ZS Ph2/3 Dose-response Study in Japan

Study identifier:D9482C00002

ClinicalTrials.gov identifier:NCT03127644

EudraCT identifier:N/A

CTIS identifier:N/A

Study Complete

Official Title

A Phase 2/3 Multicenter, Dose-response Study to Assess Efficacy and Safety of ZS (Sodium Zirconium Cyclosilicate), in Japanese Patients With Hyperkalemia

Medical condition

Hyperkalemia

Phase

Phase 2/3

Healthy volunteers

Study drug

Sodium Zirconium Cyclosilicate (ZS) 5g, Sodium Zirconium Cyclosilicate (ZS) 10g, Placebo

Sex

All

Actual Enrollment

103

Study type

Interventional

Age

18 Years +

Date

Study Start Date: 14 Jun 2017

Primary Completion Date: 23 Feb 2018

Study Completion Date: 23 Feb 2018

Study design

Allocation: Randomized
Endpoint Classification: -
Intervention Model: Parallel Assignment
Masking: Double Blind
Primary Purpose: Treatment

Verification:

Verified 01 Feb 2019 by AstraZeneca

Collaborators

Inclusion and exclusion criteria

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 (± 10) minutes apart, both values should be ≥ 5.1 mmol/L and ≤ 6.5 mmol/L and measured within 1 day before the first dose of study drug on Study Day 1.
-Ability to have repeated blood draws or effective venous catheterization.
-Female patients must be 1 year post-menopausal, surgically sterile, or using an acceptable method of contraception (an acceptable method of contraception is defined as a barrier method in conjunction with a spermicide) for the duration of the study (from the time they sign consent) and for 3 months after the last dose of ZS/matching placebo to prevent pregnancy. In addition, oral contraceptives, approved contraceptive implant, long-term injectable contraception, intrauterine device, or tubal ligation are allowed. Oral contraception alone is not acceptable; additional barrier methods in conjunction with spermicide must be used.

Exclusion Criteria

-Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
-Cause or symptoms of pseudohyperkalemia, such as
1) hemolyzed blood specimen due to excessive fist clenching to make veins prominent
2) hemolyzed blood specimen due to difficult or traumatic venepuncture
3) history of severe leukocytosis or thrombocytosis
-Patients treated with lactulose, rifaximin, or other non-absorbed antibiotics for hyperammonemia within 7 days prior to first dose of study drug on Study Day 1
-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
-Patients with a life expectancy of less than 3 months
-Patients who are severely physically or mentally incapacitated and who, in the opinion of investigator, are unable to perform the patients’ tasks associated with the protocol
-Female patients who are pregnant, lactating, or planning to become pregnant
-Patients who have an active or history of diabetic ketoacidosis
-Presence of any condition which, in the opinion of the investigator, places the patient at undue risk or potentially jeopardizes the quality of the data to be generated
-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
-Patients on dialysis

Location

Research Site

Chiba-shi, Japan, 260-8712

Location

Research Site

Kanazawa-shi, Japan, 920-8650

Location

Research Site

Hanyu-shi, Japan, 348-8505

Location

Research Site

Koga-shi, Japan, 306-0041

Location

Research Site

Shizuoka-shi, Japan, 421-0117

Location

Research Site

Yao-shi, Japan, 581-0011

Location

Research Site

Shimajiri-gun, Japan, 901-0493

Location

Research Site

Higashiibaraki-gun, Japan, 311-3193

Arms	Assigned Interventions
Experimental: Sodium Zirconium Cyclosilicate (ZS) 5g Suspension administered 5g orally three times daily for 48 hours.	Drug: Sodium Zirconium Cyclosilicate (ZS) 5g Suspension administered 5g orally three times daily for 48 hours.
Experimental: Sodium Zirconium Cyclosilicate (ZS) 10g Suspension administered 10g orally three times daily for 48 hours.	Drug: Sodium Zirconium Cyclosilicate (ZS) 10g Suspension administered 10g orally three times daily for 48 hours.
Placebo Comparator: Placebo Placebo suspension administered orally placebo three times daily for 48 hours.	Drug: Placebo Placebo suspension administered orally placebo three times daily for 48 hours.

