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

Chronic Kidney Disease Clinical Trial

— NEUTRALIZE  

Official title:

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)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04727528
• Other study ID #: D9480C00022
• Status: Terminated
• Phase: Phase 3
• Start date: March 22, 2021
• Est. completion date: September 14, 2022

Study information

• Verified date: October 2023
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 39
• Est. completion date: September 14, 2022
• Est. primary completion date: September 14, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 130 Years

Eligibility

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

Related Conditions & MeSH terms

• Acidosis
• Chronic Kidney Disease
• Hyperkalaemia
• Hyperkalemia
• Kidney Diseases
• Metabolic Acidosis
• Renal Insufficiency, Chronic

Intervention

Drug:
• Sodium zirconium cyclosilicate
Investigational medicinal product
• Placebo
Plabeco comparator

Locations

Country	Name	City	State
Puerto Rico	Research Site	San Juan
United States	Research Site	Alexandria	Virginia
United States	Research Site	Asheville	North Carolina
United States	Research Site	Aurora	Colorado
United States	Research Site	Bellevue	Washington
United States	Research Site	Bronx	New York
United States	Research Site	Chattanooga	Tennessee
United States	Research Site	Chula Vista	California
United States	Research Site	Columbus	Georgia
United States	Research Site	Coral Gables	Florida
United States	Research Site	Dallas	Texas
United States	Research Site	Dallas	Texas
United States	Research Site	Denver	Colorado
United States	Research Site	Downey	California
United States	Research Site	El Centro	California
United States	Research Site	Florence	Alabama
United States	Research Site	Hinsdale	Illinois
United States	Research Site	Kansas City	Missouri
United States	Research Site	Las Vegas	Nevada
United States	Research Site	Memphis	Tennessee
United States	Research Site	Milwaukee	Wisconsin
United States	Research Site	New Bern	North Carolina
United States	Research Site	Norfolk	Virginia
United States	Research Site	Providence	Rhode Island
United States	Research Site	S. Gate	California
United States	Research Site	San Antonio	Texas
United States	Research Site	Shenandoah	Texas
United States	Research Site	Spartanburg	South Carolina
United States	Research Site	Victorville	California
United States	Research Site	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
AstraZeneca

Countries where clinical trial is conducted

United States,  Puerto Rico, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

External Links

•   CSP_redacted
•   CSRsynopsis_redacted
•   SAP_redacted