locations across Puerto Rico, United States

Drugs / interventions tested

• Sodium zirconium cyclosilicate — full drug profile →
• Placebo

Conditions studied

• Hyperkalaemia — all drugs for Hyperkalaemia →
• Metabolic Acidosis — all drugs for Metabolic Acidosis →
• Chronic Kidney Disease — all drugs for Chronic Kidney Disease →

Sponsor

AstraZeneca — full company profile →

Who can join

Adults 18 to 130, any sex, with Hyperkalaemia or Metabolic Acidosis. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Occurrence (Yes/no) of Participants Having Normal Serum Potassium (sK+) Between 3.5 and 5.0 mmol/L Inclusive at End of Treatment (EOT) Without Need for Rescue Treatment for Hyperkalemia at Any Point During the Randomized Phase Primary · Day 1 of randomization phase to Day 29

Response was defined as a subject having serum potassium (sK+) within 3.5-5.0 mmol/L at the EOT visit, and no use of rescue therapy for hyperkalaemia at any point during the randomized placebo-controlled period. Participants who used rescue therapy for hyperkalaemia at any point during the randomized placebo-controlled period were assigned a non-response. Participants who died prior to the EOT visit were treated as non-response. Participants who were lost to follow-up prior to the EOT visit had response treated as missing.

No response

Group	Value	95% CI
Sodium Zirconium Cyclosilicate (SZC)	1
Placebo	15

Response

Group	Value	95% CI
Sodium Zirconium Cyclosilicate (SZC)	15
Placebo	4

Missing

Group	Value	95% CI
Sodium Zirconium Cyclosilicate (SZC)	1
Placebo	1

Mean Serum Bicarbonate at Day 29 Secondary · Day 29

Least-squares mean calculated with a repeated measures analysis of covariance model where the dependent variable was post randomization serum bicarbonate and with fixed terms for randomized treatment group and serum bicarbonate.

Group	Value	95% CI
Sodium Zirconium Cyclosilicate (SZC)	18.17	± 0.58
Placebo	16.52	± 0.56

Occurrence (Yes/no) of Participants Having an Increase in Serum Bicarbonate of Greater Than or Equal to 3 mmol/L From Baseline to EOT Without Need for Rescue Treatment for Metabolic Acidosis (Low Bicarbonate) Secondary · Day 1 to Day 29 of randomization phase

Occurrence (yes/no) of participants having an increase in serum bicarbonate of greater than or equal to 3 mmol/L from baseline (Day 1) to EOT (Day 29) without need for rescue treatment for metabolic acidosis (low bicarbonate). Response was defined as a participant with an increase in serum bicarbonate greater than or equal to 3 mmol/L at the EOT visit without the need for rescue therapy for low bicarbonate. Participants who used rescue therapy for low bicarbonate at any point during the randomized placebo-controlled period had their last observation prior to rescue therapy carried forward. Pa

No response

Group	Value	95% CI
Sodium Zirconium Cyclosilicate (SZC)	10
Placebo	16

Response

Group	Value	95% CI
Sodium Zirconium Cyclosilicate (SZC)	6
Placebo	3

Missing

Group	Value	95% CI
Sodium Zirconium Cyclosilicate (SZC)	1
Placebo	1

Occurrence (Yes/no) of Participants Having Serum Bicarbonate ≥22 mmol/L Secondary · Day 1 to Day 29 of randomization phase

Response was defined as a participant with an increase in serum bicarbonate greater than or equal to 22 mmol/L at the EOT visit without the need for rescue therapy for low bicarbonate. Participants who had used rescue therapy for low bicarbonate at any point during the randomized placebo-controlled period had their last observation prior to rescue therapy carried forward. Participants who died prior to the EOT visit were assigned a non-response. Participants who were lost to follow-up prior to the EOT visit had response treated as missing. Logistic regression model included response status (re

