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

Study Overview
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Brief Summary
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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

Detailed Description
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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.

Official Title
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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)

Conditions
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Hyperkalaemia, Metabolic Acidosis, Chronic Kidney Disease

Intervention / Treatment
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* Drug: Sodium zirconium cyclosilicate
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: NEUTRALIZE is a prospective, randomized, double-blind, placebo-controlled, parallel, multicenter, Phase IIIb study
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Open-label correction phase (up to 48 hours)<br>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<br>* Investigational medicinal product<br>* Other names: SZC;Drug: Placebo<br>* Plabeco comparator<br>|
| Experimental: Randomized, placebo controlled phase (Day 2 or 3 to Day 29)<br>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<br>* Investigational medicinal product<br>* Other names: SZC;Drug: Placebo<br>* Plabeco comparator<br>|

What is the study measuring?
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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 |