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Patients not receiving any therapy for hyperkalaemia and with 2 consecutive potassium values of ≥ 5.1 millimoles/litre (mmol/L) and ≤ 6.5 mmol/L (as measured by i-STAT, a portable blood analyser) were enrolled into 24 study sites in Japan from June 2017 to February 2018.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
103 patients were randomised 1:1:1 to receive double-blind treatment of sodium zirconium cyclosilicate (ZS) 5 grams (g) three times daily (TID), ZS 10 g TID, or placebo TID for 48 hours.

Reporting Groups

	Description
ZS 5 g TID	ZS suspension was administered 5 g orally TID for 48 hours.
ZS 10 g TID	ZS suspension was administered 10 g orally TID for 48 hours.
Placebo TID	Placebo suspension was administered orally TID for 48 hours.

Participant Flow: Overall Study

	ZS 5 g TID	ZS 10 g TID	Placebo TID
STARTED	34	36	33
COMPLETED	34	36	31
NOT COMPLETED	0	0	2
Study-specific withdrawal criteria	0	0	2

Baseline Characteristics

Analysis Population Description -- Explanation of how the number of participants for analysis was determined.

The full analysis set included all patients randomised in the study.

Reporting Groups

	Description
ZS 5 g TID	ZS suspension was administered 5 g orally TID for 48 hours.
ZS 10 g TID	ZS suspension was administered 10 g orally TID for 48 hours.
Placebo TID	Placebo suspension was administered orally TID for 48 hours.

Baseline Measures

	ZS 5 g TID	ZS 10 g TID	Placebo TID	Total
Number of Participants [units: Participants]	34	36	33	103
Age Continuous [units: Years] Mean ± Standard Deviation	72.4 ± 7.9	71.1 ± 7.6	76.1 ± 6.8	73.2 ± 7.7
Age, Customized [units: Participants]
<55 years	0	1	0	1
55 to 64 years	7	4	1	12
≥65 years	27	31	32	90
Sex: Female, Male [units: ]
Female	8	8	10	26
Male	26	28	23	77
Race (NIH/OMB) [units: ]
American Indian or Alaska Native	0	0	0	0
Asian	34	36	33	103
Native Hawaiian or Other Pacific Islander	0	0	0	0
Black or African American	0	0	0	0
White	0	0	0	0
More than one race	0	0	0	0
Unknown or Not Reported	0	0	0	0
Ethnicity (NIH/OMB) [units: ]
Hispanic or Latino	0	0	0	0
Not Hispanic or Latino	34	36	33	103
Unknown or Not Reported	0	0	0	0

Outcome Measures

1. Primary Outcome Measure: Exponential rate of change in serum potassium (S-K) values during the initial 48 hours of study drug treatment [ Time Frame: From 0 to 48 hours. ]

Measure Type	Primary
Measure Name	Exponential rate of change in serum potassium (S-K) values during the initial 48 hours of study drug treatment
Measure Description	Blood samples for determination of potassium were collected pre-dose, and at 1, 2, and 4 hours post Dose 1 on Day 1. An additional sample was collected at 90 minutes post Dose 2 on Day 1 if i-STAT potassium values at the 4-hour post Dose 1 time point was ≥ 6.1 or <4.0 mmol/L. On Day 2 samples were analysed pre-dose, and 1 and 4 hours post Dose 1. S-K levels were analysed at the Central Laboratory. Natural logarithm of S-K from 0 to 48 hours post dose are modelled by the random coefficients model including fixed effects of intercept, time, time x treatment and patient-level random effects for time and intercept. Exponential rate of change refers to the slope estimate from the random coefficients model.
Time Frame	From 0 to 48 hours.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The full analysis set included all patients randomised in the study.

Reporting Groups

	Description
ZS 5 g TID	ZS suspension was administered 5 g orally TID for 48 hours.
ZS 10 g TID	ZS suspension was administered 10 g orally TID for 48 hours.
Placebo TID	Placebo suspension was administered orally TID for 48 hours.

