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

A Double-blind Randomized Placebo-controlled Parallel Design Multicenter Phase IIIb Study of the Effect of Sodium Zirconium Cyclosilicate (SZC) on Serum Potassium and Serum Bicarbonate in Patients With Hyperkalemia and Metabolic Acidosis Associated With Chronic Kidney Disease (NEUTRALIZE)

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

Study Overview

• Status: Terminated
• Conditions: Chronic Kidney Disease; Metabolic Acidosis; Hyperkalaemia
• Intervention / Treatment: Drug: Sodium zirconium cyclosilicate; Drug: Placebo

Detailed Description

NEUTRALIZE is a prospective, randomized, double-blind, placebo-controlled, parallel, multicenter, Phase IIIb study to investigate the safety and efficacy of SZC in patients with hyperkalemia and low bicarbonate (metabolic acidosis ).

The study will be conducted in the United States (US) at approximately 35 investigative sites.

After screening on Day 1, all eligible patients will receive open-label SZC for up to 48 hours. Patients who achieve normokalemia within 48 hours will be randomized 1:1 into the double-blind randomized treatment phase to receive SZC or placebo. Study treatment will end with the Day 29 visit, which will be followed by a follow-up visit 7 days after the last administration of study medication.

• Study Type: Interventional
• Enrollment (Actual): 39
• Phase: Phase 3

Contacts and Locations

Study Locations

• Puerto Rico
  • San Juan, Puerto Rico, 00918
    • Research Site
• United States
  • Alabama
    • Florence, Alabama, United States, 35630
      • Research Site
  • California
    • Chula Vista, California, United States, 91910
      • Research Site
    • Downey, California, United States, 90242
      • Research Site
    • El Centro, California, United States, 92243
      • Research Site
    • S. Gate, California, United States, 90280
      • Research Site
    • Victorville, California, United States, 92395
      • Research Site
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Research Site
    • Denver, Colorado, United States, 80230
      • Research Site
  • Florida
    • Coral Gables, Florida, United States, 33134
      • Research Site
  • Georgia
    • Columbus, Georgia, United States, 31904
      • Research Site
  • Illinois
    • Hinsdale, Illinois, United States, 60521
      • Research Site
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • Research Site
  • Nevada
    • Las Vegas, Nevada, United States, 89128
      • Research Site
  • New York
    • Bronx, New York, United States, 10461
      • Research Site
  • North Carolina
    • Asheville, North Carolina, United States, 28801
      • Research Site
    • New Bern, North Carolina, United States, 28562
      • Research Site
    • Winston-Salem, North Carolina, United States, 27103
      • Research Site
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Research Site
  • South Carolina
    • Spartanburg, South Carolina, United States, 29306
      • Research Site
  • Tennessee
    • Chattanooga, Tennessee, United States, 37404
      • Research Site
    • Memphis, Tennessee, United States, 38163
      • Research Site
  • Texas
    • Dallas, Texas, United States, 75246
      • Research Site
    • Dallas, Texas, United States, 75230
      • Research Site
    • San Antonio, Texas, United States, 78258
      • Research Site
    • Shenandoah, Texas, United States, 77384
      • Research Site
  • Virginia
    • Alexandria, Virginia, United States, 22304
      • Research Site
    • Norfolk, Virginia, United States, 23510
      • Research Site
  • Washington
    • Bellevue, Washington, United States, 98004
      • Research Site
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 130 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Adults aged ≥18 years
• Participants who have CKD stage 3-5, not on dialysis.
• POCT K+ level >5 mmol/L to ≤5.9 mmol/L and POCT bicarbonate levels between 16-20 mmol/L inclusive prior to the first SZC dose on study Day 1
• Ability to have repeated blood draws or effective venous catheterization.
• Male and/or female. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
• Capable of giving signed informed consent

Exclusion Criteria:

• Participants with pseudohyperkalemia.
• Dialysis requirement or anticipated by the investigator to require dialysis therapy within 1 month, history of renal transplant, or life expectancy less than 3 months.
• Cardiac arrhythmias requiring immediate treatment.
• Active or suspected diabetic ketoacidosis.
• POCT bicarbonate low enough to need emergency intervention or treatment as judged by the investigator.
• Acute/chronic worsening renal function (eg, ≥30% decline in eGFR) in the 3 months before screening.
• Current acute decompensated HF, hospitalization due to decompensated HF within 4 weeks prior to screening, or myocardial infarction (MI), unstable angina, stroke or transient ischemic attack (TIA) within 12 weeks prior to screening.
• Coronary revascularization (percutaneous coronary intervention [PCI] or coronary artery bypass grafting [CABG]) or valvular repair/replacement within 12 weeks prior to screening or planned to undergo any of these operations.
• Symptomatic hypotension.
• Current exacerbation of chronic obstructive pulmonary disease (COPD)/asthma or hospitalization due to exacerbation of COPD/asthma within 4 weeks of screening.
• Severe constipation, bowel obstruction or impaction, including abnormal post-operative bowel motility disorders
• Active malignancy requiring treatment.
• History of QT prolongation associated with other medications that required discontinuation of that medication.
• Congenital long QT syndrome.
• Symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Patients with atrial fibrillation controlled by medication are permitted.
• QTcF (QT interval corrected by the Fridericia method) >550 msec.
• Active treatment (within 7 days prior to screening) with SZC, sodium bicarbonate, sodium polystyrene sulfonate, lactulose, or patiromer

