Open-label Safety of Sodium Zirconium Cyclosilicate for up to 12 Months in Japanese Subjects With Hyperkalemia

Study Overview
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Brief Summary
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The Open-Label Maintenance Study contains an Correction Phase, in which subjects will be dosed with ZS 10 g three times daily (tid) for 24 to 72 hours, followed by a 12-month long-term Maintenance Phase.

Detailed Description
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The study will start with the screening period, and all baseline parameters should be measured/collected up to 1 day prior to administration of first dose of study drug on Correction Phase Day 1. Subjects with 2 consecutive i-STAT potassium values ≥ 5.1 mmol/L will enter the Correction Phase and receive ZS 10 g TID for up to 72 hours, depending on potassium values. Once normokalemia (i-STAT potassium between 3.5 and 5.0 mmol/L, inclusive) is restored (whether after 24, 48 or 72 hours), subjects will be entered into the Maintenance Phase to be dosed with ZS at a starting dose of 5 g QD. Potassium (i-STAT and Central Laboratory) will be measured Days 1, 2, 5, 12, 19 and 26 throughout the first month of study and every 4 weeks thereafter until Day 362 (Visit 23) then patients will be required to complete the EOS visit which is 7±1 days after the last administration of study medication. For patients who do not enter the Maintenance Phase the last visit will be 7±1 day after the last treatment dose in the Correction Phase. The total expected study duration for an individual patient is approximately 53-54 weeks.

Official Title
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A Phase 3 Multicenter Open-label Maintenance Study to Investigate the Long-term Safety of ZS (Sodium Zirconium Cyclosilicate) in Japanese Subjects With Hyperkalemia

Conditions
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Hyperkalemia

Intervention / Treatment
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* Drug: Zirconium Cyclosilicate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of informed consent prior to any study specific procedures. Patients aged ≥18. For patients aged <20 years, a written informed consent should be obtained from the patient and his or her legally acceptable representative. Two consecutive i-STAT potassium values, measured 60-minutes (± 15 minutes) apart, both ≥ 5.1 mmol/L and measured within 1 day before the first dose of ZS on Correction Phase Study Day 1. Patients who are on peritoneal dialysis (PD) can be enrolled if their SK level is ≥5.5 and ≤ 6.5 mmol/L in two consecutive i-STAT potassium evaluation at least 24 hours apart before Day 1 (in each evaluation, two i-STAT potassium measurements at least 1 hour apart are required). i-STAT potassium measurement should be performed in the morning before breakfast and in the evening before dinner in PD patients on continuous ambulatory peritoneal dialysis (CAPD) and automated peritoneal dialysis (APD), respectively. Women of childbearing potential must be using 2 forms of medically acceptable contraception (at least 1 barrier method) and have a negative pregnancy test within 1 day prior to the first dose of ZS on Correction Phase Study Day 1. Women who are surgically sterile or those who are postmenopausal for at least 1 year are not considered to be of childbearing potential. Exclusion Criteria: Patients treated with lactulose, rifaxan (rifaximin), or other non-absorbed antibiotics for hyperammonemia within 7 days prior to first dose of ZS. Patients treated with resins (such as sevelamer hydrochloride, sodium polystyrene sulfonate [SPS; e.g. Kayexalate®] or calcium polystyrene sulfonate [CPS]), calcium acetate, calcium carbonate, or lanthanum carbonate, within 7 days prior to the first dose of study drug. Washout of SPS and CPS for 7 days (or longer) prior to the first dose of ZS is allowed, if termination of CPS or SPS is judged to be clinically acceptable by the investigator. Documented informed consent has to be obtained prior to the washout. Patients with a life expectancy of less than 12 months Female patients who are pregnant, lactating, or planning to become pregnant Patients who have an active or history of diabetic ketoacidosis Known hypersensitivity or previous anaphylaxis to ZS or to components thereof Treatment with a drug or device within the last 30 days that has not received regulatory approval at the time of study entry. Patients with cardiac arrhythmias that require immediate treatment Hemodialysis patients (including those who are on both PD and hemodialysis [HD]) Patients who have been on PD less than 6 months or more than 6 months with a history of hypokalemia within 6 months before Correction Phase Day 1 Documented Glomerular Filtration Rate (GFR) < 15 mL/min within 90 days prior to study entry (Non peritoneal dialysis (PD) patients only) If patients joined ZS study in the past, the patients cannot join this study within the last 30 days of the last study drug administration day.