Measured Values

	ZS 5 g TID	ZS 10 g TID	Placebo TID
Number of Participants Analyzed [units:participants]	34	36	33
Exponential rate of change in serum potassium (S-K) values during the initial 48 hours of study drug treatment [units: log (mmol/L) / hour] Mean (Standard Error)	-0.00273 (0.000276)	-0.00508 (0.000269)	-0.00012 (0.000288)

Statistical Analysis 1 for Exponential rate of change in serum potassium (S-K) values during the initial 48 hours of study drug treatment

Groups^[1]	ZS 10 g TID, Placebo TID
Method^[3]	Mixed Models Analysis
P-Value^[4]	<0.0001
Other^[5]	-0.00496
Standard Error of the mean	± 0.000380
95% Confidence Interval	( -0.00571 to -0.00420 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Exponential rate of change in S-K through to 48 hours was analysed with a mixed effect model (random slope model).
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Confirmatory testing proceeded sequentially (ZS 10g TID, then ZS 5g TID).
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	Negative exponential rate of change relative to placebo indicates more rapid reduction (correction) of S-K.

Statistical Analysis 2 for Exponential rate of change in serum potassium (S-K) values during the initial 48 hours of study drug treatment

Groups^[1]	ZS 5 g TID, Placebo TID
Method^[3]	Mixed Models Analysis
P-Value^[4]	<0.001
Other^[5]	-0.00261
Standard Error of the mean	± 0.000385
95% Confidence Interval	( -0.00337 to -0.00185 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Exponential rate of change in S-K through to 48 hours was analysed with a mixed effect model (random slope model).
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Confirmatory testing proceeded sequentially (ZS 10g TID, then ZS 5g TID).
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	Negative exponential rate of change relative to placebo indicates more rapid reduction (correction) of S-K.

2. Secondary Outcome Measure: Percentage of patients who achieved normokalaemia at 48 hours [ Time Frame: At 48 hours. ]

Measure Type	Secondary
Measure Name	Percentage of patients who achieved normokalaemia at 48 hours
Measure Description	The percentage of patients who achieved normokalaemia (normalisation of S-K values to between 3.5 mmol/L and 5.0 mmol/L, inclusive) at 48 hours after start of dosing was determined. Patients with missing S-K values at 48 hours were regarded as not normokalaemic.
Time Frame	At 48 hours.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The full analysis set included all patients randomised in the study.

Reporting Groups

	Description
ZS 5 g TID	ZS suspension was administered 5 g orally TID for 48 hours.
ZS 10g TID	ZS suspension was administered 10 g orally TID for 48 hours.
Placebo TID	Placebo suspension was administered orally TID for 48 hours.

Measured Values

	ZS 5 g TID	ZS 10g TID	Placebo TID
Number of Participants Analyzed [units:participants]	34	36	33
Percentage of patients who achieved normokalaemia at 48 hours [units: Percentage of Patients]	85.3	91.7	15.2

Statistical Analysis 1 for Percentage of patients who achieved normokalaemia at 48 hours

Groups^[1]	ZS 5 g TID, Placebo TID
Method^[3]	Regression, Logistic
P-Value^[4]	<0.0001
Odds Ratio (OR)^[5]	46.495
95% Confidence Interval	( 10.142 to 213.152 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Logistic regression model including treatment and baseline S-K as explanatory variables was used.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Percentage of patients who achieved normokalaemia at 48 hours

Groups^[1]	ZS 10g TID, Placebo TID
Method^[3]	Regression, Logistic
P-Value^[4]	<0.0001
Odds Ratio (OR)^[5]	71.835
95% Confidence Interval	( 13.497 to 382.337 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Logistic regression model including treatment and baseline S-K as explanatory variables was used.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

3. Secondary Outcome Measure: Exponential rate of change in S-K values during the initial 24 hours of study drug treatment [ Time Frame: From 0 to 24 hours. ]

Measure Type	Secondary
Measure Name	Exponential rate of change in S-K values during the initial 24 hours of study drug treatment
Measure Description	Blood samples for determination of potassium were collected pre-dose, and at 1, 2, and 4 hours post Dose 1 on Day 1. An additional sample was collected at 90 minutes post Dose 2 on Day 1 if i-STAT potassium values at the 4-hour post Dose 1 time point was ≥ 6.1 or <4.0 mmol/L. On Day 2 samples were analysed pre-dose, and 1 and 4 hours post Dose 1. S-K levels were analysed at the Central Laboratory. Natural logarithm of S-K from 0 to 24 hours post dose are modelled by the random coefficients model including fixed effects of intercept, time, time x treatment and patient-level random effects for time and intercept. Exponential rate of change refers to the slope estimate from the random coefficients model.
Time Frame	From 0 to 24 hours.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The full analysis set included all patients randomised in the study.

