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)

• ClinicalTrials.gov Identifier: NCT04727528
• Recruitment Status: Terminated
• First Posted: January 27, 2021
• Last Update Posted: December 9, 2022
• Sponsor: AstraZeneca
• Information provided by (Responsible Party): AstraZeneca

Study Description

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

Condition or disease	Intervention/treatment	Phase
Hyperkalaemia; Metabolic Acidosis; Chronic Kidney Disease	Drug: Sodium zirconium cyclosilicate; Drug: Placebo	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 38 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: NEUTRALIZE is a prospective, randomized, double-blind, placebo-controlled, parallel, multicenter, Phase IIIb study
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• 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)
• Actual Study Start Date: March 22, 2021
• Actual Primary Completion Date: September 14, 2022
• Actual Study Completion Date: September 14, 2022

Arms and Interventions

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 Name: 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 Name: SZC; Drug: Placebo; Plabeco comparator

Outcome Measures

Primary Outcome Measures :

1. Serum potassium [ Time Frame: From baseline to Day 29 ]
   Occurrence (yes/no)of patients having normal sK+ between 3.5 and 5.0 mmol/L inclusive at EOT without need for rescue treatment for hyperkalemia at any point during the randomized phase

Secondary Outcome Measures :

1. Serum bicarbonate [ Time Frame: From baseline to Day 29 ]
   Mean change in serum bicarbonate at Day 29 compared to baseline (Day 1)
2. Increase in serum bicarbonate of ≥3 mmol/L [ Time Frame: From baseline to Day 29 ]
   Occurrence (yes/no) of patients having an increase in serum bicarbonate of ≥3 mmol/L from baseline (Day 1) to EOT (Day 29) without need for rescue treatment for metabolic acidosis (low bicarbonate)
3. Serum bicarbonate ≥22 mmol/L [ Time Frame: From baseline to Day 29 ]
   Occurrence (yes/no) of patients having serum bicarbonate ≥22 mmol/L
4. Increase in serum bicarbonate of ≥2 mmol/L [ Time Frame: From baseline to Day 29 ]
   Occurrence (yes/no) of patients having an increase in serum bicarbonate of ≥2 mmol/L from baseline (Day 1) to EOT without need for rescue treatment for metabolic acidosis (low bicarbonate)
5. Normal serum potassium between 3.5 and 5.0 mmol/L and an increase in serum bicarb of ≥3 mmol/L [ Time Frame: From baseline to Day 29 ]
   Occurrence (yes/no)of patients having normal sK+ between 3.5 and 5.0 mmol/L inclusive at EOT and an increase in serum bicarb of ≥3 mmol/L from baseline (Day 1) without need for rescue treatment for metabolic acidosis or hyperkalemia
6. Normal serum potassium between 3.5 and 5.0 mmol/L and an increase in bicarb of ≥22 mmol/L [ Time Frame: Day 29 ]
   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)
7. The need for rescue medication for low sodium bicarbonate [ Time Frame: From baseline to Day 29 ]
   Occurrence (yes/no) of patients needing rescue treatment for low sodium bicarbonate any time during the randomized phase

Other Outcome Measures:

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

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United States, Alabama

Research Site

Florence, Alabama, United States, 35630

United States, California

Research Site

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

United States, Colorado

Research Site

Aurora, Colorado, United States, 80045

Research Site

Denver, Colorado, United States, 80230

United States, Florida

Research Site

Coral Gables, Florida, United States, 33134

United States, Georgia

Research Site

Columbus, Georgia, United States, 31904

United States, Illinois

Research Site

Hinsdale, Illinois, United States, 60521

United States, Missouri

Research Site

Kansas City, Missouri, United States, 64111

United States, Nevada

Research Site

Las Vegas, Nevada, United States, 89128

United States, New York

Research Site

Bronx, New York, United States, 10461

United States, North Carolina

Research Site

Asheville, North Carolina, United States, 28801

Research Site

New Bern, North Carolina, United States, 28562

Research Site

Winston-Salem, North Carolina, United States, 27103

United States, Rhode Island

Research Site

Providence, Rhode Island, United States, 02903

United States, South Carolina

Research Site

Spartanburg, South Carolina, United States, 29306

United States, Tennessee

Research Site

Chattanooga, Tennessee, United States, 37404

Research Site

Memphis, Tennessee, United States, 38163

United States, Texas

Research Site

Dallas, Texas, United States, 75230

Research Site

Dallas, Texas, United States, 75246

Research Site

San Antonio, Texas, United States, 78258

Research Site

Shenandoah, Texas, United States, 77384

United States, Virginia

Research Site

Alexandria, Virginia, United States, 22304

Research Site

Norfolk, Virginia, United States, 23510

United States, Washington

Research Site

Bellevue, Washington, United States, 98004

United States, Wisconsin

Research Site

Milwaukee, Wisconsin, United States, 53226

Puerto Rico

Research Site

San Juan, Puerto Rico, 00918

Sponsors and Collaborators

AstraZeneca

More Information

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT04727528
• Other Study ID Numbers: D9480C00022
• First Posted: January 27, 2021
• Last Update Posted: December 9, 2022
• Last Verified: December 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Kidney Diseases; Renal Insufficiency, Chronic; Acidosis; Hyperkalemia; Urologic Diseases; Renal Insufficiency; Acid-Base Imbalance; Metabolic Diseases; Water-Electrolyte Imbalance