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Open-label correction phase (up to 48 hours); All eligible patients will receive SZC 10 g TID for up to 48 hours. Patients with POCT (Point-of-Care-Test) K+ ≥5.1 mmol/L after 24 hours will continue on SZC 10 g TID for another 24 hours. Patients who achieve normokalemia (defined as POCT K+ between 3.5 and 5.0 mmol/L inclusive) after receiving SZC 10 g TID for up to 48 hours will proceed to randomization. Patients with POCT K+ <3.5mmol/L at any time during the open-label phase will be withdrawn from study treatment and will be followed per protocol.	Drug: Sodium zirconium cyclosilicate; Investigational medicinal product; Other Names: SZC; Drug: Placebo; Plabeco comparator
Experimental: Randomized, placebo controlled phase (Day 2 or 3 to Day 29); Patients will be randomized to SZC 10 g QD or placebo 10 g QD. The dose of SZC/placebo will be titrated by increasing or decreasing the dose by 5 g increments at 1-week intervals to between 5 g every other day (QOD) and 15 g QD of the randomized phase to maintain normokalemia by POCT K+.	Drug: Sodium zirconium cyclosilicate; Investigational medicinal product; Other Names: SZC; Drug: Placebo; Plabeco comparator

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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.	Day 1 of randomization phase to Day 29

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Serum Bicarbonate at 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.	Day 29
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)	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. 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 treatment as an independent factor. Participants who died prior to the EOT visit were assigned a non-response.	Day 1 to Day 29 of randomization phase
Occurrence (Yes/no) of Participants Having Serum Bicarbonate ≥22 mmol/L	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 (response / non-response) as the dependent variable and randomized treatment as an independent factor.	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 2 mmol/L From Baseline (Day 1) to EOT 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 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 the dependent variable and randomized treatment as an independent factor. Participants who died prior to the EOT visit were assigned a non-response.	Day 1 to Day 29 of randomization phase
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	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-controlled period had last observation prior to rescue therapy carried forward. Participants lost to follow-up prior to EOT visit had response as missing. Logistic regression model included response status (response/non-response) as dependent variable and randomized treatment as an independent factor. Participants who died prior to the EOT visit were assigned a non-response.	Day 1 to Day 29 of randomization phase
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)	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 treatment as an independent factor. Participants who died prior to the EOT visit were assigned a non-response.	Day 1 to Day 29 of randomization phase
Occurrence (Yes/no) of Participants Needing Rescue Treatment for Low Sodium Bicarbonate	Occurrence (yes/no) of participants needing rescue treatment for low sodium bicarbonate any time during the randomized phase	Day 1 to Day 29 of randomization phase

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Spot urine ammonium	Mean change in spot urine ammonium at Day 29 (End of Treatment) compared to baseline	From baseline to Day 29
Spot urine citrate	Mean change in spot urine citrate at Day 29 (End of Treatment) compared to baseline	From baseline to Day 29
Spot urine anion gap	Mean change in spot urine anion gap at Day 29 (End of Treatment) compared to baseline	From baseline to Day 29
Spot urine ammonium to creatinine ratio	Mean change in spot urine ammonium-to-creatinine ratio at Day 29 (End of Treatment) compared to baseline	From baseline to Day 29
Serum aldosterone	Mean change in serum aldosterone at Day 29 (End of Treatment) compared to baseline	From baseline to Day 29
Adverse events	Percentage of subjects with treatment-emergent adverse events (TEAEs)	From enrollment to up to 7 days post End of Treatment/Day 35
Serious adverse events	Percentage of subjects experiencing TEAEs by severity	From enrollment to up to 7 days post End of Treatment/Day 35
Withdrawal of treatment due to an adverse event	TEAEs leading to discontinuation of study treatment will be summarized by treatment group	From enrollment to up to 7 days post End of Treatment/Day 35

Collaborators and Investigators

• Sponsor: AstraZeneca

Publications and helpful links

Helpful Links

• CSRsynopsis_redacted
• SAP_redacted
• CSP_redacted

Study record dates

Study Major Dates

• Study Start (Actual): March 22, 2021
• Primary Completion (Actual): September 14, 2022
• Study Completion (Actual): September 14, 2022

Study Registration Dates

• First Submitted: December 22, 2020
• First Submitted That Met QC Criteria: January 26, 2021
• First Posted (Actual): January 27, 2021

Study Record Updates

• Last Update Posted (Actual): October 6, 2023
• Last Update Submitted That Met QC Criteria: October 5, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Urologic Diseases; Disease Attributes; Renal Insufficiency; Water-Electrolyte Imbalance; Acid-Base Imbalance; Chronic Disease; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Kidney Diseases; Renal Insufficiency, Chronic; Acidosis; Hyperkalemia
• Other Study ID Numbers: D9480C00022

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No