Reporting Groups

	Description
ZS 5 g TID	ZS suspension was administered 5 g orally TID for 48 hours.
ZS 10 g TID	ZS suspension was administered 10 g orally TID for 48 hours.
Placebo TID	Placebo suspension was administered orally TID for 48 hours.

Measured Values

	ZS 5 g TID	ZS 10 g TID	Placebo TID
Number of Participants Analyzed [units:participants]	34	36	33
Exponential rate of change in S-K values during the initial 24 hours of study drug treatment [units: log (mmol/L) / hour] Mean (Standard Error)	-0.00234 (0.000468)	-0.00403 (0.000457)	-0.00002 (0.000489)

Statistical Analysis 1 for Exponential rate of change in S-K values during the initial 24 hours of study drug treatment

Groups^[1]	ZS 5 g TID, Placebo TID
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.0004
Other^[5]	-0.00231
Standard Error of the mean	± 0.000645
95% Confidence Interval	( -0.00359 to -0.00104 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Exponential rate of change in S-K through to 24 hours was analysed with a mixed effect model (random slope model).
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	Negative exponential rate of change relative to placebo indicates more rapid reduction (correction) of S-K.

Statistical Analysis 2 for Exponential rate of change in S-K values during the initial 24 hours of study drug treatment

Groups^[1]	ZS 10 g TID, Placebo TID
Method^[3]	Mixed Models Analysis
P-Value^[4]	<0.0001
Other^[5]	-0.00401
Standard Error of the mean	± 0.000637
95% Confidence Interval	( -0.00527 to -0.00275 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Exponential rate of change in S-K through to 24 hours was analysed with a mixed effect model (random slope model).
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	Negative exponential rate of change relative to placebo indicates more rapid reduction (correction) of S-K.

4. Secondary Outcome Measure: Percentage of patients who achieved normokalaemia at 24 hours [ Time Frame: At 24 hours. ]

Measure Type	Secondary
Measure Name	Percentage of patients who achieved normokalaemia at 24 hours
Measure Description	The percentage of patients who achieved normokalaemia (normalisation of S-K values to between 3.5 mmol/L and 5.0 mmol/L, inclusive) at 24 hours after start of dosing was determined. Patients with missing S-K values at 24 hours were regarded as not normokalaemic.
Time Frame	At 24 hours.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The full analysis set included all patients randomised in the study.

Reporting Groups

	Description
ZS 5 g TID	ZS suspension was administered 5 g orally TID for 48 hours.
ZS 10g TID	ZS suspension was administered 10 g orally TID for 48 hours.
Placebo TID	Placebo suspension was administered orally TID for 48 hours.

Measured Values

	ZS 5 g TID	ZS 10g TID	Placebo TID
Number of Participants Analyzed [units:participants]	34	36	33
Percentage of patients who achieved normokalaemia at 24 hours [units: Percentage of Patients]	35.3	83.3	27.3

Statistical Analysis 1 for Percentage of patients who achieved normokalaemia at 24 hours

Groups^[1]	ZS 5 g TID, Placebo TID
Method^[3]	Regression, Logistic
P-Value^[4]	0.6167
Odds Ratio (OR)^[5]	1.347
95% Confidence Interval	( 0.419 to 4.329 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Logistic regression model including treatment and baseline S-K as explanatory variables was used.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Percentage of patients who achieved normokalaemia at 24 hours

Groups^[1]	ZS 10g TID, Placebo TID
Method^[3]	Regression, Logistic
P-Value^[4]	<0.0001
Odds Ratio (OR)^[5]	15.334
95% Confidence Interval	( 4.006 to 58.697 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Logistic regression model including treatment and baseline S-K as explanatory variables was used.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

5. Secondary Outcome Measure: Percentage of patients who achieved normokalaemia at each scheduled potassium assessment time point [ Time Frame: From baseline to end of study (9 days). ]

Measure Type	Secondary
Measure Name	Percentage of patients who achieved normokalaemia at each scheduled potassium assessment time point
Measure Description	The percentage of patients who achieved normokalaemia (normalisation of S-K values to between 3.5 mmol/L and 5.0 mmol/L, inclusive) at each each scheduled potassium assessment time point after the start of dosing was determined. Patients with missing S-K values were regarded as not normokalaemic.
Time Frame	From baseline to end of study (9 days).
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The full analysis set included all patients randomised in the study.

