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

NCT04727528 | Terminated Phase 3 Results FDA Drug

• 1 other identifier: D9480C00022
• Study Type: interventional
• Target: 39
• Locations: 2 countries
• Sites: 30

Brief Summary

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

Conditions

Hyperkalaemia; Metabolic Acidosis; Chronic Kidney Disease

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (7)

• Mean Serum Bicarbonate at Day 29

  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)

  Day 1 to Day 29 of randomization phase

• Occurrence (Yes/no) of Participants Having Serum Bicarbonate ≥22 mmol/L

  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)

  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

  Day 1 to Day 29 of randomization phase

Study Arms (2)

Open-label correction phase (up to 48 hours)

EXPERIMENTAL

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; Drug: Placebo

Randomized, placebo controlled phase (Day 2 or 3 to Day 29)

EXPERIMENTAL

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; Drug: Placebo

Interventions

Sodium zirconium cyclosilicate DRUG

Investigational medicinal product

Also known as: SZC

Open-label correction phase (up to 48 hours); Randomized, placebo controlled phase (Day 2 or 3 to Day 29)

Placebo DRUG

Plabeco comparator

Open-label correction phase (up to 48 hours); Randomized, placebo controlled phase (Day 2 or 3 to Day 29)

Eligibility Criteria

• Age: 18 Years - 130 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (30)

Research Site

Florence, Alabama, 35630, United States

Location

Research Site

Chula Vista, California, 91910, United States

Location

Research Site

Downey, California, 90242, United States

Location

Research Site

El Centro, California, 92243, United States

Location

Research Site

South Gate, California, 90280, United States

Location

Research Site

Victorville, California, 92395, United States

Location

Research Site

Aurora, Colorado, 80045, United States

Location

Research Site

Denver, Colorado, 80230, United States

Location

Research Site

Coral Gables, Florida, 33134, United States

Location

Research Site

Columbus, Georgia, 31904, United States

Location

Research Site

Hinsdale, Illinois, 60521, United States

Location

Research Site

Kansas City, Missouri, 64111, United States

Location

Research Site

Las Vegas, Nevada, 89128, United States

Location

Research Site

The Bronx, New York, 10461, United States

Location

Research Site

Asheville, North Carolina, 28801, United States

Location

Research Site

New Bern, North Carolina, 28562, United States

Location

Research Site

Winston-Salem, North Carolina, 27103, United States

Location

Research Site

Providence, Rhode Island, 02903, United States

Location

Research Site

Spartanburg, South Carolina, 29306, United States

Location

Research Site

Chattanooga, Tennessee, 37404, United States

Location

Research Site

Memphis, Tennessee, 38163, United States

Location

Research Site

Dallas, Texas, 75230, United States

Location

Research Site

Dallas, Texas, 75246, United States

Location

Research Site

San Antonio, Texas, 78258, United States

Location

Research Site

Shenandoah, Texas, 77384, United States

Location

Research Site

Alexandria, Virginia, 22304, United States

Location

Research Site

Norfolk, Virginia, 23510, United States

Location

Research Site

Bellevue, Washington, 98004, United States

Location

Research Site

Milwaukee, Wisconsin, 53226, United States

Location

Research Site

San Juan, 00918, Puerto Rico

Location

Related Publications (1)

• Ash SR, Batlle D, Kendrick J, Oluwatosin Y, Kooienga L, Eudicone JM, Sundin AK, Guerrieri E, Fried LF. Sodium Zirconium Cyclosilicate in CKD, Hyperkalemia, and Metabolic Acidosis: NEUTRALIZE Randomized Study. Kidney360. 2024 Jun 1;5(6):812-820. doi: 10.34067/KID.0000000000000446. Epub 2024 Apr 16.

  PMID: 38622759 DERIVED

Related Links

• CSRsynopsis\_redacted
• SAP\_redacted
• CSP\_redacted

MeSH Terms

Conditions

Hyperkalemia; Acidosis; Renal Insufficiency, Chronic

Interventions

sodium zirconium cyclosilicate

Condition Hierarchy (Ancestors)

Water-Electrolyte Imbalance; Metabolic Diseases; Nutritional and Metabolic Diseases; Acid-Base Imbalance; Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Limitations and Caveats

Due to a screening failure rate higher than expected which led to early termination of the study, only 39 (17.0%) patients entered the open-label phase. Due to the early termination of the study and small sample size, the study was underpowered for the secondary efficacy endpoints.

Results Point of Contact

• Title: Global Clinical Lead
• Organization: AstraZeneca

information.center@astrazeneca.com

1-877-240-9479

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: NEUTRALIZE is a prospective, randomized, double-blind, placebo-controlled, parallel, multicenter, Phase IIIb study

Study Record Dates

• First Submitted: December 22, 2020
• First Posted: January 27, 2021
• Study Start: March 22, 2021
• Primary Completion: September 14, 2022
• Study Completion: September 14, 2022
• Last Updated: October 6, 2023
• Results First Posted: October 6, 2023

Record last verified: 2023-10

Locations

PR (1); US (29)