A Study to Test Whether ZS (Sodium Zirconium Cyclosilicat... | NCT03303521

ID	Type	Description	Link
2017-003029-14	EudraCT Number

Status Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Sodium Zirconium Cyclosilicate (ZS)	Experimental	Suspension administered orally for a treatment period of eight weeks (4 weeks of dose adjustment, 4 weeks in stable dose) Single dose contains from 1 to 3 sachets of ZS 5g depending on dose level assigned to a patient per non-dialysis days.	Drug: Sodium Zirconium Cyclosilicate (ZS)
Placebo	Placebo Comparator	Suspension administered orally for a treatment period of eight weeks (4 weeks of dose adjustment, 4 weeks in stable dose) Single dose contains from 1 to 3 sachets of Placebo depending on dose level assigned to a patient per non-dialysis days.	Drug: Placebo

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Placebo	Drug	Suspension administered orally for a treatment period of eight weeks (4 weeks of dose adjustment, 4 weeks in stable dose) . Single dose contains from 1 to 3 sachets of Placebo depending on dose level assigned to a patient per non-dialysis days.

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Percentage of Responders	A subject was considered to be a responder if, during the evaluation period, they maintained a pre-dialysis serum potassium (S-K) between 4.0 and 5.0 mmol/L on at least 3 out of 4 dialysis treatments following the long inter-dialytic interval and did not receive rescue therapy. The S-K levels used for this analysis were based on the measurements obtained by the central laboratory.	Evaluation period runs over the last 4 weeks of the treatment period up to 8 weeks, starting after visit 11 and ending on visit 15, thus it comprises post-long inter-dialytic interval visits 12, 13, 14 and 15.
Percentage of Responders When Accounting for Missing Central Laboratory Serum Potassium Data	The sensitivity analysis assessed the impact of subjects classified as non-responders due to missing serum potassium (S-K) data. Missing central lab (c-lab) pre-dialysis values were imputed using corresponding pre-dialysis i-STAT (a portable blood analyser) measurements. In addition, a "last observation carried forward" (LOCF) approach was utilized to further impute missing values of pre-dialysis S-K during the evaluation period. This technique will replace missing c-lab S-K values with the last available non-missing pre-dialysis LIDI observation recorded for that patient (and this could be a c-lab value or an imputed c-lab value). The Primary endpoint analysis was repeated on the imputed data.	Evaluation period runs over the last 4 weeks of the treatment period up to 8 weeks, starting after visit 11 and ending on visit 15, thus it comprises post-long inter-dialytic interval visits 12, 13, 14 and 15.

Secondary Outcomes

Measure	Description	Time Frame
Percentage of Patients Needing Rescue Therapy	Patients requiring any urgent intervention consistent with local practice patterns to reduce serum potassium (S-K) including insulin/glucose, beta-adrenergic agonists, sodium bicarbonate, K binders or any form of renal replacement therapy.	An 8 week overall treatment period (a 4 week adjustment phase plus a 4 week evaluation phase) and a 2 week follow up period.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Provision of informed consent prior to any study specific procedures
Female or male aged ≥ 18 years at screening Visit 1. For patients aged <20 years and enrolled in Japan, a written informed consent should be obtained from the patient and his or her legally acceptable representative.
Receiving hemodialysis (or hemodiafiltration) 3 times a week for treatment of endstage renal disease (ESRD) for at least 3 months before randomization.
Patients must have hemodialysis access consisting of an arteriovenous fistula, AV graft, or tunneled (permanent) catheter which is expected to remain in place for the entire duration of the study.
Pre-dialysis serum K >5.4 mmol/L after long inter-dialytic interval and >5.0 mmol/L after one short inter-dialytic interval during screening (as assessed by central lab).
Prescribed dialysate K concentration ≤ 3 mmol/L during screening
Sustained Qb ≥200 ml/min and spKt/V ≥1.2 (or URR ≥ 63) on stable hemodialysis/hemodiafltration prescription during screening with prescription (time, dialyzer, blood flow [Qb], dialysate flow rate [Qd] and bicarbonate concentration) expected to remain unchanged during study
Heparin dose (if used) must be stable during screening and expected to be stable during the study
Subjects must be receiving dietary counseling appropriate for ESRD patients treated with hemodialysis/hemodiafiltration as per local guidelines, which includes dietary potassium restriction.