Reporting Groups

	Description
ZS 5 g TID	ZS suspension was administered 5 g orally TID for 48 hours.
ZS 10g TID	ZS suspension was administered 10 g orally TID for 48 hours.
Placebo TID	Placebo suspension was administered orally TID for 48 hours.

Measured Values

	ZS 5 g TID	ZS 10g TID	Placebo TID
Number of Participants Analyzed [units:participants]	34	36	33
Percentage of patients who achieved normokalaemia at each scheduled potassium assessment time point [units: Percentage of Patients]
Baseline	2.9	5.6	0.0
1 hour after first dose	29.4	47.2	21.2
2 hours after first dose	41.2	58.3	42.4
4 hours after first dose	44.1	63.9	42.4
24 hours after first dose	35.3	83.3	27.3
25 hours after first dose	73.5	97.2	18.2
28 hours after first dose	67.6	97.2	36.4
48 hours after first dose	85.3	91.7	15.2
End of study (Last dose + 7 days)	55.9	61.1	27.3

No statistical analysis provided for Percentage of patients who achieved normokalaemia at each scheduled potassium assessment time point

6. Secondary Outcome Measure: Mean change from baseline in S-K values at all measured time intervals [ Time Frame: From baseline to end of study (9 days). ]

Measure Type	Secondary
Measure Name	Mean change from baseline in S-K values at all measured time intervals
Measure Description	Blood samples for determination of potassium were collected pre-dose, and at 1, 2, and 4 hours post Dose 1 on Day 1. An additional sample was collected at 90 minutes post Dose 2 on Day 1 if i-STAT potassium values at the 4-hour post Dose 1 time point was ≥ 6.1 or <4.0 mmol/L. On Day 2 samples were analysed pre-dose, and 1 and 4 hours post Dose 1. S-K levels were analysed locally using i-STAT devices, and at the Central Laboratory. S-K values measured at each time point and end of study visit were recorded and mean change from baseline is displayed.
Time Frame	From baseline to end of study (9 days).
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The full analysis set included all patients randomised in the study.

Reporting Groups

	Description
ZS 5 g TID	ZS suspension was administered 5 g orally TID for 48 hours.
ZS 10g TID	ZS suspension was administered 10 g orally TID for 48 hours.
Placebo TID	Placebo suspension was administered orally TID for 48 hours.

Measured Values

	ZS 5 g TID	ZS 10g TID	Placebo TID
Number of Participants Analyzed [units:participants]	34	36	33
Mean change from baseline in S-K values at all measured time intervals [units: mmol/L] Mean (Standard Deviation)
1 hour after first dose	-0.20 (0.34)	-0.37 (0.35)	-0.13 (0.32)
2 hours after first dose	-0.41 (0.28)	-0.50 (0.40)	-0.33 (0.30)
4 hours after first dose	-0.40 (0.32)	-0.53 (0.36)	-0.43 (0.31)
24 hours after first dose	-0.51 (0.30)	-0.69 (0.38)	-0.22 (0.35)
25 hours after first dose	-0.74 (0.31)	-1.00 (0.45)	-0.27 (0.31)
28 hours after first dose	-0.72 (0.35)	-1.12 (0.39)	-0.41 (0.43)
48 hours after first dose	-0.83 (0.31)	-1.30 (0.48)	-0.24 (0.34)
End of study (Last dose + 7 days)	-0.56 (0.38)	-0.66 (0.52)	-0.20 (0.59)

No statistical analysis provided for Mean change from baseline in S-K values at all measured time intervals

7. Secondary Outcome Measure: Mean percent change from baseline in S-K values at all measured time intervals [ Time Frame: From baseline to end of study (9 days). ]

Measure Type	Secondary
Measure Name	Mean percent change from baseline in S-K values at all measured time intervals
Measure Description	Blood samples for determination of potassium were collected pre-dose, and at 1, 2, and 4 hours post Dose 1 on Day 1. An additional sample was collected at 90 minutes post Dose 2 on Day 1 if i-STAT potassium values at the 4-hour post Dose 1 time point was ≥ 6.1 or <4.0 mmol/L. On Day 2 samples were analysed pre-dose, and 1 and 4 hours post Dose 1. S-K levels were analysed locally using i-STAT devices, and at the Central Laboratory. S-K values measured at each time point and end of study visit were recorded and mean percent change from baseline is displayed.
Time Frame	From baseline to end of study (9 days).
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The full analysis set included all patients randomised in the study.

