Clinical Trials Register

Summary
EudraCT Number:	2014-004555-31
Sponsor's Protocol Code Number:	ZS-005
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-04-01
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2014-004555-31

A.3

Full title of the trial

A Phase 3 Multicenter, Multi-dose, Open-label Maintenance Study to Investigate the Long-term Safety and Efficacy of ZS (Sodium Zirconium Cyclosilicate), an Oral Sorbent, in Subjects with Hyperkalemia

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A study to investigate the long term safety and effectiveness of ZS (the study drug which is taken orally and acts by absorbing otassium) in patients with Hyperkalemia (excess potassium).

A.4.1

Sponsor's protocol code number

ZS-005

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02163499

A.5.4

Other Identifiers

Name:

IND

Number:

108951

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	ZS Pharma Inc
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	ZS Pharma, Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	ZS Pharma Inc
B.5.2	Functional name of contact point	Director, Regulatory Affairs
B.5.3	Address:
B.5.3.1	Street Address	508 Wrangler Drive, Suite 100
B.5.3.2	Town/ city	Coppell
B.5.3.3	Post code	TX 75019
B.5.3.4	Country	United States
B.5.6	E-mail	info@zspharma.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	ZS
D.3.2	Product code	ZS
D.3.4	Pharmaceutical form	Oral suspension in sachet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	UNKNOWN
D.3.9.1	CAS number	242800-27-7
D.3.9.2	Current sponsor code	ZS
D.3.9.3	Other descriptive name	SODIUM ZIRCONIUM CYCLOSILICATE
D.3.9.4	EV Substance Code	SUB121702
D.3.10	Strength
D.3.10.1	Concentration unit	g gram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	ZS
D.3.2	Product code	ZS
D.3.4	Pharmaceutical form	Oral suspension in sachet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	UNKNOWN
D.3.9.1	CAS number	242800-27-7
D.3.9.2	Current sponsor code	ZS
D.3.9.3	Other descriptive name	SODIUM ZIRCONIUM CYCLOSILICATE
D.3.9.4	EV Substance Code	SUB121702
D.3.10	Strength
D.3.10.1	Concentration unit	g gram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Oral suspension in sachet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Hyperkalemia

E.1.1.1

Medical condition in easily understood language

high levels of potassium ions in blood

E.1.1.2

Therapeutic area

Body processes [G] - Cell Physiological Phenomena [G04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.1
E.1.2	Level	LLT
E.1.2	Classification code	10020647
E.1.2	Term	Hyperkalemia
E.1.2	System Organ Class	100000004861

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Open-Label Maintenance Study
To generate open-label, long-term (up to 12 months) safety and tolerability data for ZS in subjects with hyperkalemia (serum potassium [S-K] ≥ 5.1 mmol/L).

E.2.2

Secondary objectives of the trial

•To evaluate the proportion of ZS-treated subjects in whom normokalemia can be maintained over prolonged periods of time, using a dose range from 5 g every other day to 15 g once daily (qd).

•To evaluate the effect of ZS on various renal and bone biomarkers over prolonged periods of time, using doses from 5 g every other day to 15 g qd.

To evaluate the safety and tolerability of investigational product consumed in ~40ml of water with no mandatory rinses and in ~180ml of water with two ~30ml rinses

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Provision of written informed consent.
2.Age 18 years and older.
3.For all subjects enrolled outside Germany: Two consecutive i STAT potassium values, measured 60 (+/-15) minutes apart, both ≥ 5.1 mmol/L and measured within 1 day before the first dose of ZS on Acute Phase Study Day 1.
For all subjects enrolled in Germany: Two consecutive i-STAT potassium
values, measured 60 (± 15) minutes apart, both ≥ 5.1 mmol/L and ≤ 6.5
mmol/L and measured within 1 day before the first dose of ZS on Acute
Phase Study Day 1.
4.Ability to have repeated blood draws or effective venous catheterization.
5.For all subjects outside the European Union: Women of childbearing
potential must have a negative pregnancy test within 1 day prior to the
first dose of ZS on Acute Phase Study Day 1 and sexually active women
of childbearing potential must be using 2 forms of medically acceptable
contraception with at least one being a barrier method. Women who are
surgically sterile or those who are postmenopausal for at least 2 years
are not considered to be of childbearing potential.
For all subjects in the European Union:Women of childbearing potential must have a negative pregnancy test within 1 day prior to the first dose of ZS on Acute Phase Study Day 1 and sexually active women of childbearing potential must be using a highly effective medically acceptable contraception such as:
• combined or hormonal contraception associated with inhibition of ovulation
• progesterone only hormonal contraception, associated with inhibition of ovulation
• IUD (intrauterine device)
• IUS (intrauterine hormone-releasing system)
• bilateral tubal occlusion
• vasectomised partner
• sexual abstinence (True abstinence in line with the subjects preferred and usual lifestyle. Subjects practicing abstinence will agree to have a documented second acceptable method of birth control should they become sexually active during the course of study participation)
Women who are surgically sterile or those who are postmenopausal for at least 2 years are not considered to be of childbearing potential.
Note: Controlled diabetic subjects are eligible for enrollment. Whenever possible, all blood draws collected before meals should be collected prior to insulin/insulin analog treatment.