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: Supportive Care
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sodium Zirconium Cyclosilicate<br>Correction Phase Dosing: Sodium Zirconium Cyclosilicate 10 g three times daily (TID) from 24 to 72 Extended Dosing: Sodium Zirconium Cyclosilicate 5 g once daily (QD). Sodium Zirconium Cyclosilicate dose increased or decreased in increments/decrements of 5 g QD up to a maximum of 15 g QD or a minimum of 5 g every other day (QOD) (or 2.5 g QD) based on i-STAT potassium measurements up to 12 months. | Drug: Zirconium Cyclosilicate<br>* Correction Phase Dosing: Sodium Zirconium Cyclosilicate 10 g three times daily (TID) from 24 to 72 Extended Dosing: Sodium Zirconium Cyclosilicate 5 g once daily (QD). Sodium Zirconium Cyclosilicate dose increased or decreased in increments/decrements of 5 g QD up to a maximum of 15 g QD or a minimum of 5 g every other day (QOD) (or 2.5 g QD) based on i-STAT potassium measurements up to 12 months.<br>* Other names: ZS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Who Experienced Adverse Events (AEs) in the MP | The number of patients who experienced any AE, including those which were serious (SAE), had an outcome of death, were severe, led to discontinuation of ZS or were causally related to ZS are presented for the MP. AEs of special interest are also presented, including oedema-related AEs, cardiac failure and hypertension. | First MP dose up to 1 day (2 days for QOD regimen) after last MP dose. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients Who Were Normokalemic in the MP | The percentage of patients who were normokalemic at each study visit in the MP is presented. Normokalemia was defined as a serum potassium (S-K) level of ≥ 3.5 and ≤ 5.0 mmol/L. The percentage of patients who were normokalemic at their last on-treatment visit is also presented. The last on-treatment value was defined as the last measurement taken within 1 day (2 days on QOD regimen) after the last ZS dose. End of Study was defined as the last ZS dose + 7 days. | MP Day 1 to End of Study visit (up to 12 months). | 
| Percentage of Patients With Average S-K Levels of ≤5.1 mmol/L and ≤5.5 mmol/L in the MP | The percentage of patients who had an average S-K level of ≤5.1 mmol/L and ≤5.5 mmol/L over the MP up to Day 362 is presented. | MP Day 2 to Day 362. | 
| Percentage of Patients Who Were Hypokalemic in the MP | The percentage of patients who were hypokalemic at each study visit in the MP is presented. Hypokalemia was defined as a S-K level of < 3.5 mmol/L. The percentage of patients who were hypokalemic at their last on-treatment visit is also presented. The last on-treatment value was defined as the last measurement taken within 1 day (2 days on QOD regimen) after the last ZS dose. End of Study was defined as the last ZS dose + 7 days. | MP Day 1 to End of Study visit (up to 12 months). | 
| Percentage of Patients Who Were Hyperkalemic in the MP | The percentage of patients who were hyperkalemic at each study visit in the MP is presented. Hyperkalemia was defined as a S-K level of >5.0 mmol/L. The percentage of patients who were hyperkalemic at their last on-treatment visit is also presented. The last on-treatment value was defined as the last measurement taken within 1 day (2 days on QOD regimen) after the last ZS dose. End of Study was defined as the last ZS dose + 7 days. | MP Day 1 to End of Study visit (up to 12 months). | 
| Mean Change From CP Baseline in the Mean S-K Level Over Specified Time Periods in the MP | The mean changes from the CP baseline in S-K level over specified periods of time in the MP are presented. Baseline for the CP was defined as the mean of 2 different S-K values, recorded 60 minutes apart (to confirm qualification for study entry) on the CP Day 1. | CP Day 1 to MP Day 362. | 
| Mean Change From MP Baseline in the Mean S-K Level Over Specified Time Periods in the MP | The mean changes from the MP baseline in S-K level over specified periods of time in the MP are presented. Baseline for the MP was defined as the measurement taken in the morning of the day of entering the MP (MP Day 1). | MP Day 1 to Day 362. | 
| Mean Number of Normokalemic Days During the MP | The number of normokalemic days during the MP was calculated assuming the time interval between assessments was normokalemic if both the beginning and end assessments for that time interval displayed normal S-K values. If an intermediate scheduled assessment time point was missing, then the scheduled assessment was regarded as not normokalemic. The mean number of normokalemic days for a patient in the MP is presented. | MP Day 1 to Day 362. | 