Reporting Groups

	Description
ZS 5 g TID	ZS suspension was administered 5 g orally TID for 48 hours.
ZS 10g TID	ZS suspension was administered 10 g orally TID for 48 hours.
Placebo TID	Placebo suspension was administered orally TID for 48 hours.

Measured Values

	ZS 5 g TID	ZS 10g TID	Placebo TID
Number of Participants Analyzed [units:participants]	34	36	33
Mean percent change from baseline in S-K values at all measured time intervals [units: Percent change] Mean (Standard Deviation)
1 hour after first dose	-3.61 (6.28)	-6.72 (6.29)	-2.32 (5.60)
2 hours after first dose	-7.46 (5.04)	-9.07 (6.88)	-6.06 (5.40)
4 hours after first dose	-7.08 (5.65)	-9.70 (6.53)	-7.77 (5.62)
24 hours after first dose	-8.98 (5.33)	-12.51 (6.30)	-3.81 (6.24)
25 hours after first dose	-13.20 (5.42)	-18.06 (7.05)	-4.77 (5.66)
28 hours after first dose	-12.90 (6.10)	-20.47 (6.38)	-7.21 (7.61)
48 hours after first dose	-14.81 (5.08)	-23.64 (8.27)	-4.06 (5.93)
End of study (Last dose + 7 days)	-9.85 (6.51)	-11.89 (9.07)	-3.15 (9.99)

No statistical analysis provided for Mean percent change from baseline in S-K values at all measured time intervals

8. Secondary Outcome Measure: Time to normalisation in S-K values [ Time Frame: From 0 to 48 hours. ]

Measure Type	Secondary
Measure Name	Time to normalisation in S-K values
Measure Description	The distribution of time to normalisation of S-K values (defined as S-K values between 3.5 mmol/L and 5.0 mmol/L, inclusive) was measured. A patient who reached at least one S-K within normal range was counted as an event regardless of S-K value after that time point. Patients who did not achieve normokalaemia within 48 hours were censored.
Time Frame	From 0 to 48 hours.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The full analysis set included all patients randomised in the study.

Reporting Groups

	Description
ZS 5g TID	ZS suspension was administered 5 g orally TID for 48 hours.
ZS 10g TID	ZS suspension was administered 10 g orally TID for 48 hours.
Placebo TID	Placebo suspension was administered orally TID for 48 hours.

Measured Values

	ZS 5g TID	ZS 10g TID	Placebo TID
Number of Participants Analyzed [units:participants]	34	36	33
Time to normalisation in S-K values [units: Hours] Median (95% Confidence Interval)	3.883 (1.767 to 23.083)	1.758 (1.000 to 3.967)	3.867 (1.917 to NA) ^[1]

Statistical Analysis 1 for Time to normalisation in S-K values

Groups^[1]	ZS 5g TID, Placebo TID
Method^[3]	Log Rank
P-Value^[4]	0.0586

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Nominal p value

Statistical Analysis 2 for Time to normalisation in S-K values

Groups^[1]	ZS 10g TID, Placebo TID
Method^[3]	Log Rank
P-Value^[4]	0.0006

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Nominal p value

9. Secondary Outcome Measure: Time to a decrease in S-K levels of 0.5 mmol/L [ Time Frame: From 0 to 48 hours. ]

Measure Type	Secondary
Measure Name	Time to a decrease in S-K levels of 0.5 mmol/L
Measure Description	The median time (hours) for S-K values to decrease by 0.5 mmol/L was measured.
Time Frame	From 0 to 48 hours.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The full analysis set included all patients randomised in the study.

Reporting Groups

	Description
ZS 5g TID	ZS suspension was administered 5 g orally TID for 48 hours.
ZS 10g TID	ZS suspension was administered 10 g orally TID for 48 hours.
Placebo TID	Placebo suspension was administered orally TID for 48 hours.