Exclusion Criteria:

Involvement in the planning and/or conduct of the study (applies to both AstraZeneca, including ZS Pharma staff and/or staff at the study site)
Hemoglobin <9 g/dL on screening (as assessed on Visit 1)
Lack of compliance with hemodialysis prescription (both number and duration of treatments) during the two-week period preceding screening (100% compliance required)
Patients treated with sodium polystyrene sulfonate (SPS, Kayexalate, Resonium), calcium polystyrene sulfonate (CPS, Resonium calcium) or patiromer (Veltassa) within 7 days before screening or anticipated in requiring any of these agents during the study
Myocardial infarction, acute coronary syndrome, stroke, seizure or a thrombotic/thromboembolic event (e.g., deep vein thrombosis or pulmonary embolism, but excluding vascular access thrombosis) within 12 weeks prior to randomization
Laboratory diagnosis of hypokalemia (K < 3.5 mmol/L), hypocalcemia (Ca < 8.2 mg/dL; for Japan hypocalcemia is defined as albumin-corrected Ca < 8.0 mg/dL), hypomagnesemia (Mg < 1.7 mg/dL) or severe acidosis (serum bicarbonate 16 mEq/L or less) in the 4 weeks preceding randomization
Pseudohyperkalemia secondary to hemolyzed blood specimen (this situation is not considered screening failure, sampling or full screening can be postponed to a later time as applicable).
Severe leukocytosis (>20× 10^9/L) or thrombocytosis (≥450 × 10^9/L) during screening
Polycythemia (Hb >14 g/dL) during screening
Diagnosis of rhabdomyolysis during the 4 weeks preceding randomization
Patients treated with lactulose, xifaxan (rifaximin) or other non-absorbed antibiotics for hyperammonemia within 7 days prior to the first dose of study drug
Patients unable to take oral ZS drug mix
Scheduled date for living donor kidney transplant
Patients with a life expectancy of less than 6 months
Female patients who are pregnant or breastfeeding
Females of childbearing potential, unless using contraception as detailed in the protocol or sexual abstinence.
Known hypersensitivity or previous anaphylaxis to ZS or to components thereof
Participation in another clinical study with an investigational product during the last 1 month before screening
Any medical condition, including active, clinically significant infection, that in the opinion of the investigator or Sponsor may pose a safety risk to a patient in this study, which may confound safety or efficacy assessment and jeopardize the quality of the data, or may interfere with study participation
Presence of cardiac arrhythmias or conduction defects that require immediate treatment
History of alcohol or drug abuse within 2 years prior to randomization
Previous randomization in the present study

Name	Affiliation	Role
Steven Fishbane, MD	NSUH,Dept of Medicine,300 Community Drive,Manhasset,NY11030	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Research Site		Los Angeles	California	90022	United States
Research Site

PubMed Identifier	Type	Citation	Retractions
35135481	Derived	Fishbane S, Ford M, Fukagawa M, McCafferty K, Rastogi A, Spinowitz B, Staroselskiy K, Vishnevskiy K, Lisovskaja V, Al-Shurbaji A, Guzman N, Bhandari S. Potassium responses to sodium zirconium cyclosilicate in hyperkalemic hemodialysis patients: post-hoc analysis of DIALIZE. BMC Nephrol. 2022 Feb 8;23(1):59. doi: 10.1186/s12882-021-02569-7.
32588430

Label	URL
CSP redacted	View source

ID	Title	Description
FG000	Sodium Zirconium Cyclosilicate (SZC)	Suspension administered orally for a treatment period of eight weeks (4 weeks of dose adjustment, 4 weeks in stable dose). Single dose contains 1 to 3 sachets that should be suspended in 45 mL of water by patient and administered on non-dialysis days.
FG001

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Feb 5, 2018	Nov 5, 2019

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Percentage of Responders

A subject was considered to be a responder if, during the evaluation period, they maintained a pre-dialysis serum potassium (S-K) between 4.0 and 5.0 mmol/L on at least 3 out of 4 dialysis treatments following the long inter-dialytic interval and did not receive rescue therapy. The S-K levels used for this analysis were based on the measurements obtained by the central laboratory.