| Mean Change in S-K Level From Last On-treatment MP Visit to the End of Study | The mean change in the S-K level from the last on-treatment MP visit to the End of Study is presented. The last on-treatment value was defined as the last measurement taken within 1 day (2 days if on QOD regimen) after the last ZS dose. The End of Study was 7 days after the last ZS dose. | MP Day 1 to End of Study visit (up to 12 months). | 
| Change From CP Baseline in S-Aldosterone Levels Over the MP | The mean change from CP baseline to MP Day 166 and MP Day 362 in S-aldosterone levels is presented. In addition, the mean change from CP baseline to the last on-treatment value is presented. The CP baseline was defined as the last S-aldosterone assessment immediately prior to the start of the first dose of ZS during the CP. The last on-treatment value was defined as the last measurement taken within 1 day (2 days if on QOD regimen) after the last ZS dose. | CP Day 1, MP Day 166 and MP Day 362. | 
| Percentage of Patients With Normal S-Aldosterone Levels Over the MP | The percentage of patients with normal S-aldosterone levels up to Day 362 of the MP is presented. The normal range for S-aldosterone was 0 - 776.72 pmol/L. In addition, the percentage of patients with normal S-aldosterone levels at the last on-treatment visit is presented. The CP baseline was defined as the last S-aldosterone assessment immediately prior to the start of the first dose of ZS during the CP. The last on-treatment value was defined as the last measurement taken within 1 day (2 days if on QOD regimen) after the last ZS dose. | CP Day 1, MP Day 166 and MP Day 362. | 
| Change From CP Baseline in S-Bicarbonate Levels Over the MP | The mean change from CP baseline to timepoints in the MP in S-bicarbonate levels is presented. In addition, the mean change from CP baseline to the last on-treatment value is presented. The CP baseline was defined as the last S-bicarbonate assessment immediately prior to the start of the first dose of ZS during the CP. The last on-treatment value was defined as the last measurement taken within 1 day (2 days if on QOD regimen) after the last ZS dose. The End of Study was 7 days after the last ZS dose. | CP Day 1, and MP Day 1 to End of Study visit (up to 12 months). | 
| Percentage of Patients With Normal S-Bicarbonate Levels Over the MP | The percentage of patients with normal S-bicarbonate levels up to the End of Study visit in the MP is presented. The normal range for S-bicarbonate was 17 - 32 mmol/L. In addition, the percentage of patients with normal S-bicarbonate levels at the last on-treatment visit is presented. The CP baseline was defined as the last S-bicarbonate assessment immediately prior to the start of the first dose of ZS during the CP. The last on-treatment value was defined as the last measurement taken within 1 day (2 days if on QOD regimen) after the last ZS dose. The End of Study was 7 days after the last ZS dose. | CP Day 1 and MP Day 1 to End of Study visit (up to 12 months). | 
| Baseline and Post-baseline 36-Item Short Form Health Survey Version 2 (SF-36 v2) Physical Component Summary (PCS) and Mental Component Summary (MCS) Scores | Patients completed the SF-36 v2 questionnaire on Day 1 of the CP and on Day 362 of the MP. The responses to the items assessing the physical and mental health of the patients determined the PCS and MCS based on a standard algorithm. The PCS and MCS scores ranged from 0 (worst possible health state) to 100 (best possible health state). The mean PCS and MCS are presented for the baseline and post-baseline assessments. | CP Day 1 (baseline) and MP Day 362 (post-baseline). | 
| Mean Change From CP Baseline in the Mean S-K Levels in the CP | The mean change from the CP baseline at 24, 48 and 72 hours in the CP is presented. The mean change from baseline to the last on-treatment CP value is also presented. The last on-treatment value was defined as the last measurement taken with 1 day (2 days if on the QOD regimen) after the last ZS dose. Baseline for the CP was defined as the mean of 2 different S-K values, recorded 60 minutes apart (to confirm qualification for study entry) on the CP Day 1. | CP Day 1 to Day 3. | 
| Percentage of Patients Who Were Normokalemic in the CP | The percentage of patients who were normokalemic at 24, 48 and 72 hours in the CP is presented. Normokalemia was defined as a S-K level of ≥ 3.5 and ≤ 5.0 mmol/L. | CP Day 1 to Day 3. | 
| Number of Patients Who Experienced AEs in the CP | The number of patients who experienced any AE, including SAEs, those which had an outcome of death, were severe, led to discontinuation of ZS or were causally related to ZS are presented for the CP. AEs of special interest are also presented, including oedema-related AEs, cardiac failure and hypertension. | Day 1 of CP to last CP dose + 1 day or first MP dose -1 day, earlier. |