E.4

Principal exclusion criteria

1.Pseudohyperkalemia signs and symptoms, such as hemolyzed blood specimen due to excessive fist clenching to make veins prominent, difficult or traumatic venipuncture, or history of severe leukocytosis or thrombocytosis.
2.Subjects treated with lactulose, Rifaximin, or other non-absorbed antibiotics for hyperammonemia within 7 days prior to first dose of ZS on Acute Phase Study Day 1.
3.Subjects treated with sodium polystyrene sulfonate (SPS; eg, Kayexalate®) or calcium polystyrene sulfonate (eg, Resonium) within 3 days prior to first dose of ZS on Acute Phase Study Day 1.
4.Subjects with a life expectancy of less than 12 months.
5.Subjects who are severely physically or mentally incapacitated and who, in the opinion of investigator, are unable to perform the subjects’ tasks associated with the protocol.
6.Women who are pregnant, lactating, or planning to become pregnant.
7.Subjects with diabetic ketoacidosis.
8.Presence of any condition which, in the opinion of the investigator, places the subject at undue risk or potentially jeopardizes the quality of the data to be generated.
9.Known hypersensitivity or previous anaphylaxis to ZS or to components thereof.
10.Treatment with a drug or device within the last 30 days that has not received regulatory approval at the time of study entry.
11.Subjects with cardiac arrhythmias that require immediate treatment.
12.Subjects on dialysis.
13.Subjects randomized into the previous ZS-002, ZS-003, ZS-004, or ZS-004E studies.
14. Documented GFR <15mL/min within 90 days prior to study entry.
15. For Germany only: Subjects presenting with QTc Interval of 450 ms
AND additional risk factors for Torsade de pointes (e.g. heart failure or
family history of long QT-syndrome) AND taking concomitant
medications causing QT prolongation.
16. For Germany only: Patients who are committed to an institution by
virtue of an order issued either by the judicial or the administrative
authorities.
17. For Germany only: Subjects who are dependents of either the
Sponsor, Investigator or Institution.

E.5 End points

E.5.1

Primary end point(s)

Open-Label Maintenance Study: The primary endpoint will be safety and tolerability as measured by adverse event reporting, vital signs, ECGs, physical examinations, and safety laboratory measurements.

E.5.1.1

Timepoint(s) of evaluation of this end point

Open-Label Maintenance Study:
AEs are collected and potassium levels measured at every visit
Vital signs, ECGs, physical examinations, and safety laboratory measurements are measured on Study days 8, 15, 22, 29, 57, 85, 176, 267 and 365

E.5.2

Secondary end point(s)

•The proportion of subjects with average S-K equal to or less than 5.1mmol/l between Month 3 and Month 12
•The proportion of subjects who maintain or achieve normal aldosterone values (normal range: 4.0 to 31.0 ng/dL) on ZS at Study Days 85, 176, and 365
• Change from Acute Phase and Maintenance Phase baselines in S-K
levels at all measured Maintenance Phase Study Days
• Change in Serum-bicarbonate from Acute Phase baseline at all
measured Maintenance Phase Study Days

E.5.2.1

Timepoint(s) of evaluation of this end point

Study Days 85, 176, 267, and 365

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Australia

France

Germany

Netherlands

Poland

Romania

South Africa

Sweden

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

385

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

365

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

100

F.4.2.2

In the whole clinical trial

750

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Patients will receive standard of care treatment following participation in the study

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2015-04-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-01-22

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-11-04

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