Full Analysis Set (all randomized patients)

Posted

Number

Percentage of participants

Evaluation period runs over the last 4 weeks of the treatment period up to 8 weeks, starting after visit 11 and ending on visit 15, thus it comprises post-long inter-dialytic interval visits 12, 13, 14 and 15.

ID	Title	Description
OG000	Sodium Zirconium Cyclosilicate (SZC)	Suspension administered orally for a treatment period of eight weeks (4 weeks of dose adjustment, 4 weeks in stable dose). Single dose contains 1 to 3 sachets that should be suspended in 45 mL of water by patient and administered on non-dialysis days.
OG001	Placebo	Suspension administered orally for a treatment period of eight weeks (4 weeks of dose adjustment, 4 weeks in stable dose). Single dose contains 1 to 3 sachets that should be suspended in 45 mL of water by patient and administered on non-dialysis days.

Units	Counts
Participants	OG00097 OG00199

Title

Denominators

Categories

Title	Measurements
	OG00041.2 OG0011.0

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001		Fisher Exact		<0.001		Odds Ratio (OR)	68.77			2-Sided	95	10.85	2810.85					Superiority

Secondary

Percentage of Patients Needing Rescue Therapy

Patients requiring any urgent intervention consistent with local practice patterns to reduce serum potassium (S-K) including insulin/glucose, beta-adrenergic agonists, sodium bicarbonate, K binders or any form of renal replacement therapy.

Full Analysis Set (all randomized patients)

Posted

Number

Percentage of participants

An 8 week overall treatment period (a 4 week adjustment phase plus a 4 week evaluation phase) and a 2 week follow up period.

ID	Title	Description
OG000	Sodium Zirconium Cyclosilicate (SZC)	Suspension administered orally for a treatment period of eight weeks (4 weeks of dose adjustment, 4 weeks in stable dose). Single dose contains 1 to 3 sachets that should be suspended in 45 mL of water by patient and administered on non-dialysis days.
OG001	Placebo	Suspension administered orally for a treatment period of eight weeks (4 weeks of dose adjustment, 4 weeks in stable dose). Single dose contains 1 to 3 sachets that should be suspended in 45 mL of water by patient and administered on non-dialysis days.

Units	Counts
Participants

Primary

Percentage of Responders When Accounting for Missing Central Laboratory Serum Potassium Data

The sensitivity analysis assessed the impact of subjects classified as non-responders due to missing serum potassium (S-K) data. Missing central lab (c-lab) pre-dialysis values were imputed using corresponding pre-dialysis i-STAT (a portable blood analyser) measurements. In addition, a "last observation carried forward" (LOCF) approach was utilized to further impute missing values of pre-dialysis S-K during the evaluation period. This technique will replace missing c-lab S-K values with the last available non-missing pre-dialysis LIDI observation recorded for that patient (and this could be a c-lab value or an imputed c-lab value). The Primary endpoint analysis was repeated on the imputed data.

Full Analysis Set (all randomized patients)

Posted

Number

Percentage of participants

ID	Title	Description
OG000	Sodium Zirconium Cyclosilicate (SZC)	Suspension administered orally for a treatment period of eight weeks (4 weeks of dose adjustment, 4 weeks in stable dose). Single dose contains 1 to 3 sachets that should be suspended in 45 mL of water by patient and administered on non-dialysis days.
OG001	Placebo	Suspension administered orally for a treatment period of eight weeks (4 weeks of dose adjustment, 4 weeks in stable dose). Single dose contains 1 to 3 sachets that should be suspended in 45 mL of water by patient and administered on non-dialysis days.