Measured Values

	ZS 5g TID	ZS 10g TID	Placebo TID
Number of Participants Analyzed [units:participants]	34	36	33
Time to a decrease in S-K levels of 0.5 mmol/L [units: Hours] Median (95% Confidence Interval)	3.883 (1.933 to 19.767)	2.892 (1.083 to 4.100)	4.050 (1.983 to 23.667)

Statistical Analysis 1 for Time to a decrease in S-K levels of 0.5 mmol/L

Groups^[1]	ZS 5g TID, Placebo TID
Method^[3]	Log Rank
P-Value^[4]	0.0250

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Nominal p value

Statistical Analysis 2 for Time to a decrease in S-K levels of 0.5 mmol/L

Groups^[1]	ZS 10g TID, Placebo TID
Method^[3]	Log Rank
P-Value^[4]	0.0064

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Nominal p value

Serious Adverse Events

Time Frame	Treatment-emergent adverse events (TEAEs) were reported from Day 1 to Day 3 inclusive.
Additional Description	No text entered.

Reporting Groups

	Description
ZS 5 g TID	ZS suspension was administered 5 g orally TID for 48 hours.
ZS 10 g TID	ZS suspension was administered 10 g orally TID for 48 hours.
Placebo TID	Placebo suspension was administered orally TID for 48 hours.

Serious Adverse Events

	ZS 5 g TID	ZS 10 g TID	Placebo TID
Total, serious adverse events
# participants affected / at risk	0/34 (0.00%)	0/36 (0.00%)	0/33 (0.00%)

Other Adverse Events

Time Frame	Treatment-emergent adverse events (TEAEs) were reported from Day 1 to Day 3 inclusive.
Additional Description	No text entered.

Frequency Threshold

Threshold above which other adverse events are reported	0%

Reporting Groups

	Description
ZS 5 g TID	ZS suspension was administered 5 g orally TID for 48 hours.
ZS 10 g TID	ZS suspension was administered 10 g orally TID for 48 hours.
Placebo TID	Placebo suspension was administered orally TID for 48 hours.

Other Adverse Events

ZS 5 g TID

ZS 10 g TID

Placebo TID

Total, other (not including serious) adverse events

# participants affected / at risk

4/34 (11.76%)

5/36 (13.89%)

1/33 (3.03%)

Infections and infestations

Respiratory tract infection¹,^†

# participants affected / at risk

0/34 (0.00%)

0/36 (0.00%)

1/33 (3.03%)

# events

Infections and infestations

Viral upper respiratory tract infection¹,^†

# participants affected / at risk

1/34 (2.94%)

0/36 (0.00%)

0/33 (0.00%)

# events

Blood and lymphatic system disorders

Nephrogenic anaemia¹,^†

# participants affected / at risk

1/34 (2.94%)

0/36 (0.00%)

0/33 (0.00%)

# events

Metabolism and nutrition disorders

Hypoglycaemia¹,^†

# participants affected / at risk

0/34 (0.00%)

1/36 (2.78%)

0/33 (0.00%)

# events

Nervous system disorders

Tension headache¹,^†

# participants affected / at risk

0/34 (0.00%)

1/36 (2.78%)

0/33 (0.00%)

# events

Nervous system disorders

Tremor¹,^†

# participants affected / at risk

0/34 (0.00%)

1/36 (2.78%)

0/33 (0.00%)

# events

Cardiac disorders

Ventricular extrasystoles¹,^†

# participants affected / at risk

0/34 (0.00%)

1/36 (2.78%)

0/33 (0.00%)

# events

Gastrointestinal disorders

Constipation¹,^†

# participants affected / at risk

1/34 (2.94%)

0/36 (0.00%)

0/33 (0.00%)

# events

Skin and subcutaneous tissue disorders

Erythema¹,^†

# participants affected / at risk

0/34 (0.00%)

1/36 (2.78%)

0/33 (0.00%)

# events

General disorders

Thirst¹,^†

# participants affected / at risk

1/34 (2.94%)

0/36 (0.00%)

0/33 (0.00%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA version 20.0

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.

Results Point of Contact

Name/Title:	Global Clinical Lead
Organization:	AstraZeneca
Phone	+1 302 885 1180
E-mail:	[email protected]

Documents available

Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

information.center@astrazeneca.com

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Trial Results Summaries