No response

Group	Value	95% CI
Sodium Zirconium Cyclosilicate (SZC)	14
Placebo	19

Response

Group	Value	95% CI
Sodium Zirconium Cyclosilicate (SZC)	2
Placebo	0

Missing

Group	Value	95% CI
Sodium Zirconium Cyclosilicate (SZC)	1
Placebo	1

Occurrence (Yes/no) of Participants Having an Increase in Serum Bicarbonate of Greater Than or Equal to 2 mmol/L From Baseline (Day 1) to EOT Without Need for Rescue Treatment for Metabolic Acidosis (Low Bicarbonate) Secondary · Day 1 to Day 29 of randomization phase

Response was defined as a participant with an increase in serum bicarbonate greater than or equal to 2 mmol/L at the EOT visit and no use of rescue therapy for low bicarbonate at any point during the randomized placebo-controlled period. Participants who used rescue therapy for low bicarbonate at any point during the randomized placebo-controlled period had their last observation prior to rescue therapy carried forward. Participants who were lost to follow-up prior to the EOT visit had response treated as missing. Logistic regression model included response status (response / non-response) as

No response

Group	Value	95% CI
Sodium Zirconium Cyclosilicate (SZC)	8
Placebo	13

Response

Group	Value	95% CI
Sodium Zirconium Cyclosilicate (SZC)	8
Placebo	6

Missing

Group	Value	95% CI
Sodium Zirconium Cyclosilicate (SZC)	1
Placebo	1

Participants Having Normal sK+ at EOT and an Increase in Serum Bicarbonate of ≥3 mmol/L From Baseline Without Need for Rescue Treatment for Metabolic Acidosis (Low Bicarbonate) or Hyperkalemia Secondary · Day 1 to Day 29 of randomization phase

Participants with normal sK+ between 3.5 and 5.0 mmol/L inclusive at EOT and increase in serum bicarbonate greater than or equal to 3 mmol/L from Day 1 without rescue treatment for metabolic acidosis (low bicarbonate) or hyperkalemia. Response was a participant with sK+ within 3.5-5.0 mmol/L and increase in serum bicarbonate greater than or equal to 3 mmol/L at the EOT visit and no use of rescue therapy for hyperkalaemia or low bicarbonate at any point during the randomized placebo-controlled period. Participants who used rescue therapy for low bicarbonate or HK during the randomized placebo-

No response

Group	Value	95% CI
Sodium Zirconium Cyclosilicate (SZC)	10
Placebo	18

Response

Group	Value	95% CI
Sodium Zirconium Cyclosilicate (SZC)	6
Placebo	1

Missing

Group	Value	95% CI
Sodium Zirconium Cyclosilicate (SZC)	1
Placebo	1

Occurrence (Yes/no) of Patients Having a Normal sK+ Between 3.5 and 5.0 mmol/L Inclusive and Bicarbonate ≥22 mmol/L at Day 29 Without Need for Rescue Treatment for Hyperkalemia or Metabolic Acidosis (Low Bicarbonate) Secondary · Day 1 to Day 29 of randomization phase

Response was defined as a participant with sK+ within 3.5-5.0 mmol/L and serum bicarbonate greater than or equal to 22 mmol/L at the EOT visit without the need for rescue therapy for hyperkalaemia or low bicarbonate. Participants who used rescue therapy for hyperkalaemia or low bicarbonate at any point during the randomized placebo-controlled period were assigned a non-response. Participants who were lost to follow-up prior to the EOT visit had response treated as missing. Logistic regression model included response status (response / non-response) as the dependent variable and randomized trea

No response

Group	Value	95% CI
Sodium Zirconium Cyclosilicate (SZC)	14
Placebo	19

Response

Group	Value	95% CI
Sodium Zirconium Cyclosilicate (SZC)	2
Placebo	0

Missing

Group	Value	95% CI
Sodium Zirconium Cyclosilicate (SZC)	1
Placebo	1

Occurrence (Yes/no) of Participants Needing Rescue Treatment for Low Sodium Bicarbonate Secondary · Day 1 to Day 29 of randomization phase