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Bacteraemia	Infections and infestations	MedDRA 21.0	Systematic Assessment	EG0000 events0 affected96 at risk EG0011 events1 affected99 at risk
Gangrene	Infections and infestations	MedDRA 21.0	Systematic Assessment	EG0001 events1 affected96 at risk EG0010 events0 affected99 at risk
Gastroenteritis viral	Infections and infestations	MedDRA 21.0	Systematic Assessment	EG0001 events1 affected96 at risk EG0010 events0 affected99 at risk
Vascular device infection	Infections and infestations	MedDRA 21.0	Systematic Assessment	EG0000 events0 affected96 at risk EG0011 events1 affected99 at risk
Fluid overload	Metabolism and nutrition disorders	MedDRA 21.0	Systematic Assessment	EG0000 events0 affected96 at risk EG0012 events2 affected99 at risk
Hyperkalaemia	Metabolism and nutrition disorders	MedDRA 21.0	Systematic Assessment	EG0001 events1 affected96 at risk EG0013 events3 affected99 at risk
Angina pectoris	Cardiac disorders	MedDRA 21.0	Systematic Assessment	EG0003 events2 affected96 at risk EG0010 events0 affected99 at risk
Cardiac failure congestive	Cardiac disorders	MedDRA 21.0	Systematic Assessment	EG0000 events0 affected96 at risk EG0011 events1 affected99 at risk
Peripheral arterial occlusive disease	Vascular disorders	MedDRA 21.0	Systematic Assessment	EG0001 events1 affected96 at risk EG0010 events0 affected99 at risk
Gastrointestinal haemorrhage	Gastrointestinal disorders	MedDRA 21.0	Systematic Assessment	EG0001 events1 affected96 at risk EG0012 events1 affected99 at risk
Small intestinal obstruction	Gastrointestinal disorders	MedDRA 21.0	Systematic Assessment	EG0001 events1 affected96 at risk EG0010 events0 affected99 at risk
Arteriovenous fistula occlusion	Injury, poisoning and procedural complications	MedDRA 21.0	Systematic Assessment	EG0001 events1 affected96 at risk EG0010 events0 affected99 at risk
Arteriovenous fistula site complication	Injury, poisoning and procedural complications	MedDRA 21.0	Systematic Assessment	EG0000 events0 affected96 at risk EG0011 events1 affected99 at risk
Fall	Injury, poisoning and procedural complications	MedDRA 21.0	Systematic Assessment	EG0000 events0 affected96 at risk EG0011 events1 affected99 at risk

ID	Term
D014883	Water-Electrolyte Imbalance
D008659	Metabolic Diseases
D009750	Nutritional and Metabolic Diseases

ID	Title	Description
BG000	Sodium Zirconium Cyclosilicate (SZC)	Suspension administered orally for a treatment period of eight weeks (4 weeks of dose adjustment, 4 weeks in stable dose). Single dose contains 1 to 3 sachets that should be suspended in 45 mL of water by patient and administered on non-dialysis days.
BG001	Placebo	Suspension administered orally for a treatment period of eight weeks (4 weeks of dose adjustment, 4 weeks in stable dose). Single dose contains 1 to 3 sachets that should be suspended in 45 mL of water by patient and administered on non-dialysis days.
BG002	Total	Total of all reporting groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Sodium Zirconium Cyclosilicate (SZC)	Suspension administered orally for a treatment period of eight weeks (4 weeks of dose adjustment, 4 weeks in stable dose). Single dose contains 1 to 3 sachets that should be suspended in 45 mL of water by patient and administered on non-dialysis days.	1	96	7	96	7	96
EG001	Placebo	Suspension administered orally for a treatment period of eight weeks (4 weeks of dose adjustment, 4 weeks in stable dose). Single dose contains 1 to 3 sachets that should be suspended in 45 mL of water by patient and administered on non-dialysis days.	0	99	8	99	11	99

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Nasopharyngitis	Infections and infestations	MedDRA 21.0	Systematic Assessment		EG0004 events3 affected96 at risk EG0015 events5 affected99 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA 21.0	Systematic Assessment		EG0005 events4 affected96 at risk EG0016 events6 affected99 at risk