A study to test whether ZS (Sodium Zirconium Cyclosilicate) can reduce the incidence of increased blood potassium levels among dialized patients. - DIALIZE

Study identifier:D9480C00006

ClinicalTrials.gov identifier:NCT03303521

EudraCT identifier:2017-003029-14

CTIS identifier:N/A

Study Complete

Official Title

A phase 3b, multicenter, prospective, randomized, double blind, placebocontrolled study to reduce incidence of pre-dialysis hyperkalemia with Sodium Zirconium Cyclosilicate (DIALIZE)

Medical condition

Hyperkalemia

Phase

Phase 3

Healthy volunteers

Study drug

Placebo, Sodium Zirconium Cyclosilicate (ZS)

Sex

All

Actual Enrollment

196

Study type

Interventional

Age

18 Years - 130 Years

Date

Study Start Date: 14 Dec 2017

Primary Completion Date: 07 Nov 2018

Study Completion Date: 07 Nov 2018

Study design

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

Verification:

Verified 01 Feb 2020 by AstraZeneca

Collaborators

Inclusion and exclusion criteria

Inclusion Criteria

1. Provision of informed consent prior to any study specific procedures
2. 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.
3. Receiving hemodialysis (or hemodiafiltration) 3 times a week for treatment of endstage renal disease (ESRD) for at least 3 months before randomization.
4. 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.
5. 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).
6. Prescribed dialysate K concentration ≤ 3 mmol/L during screening
7. 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
8. Heparin dose (if used) must be stable during screening and expected to be stable during the study
9. 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

1. 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)
2. Hemoglobin <9 g/dL on screening (as assessed on Visit 1)
3. Lack of compliance with hemodialysis prescription (both number and duration of treatments) during the two-week period preceding screening (100% compliance required)
4. 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
5. 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
6. 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
7. 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).
8. Severe leukocytosis (>20× 10^9/L) or thrombocytosis (≥450 × 10^9/L) during screening
9. Polycythemia (Hb >14 g/dL) during screening
10. Diagnosis of rhabdomyolysis during the 4 weeks preceding randomization
11. Patients treated with lactulose, xifaxan (rifaximin) or other non-absorbed antibiotics for hyperammonemia within 7 days prior to the first dose of study drug
12. Patients unable to take oral ZS drug mix
13. Scheduled date for living donor kidney transplant
14. Patients with a life expectancy of less than 6 months
15. Female patients who are pregnant or breastfeeding
16. Females of childbearing potential, unless using contraception as detailed in the protocol or sexual abstinence.
17. Known hypersensitivity or previous anaphylaxis to ZS or to components thereof
18. Participation in another clinical study with an investigational product during the last 1 month before screening
19. 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
20. Presence of cardiac arrhythmias or conduction defects that require immediate treatment
21. History of alcohol or drug abuse within 2 years prior to randomization
22. Previous randomization in the present study

Location

Research Site

Kansas City, MO, United States, 64108

Location

Research Site

Fresh Meadows, NY, United States, 11365

Location

Research Site

East Providence, RI, United States, 02914

Location

Research Site

Great Neck, NY, United States, 11021

Location

Research Site

Paterson, NJ, United States, 07504

Location

Research Site

Bronx, NY, United States, 10461

Location

Research Site

Whittier, CA, United States, 90606

Location

Research Site

St-Petersburg, Russian Federation, 196247

Arms	Assigned Interventions
Experimental: Sodium Zirconium Cyclosilicate (ZS) 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) 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.
Placebo Comparator: Placebo 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 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.

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups

	Description
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.
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.

Participant Flow: Overall Study

	Sodium Zirconium Cyclosilicate (SZC)	Placebo
STARTED	97	99
COMPLETED	92	96
NOT COMPLETED	5	3
Withdrawal by Subject	2	0
Death	1	0
Kidney transplantation	0	1
Investigational product discontinuation	0	1
Transferred to non-study dialysis center	1	0
Non-comliance to study protocol	0	1
Adverse Event	1	0

Baseline Characteristics

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

Reporting Groups

	Description
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.
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.