Occurrence (yes/no) of participants needing rescue treatment for low sodium bicarbonate any time during the randomized phase

Rescue treatment required

Group	Value	95% CI
Sodium Zirconium Cyclosilicate (SZC)	0
Placebo	0

Rescue treatment not required

Group	Value	95% CI
Sodium Zirconium Cyclosilicate (SZC)	17
Placebo	20

Adverse events — posted to ClinicalTrials.gov

Time frame: Adverse events were collected at screening, during the open-label correction phase (Days 1 and 2), throughout the treatment period of the the randomization phase (Days 2 or 3 to 29 or 30 [end of treatment] or discontinuation), and during the follow up phase (Day 36 to 39).. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Open-Label Phase

Serious: 0/38 (0%)

Deaths: 0/38

Sodium Zirconium Cyclosilicate (SZC) Double-blind Treatment Phase

Serious: 1/17 (6%)

Deaths: 0/17

Placebo Double-blind Treatment Phase

Serious: 2/20 (10%)

Deaths: 1/20

Serious adverse events (3 terms)

Reaction	System	Open-Label Phase	Sodium Zirconium Cyclosili…	Placebo Double-blind Treat…
Hypervolaemia	Metabolism and nutrition disorders	—	—	—
Acute kidney injury	Renal and urinary disorders	—	—	—
Hypertension	Vascular disorders	—	—	—

Other adverse events (23 terms — click to expand)

Reaction	System	Open-Label Phase	Sodium Zirconium Cyclosili…	Placebo Double-blind Treat…
Hyperkalaemia	Metabolism and nutrition disorders	—	—	—
Nausea	Gastrointestinal disorders	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—
Oedema peripheral	General disorders	—	—	—
Peripheral swelling	General disorders	—	—	—
COVID-19	Infections and infestations	—	—	—
Herpes zoster	Infections and infestations	—	—	—
Ankle fracture	Injury, poisoning and procedural complications	—	—	—
Fall	Injury, poisoning and procedural complications	—	—	—
Atrioventricular block first degree	Cardiac disorders	—	—	—
Hyponatraemia	Metabolism and nutrition disorders	—	—	—
Metabolic acidosis	Metabolism and nutrition disorders	—	—	—
Muscle spasms	Musculoskeletal and connective tissue disorders	—	—	—
Headache	Nervous system disorders	—	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—	—
Hypertension	Vascular disorders	—	—	—
Diastolic dysfunction	Cardiac disorders	—	—	—
Left ventricular hypertrophy	Cardiac disorders	—	—	—
Mitral valve incompetence	Cardiac disorders	—	—	—
Tinnitus	Ear and labyrinth disorders	—	—	—
Vision blurred	Eye disorders	—	—	—
Vitreous floaters	Eye disorders	—	—	—
Abdominal discomfort	Gastrointestinal disorders	—	—	—

Most-reported serious reactions: Hypervolaemia, Acute kidney injury, Hypertension.

Data from ClinicalTrials.gov NCT04727528 adverse events section.

Sponsor's own description

The main objective of this study is to evaluate the efficacy of SZC as compared to placebo in maintaining normal sK+ in patients with hyperkalemia and metabolic acidosis associated with CKD

Publications & conference data

2 peer-reviewed publications reference this trial (live from Europe PMC):

1. Effect of Sodium Zirconium Cyclosilicate on Serum Potassium and Bicarbonate in Patients with Hyperkalemia and Metabolic Acidosis Associated with Chronic Kidney Disease: Rationale and Design of the NEUTRALIZE Study.
   Ash SR, Batlle D, Kendrick J, Oluwatosin Y, et al · · 2022 · cited 6× · PMID 35462371 · DOI 10.1159/000523911
2. Sodium Zirconium Cyclosilicate in CKD, Hyperkalemia, and Metabolic Acidosis: NEUTRALIZE Randomized Study.
   Ash SR, Batlle D, Kendrick J, Oluwatosin Y, et al · · 2024 · PMID 38622759 · DOI 10.34067/kid.0000000000000446