Baseline Measures

	Sodium Zirconium Cyclosilicate (SZC)	Placebo	Total
Number of Participants [units: Participants]	97	99	196
Age Continuous [units: Years] Mean ± Standard Deviation	55.7 ± 13.84	60.4 ± 13.2	58.1 ± 13.69
Sex: Female, Male [units: ]
Female	40	41	81
Male	57	58	115
Race/Ethnicity, Customized [units: ]
White	50	52	102
Black Or African American	11	8	19
Asian	33	33	66
American Indian Or Alasa Native	1	2	3
Other	2	4	6

Outcome Measures

1. Primary Outcome Measure: Percentage of responders [ Time Frame: 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. ]

Measure Type	Primary
Measure Name	Percentage of responders
Measure Description	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.
Time Frame	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.
Safety Issue?	No

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.
Full Analysis Set (all randomized patients)

Reporting Groups

	Description
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.
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.

Measured Values

	Sodium Zirconium Cyclosilicate (SZC)	Placebo
Number of Participants Analyzed [units:participants]	97	99
Percentage of responders [units: Percentage of participants]	41.2	1.0

Statistical Analysis 1 for Percentage of responders

Groups^[1]	All groups
Method^[3]	Fisher Exact
P-Value^[4]	<0.001
Odds Ratio (OR)^[5]	68.77
95% Confidence Interval	( 10.85 to 2810.85 )

[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:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

2. Primary Outcome Measure: Percentage of Responders When Accounting for Missing central laboratory Serum Potassium Data [ Time Frame: 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. ]

Measure Type	Primary
Measure Name	Percentage of Responders When Accounting for Missing central laboratory Serum Potassium Data
Measure Description	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.
Time Frame	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.
Safety Issue?	No

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.
Full Analysis Set (all randomized patients)

Reporting Groups

	Description
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.
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.

Measured Values

	Sodium Zirconium Cyclosilicate (SZC)	Placebo
Number of Participants Analyzed [units:participants]	97	99
Percentage of Responders When Accounting for Missing central laboratory Serum Potassium Data [units: Percentage of participants]	42.3	2.0

Statistical Analysis 1 for Percentage of Responders When Accounting for Missing central laboratory Serum Potassium Data

Groups^[1]	All groups
Method^[3]	Fisher Exact
P-Value^[4]	<0.001
Odds Ratio (OR)^[5]	35.51
95% Confidence Interval	( 8.53 to 309.48 )

[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:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

3. Secondary Outcome Measure: Percentage of patients needing rescue therapy [ Time Frame: An 8 week overall treatment period (a 4 week adjustment phase plus a 4 week evaluation phase) and a 2 week follow up period. ]

Measure Type	Secondary
Measure Name	Percentage of patients needing rescue therapy
Measure Description	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.
Time Frame	An 8 week overall treatment period (a 4 week adjustment phase plus a 4 week evaluation phase) and a 2 week follow up period.
Safety Issue?	No

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.
Full Analysis Set (all randomized patients)

Reporting Groups

	Description
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.
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.

Measured Values

	Sodium Zirconium Cyclosilicate (SZC)	Placebo
Number of Participants Analyzed [units:participants]	97	99
Percentage of patients needing rescue therapy [units: Percentage of participants]	2.1	5.1

No statistical analysis provided for Percentage of patients needing rescue therapy

Serious Adverse Events

Time Frame	Adverse Events will be collected from time of randomization throughout the treatment period and including the follow-up period (until Visit 16 or the last patient visit in the study), up to 10 weeks (Day 71 +/- 3 days). SAEs will be recorded from the time of informed consent.
Additional Description	Safety Analysis Set (All randomized subjects who received at least 1 dose of investigational product, SZC or placebo. N=96 for SZC, N=99 for Placebo). Subjects excluded from the Safety Analysis Set (n=1 for SZC, n=0 Placebo) did not receive treatment.

Reporting Groups

	Description
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.
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

Sodium Zirconium Cyclosilicate (SZC)

Placebo

Total, serious adverse events

# participants affected / at risk

7/96 (7.29%)

8/99 (8.08%)

Infections and infestations

Bacteraemia¹,^†

# participants affected / at risk

0/96 (0.00%)

1/99 (1.01%)

# events

Infections and infestations

Gangrene¹,^†

# participants affected / at risk

1/96 (1.04%)

0/99 (0.00%)

# events

Infections and infestations

Gastroenteritis viral¹,^†

# participants affected / at risk

1/96 (1.04%)

0/99 (0.00%)

# events

Infections and infestations

Vascular device infection¹,^†

# participants affected / at risk

0/96 (0.00%)

1/99 (1.01%)

# events

Metabolism and nutrition disorders

Fluid overload¹,^†

# participants affected / at risk

0/96 (0.00%)

2/99 (2.02%)

# events

Metabolism and nutrition disorders

Hyperkalaemia¹,^†

# participants affected / at risk

1/96 (1.04%)

3/99 (3.03%)

# events

Cardiac disorders

Angina pectoris¹,^†

# participants affected / at risk

2/96 (2.08%)

0/99 (0.00%)

# events

Cardiac disorders

Cardiac failure congestive¹,^†

# participants affected / at risk

0/96 (0.00%)

1/99 (1.01%)

# events

Vascular disorders

Peripheral arterial occlusive disease¹,^†

# participants affected / at risk

1/96 (1.04%)

0/99 (0.00%)

# events

Gastrointestinal disorders

Gastrointestinal haemorrhage¹,^†

# participants affected / at risk

1/96 (1.04%)

1/99 (1.01%)

# events

Gastrointestinal disorders

Small intestinal obstruction¹,^†

# participants affected / at risk

1/96 (1.04%)

0/99 (0.00%)

# events

Injury, poisoning and procedural complications

Arteriovenous fistula occlusion¹,^†

# participants affected / at risk

1/96 (1.04%)

0/99 (0.00%)

# events

Injury, poisoning and procedural complications

Arteriovenous fistula site complication¹,^†

# participants affected / at risk

0/96 (0.00%)

1/99 (1.01%)

# events

Injury, poisoning and procedural complications

Fall¹,^†

# participants affected / at risk

0/96 (0.00%)

1/99 (1.01%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 21.0

Other Adverse Events

Time Frame	Adverse Events will be collected from time of randomization throughout the treatment period and including the follow-up period (until Visit 16 or the last patient visit in the study), up to 10 weeks (Day 71 +/- 3 days). SAEs will be recorded from the time of informed consent.
Additional Description	Safety Analysis Set (All randomized subjects who received at least 1 dose of investigational product, SZC or placebo. N=96 for SZC, N=99 for Placebo). Subjects excluded from the Safety Analysis Set (n=1 for SZC, n=0 Placebo) did not receive treatment.

Frequency Threshold

Threshold above which other adverse events are reported	5%

Reporting Groups

	Description
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.
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.

Other Adverse Events

Sodium Zirconium Cyclosilicate (SZC)

Placebo

Total, other (not including serious) adverse events

# participants affected / at risk

7/96 (7.29%)

11/99 (11.11%)

Infections and infestations

Nasopharyngitis¹,^†

# participants affected / at risk

3/96 (3.13%)

5/99 (5.05%)

# events

Gastrointestinal disorders

Diarrhoea¹,^†

# participants affected / at risk

4/96 (4.17%)

6/99 (6.06%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 21.0

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:	AstraZeneca Clinical
Organization:	AstraZeneca
Phone	1-877-240-9479
E-mail:	[email protected]

Documents available

CSP redacted
Download
D9480C00006 SAP redacted
Download
Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

information.center@astrazeneca.com

Investigators

Principal Investigator

Steven Fishbane

NSUH,Dept of Medicine,300 Community Drive,Manhasset,NY11030

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

CSP redacted

D9480C00006 SAP redacted

Trial Results Summaries