Clinical Trials Register

Summary
EudraCT Number:	2021-003527-14
Sponsor's Protocol Code Number:	D9480C00023
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-09-27
Trial 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

Italy - Italian Medicines Agency

A.2

EudraCT number

2021-003527-14

A.3

Full title of the trial

An Open-Label, Randomised, Phase 4 Study of Continuing Sodium Zirconium Cyclosilicate (SZC) after Discharge in Participants with Chronic Kidney Disease treated for Hyperkalaemia

Studio in aperto, randomizzato, di fase 4 sulla prosecuzione del ciclosilicato di sodio zirconio (SZC) dopo la dimissione nei partecipanti con malattia renale cronica trattati per iperkaliemia

A.3.1

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

Continuing Sodium Zirconium Cyclosilicate (SZC) after discharge study

Studio di prosecuzione del ciclosilicato di sodio zirconio (SZC) dopo la dimissione

A.3.2

Name or abbreviated title of the trial where available

CONTINUITY

A.4.1

Sponsor's protocol code number

D9480C00023

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	ASTRAZENECA AB
B.1.3.4	Country	Sweden
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	AstraZeneca AB
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	AstraZeneca AB
B.5.2	Functional name of contact point	Clinical Study Information Center
B.5.3	Address:
B.5.3.1	Street Address	1800 Concord Pike
B.5.3.2	Town/ city	Wilmington DE
B.5.3.3	Post code	19803
B.5.3.4	Country	United States
B.5.6	E-mail	information.center@astrazeneca.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	Yes
D.2.1.1.1	Trade name	Lokelma
D.2.1.1.2	Name of the Marketing Authorisation holder	AstraZeneca AB
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Sodium zirconium cyclosilicate
D.3.2	Product code	[SZC]
D.3.4	Pharmaceutical form	Powder for oral suspension
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	Sodium zirconium cyclosilicate
D.3.9.1	CAS number	242800-27-7
D.3.9.2	Current sponsor code	Sodium zirconium cyclosilicate
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Patients with Chronic Kidney Disease treated for Hyperkalaemia whilst in hospital, who are normokalemic and established on maintenance dose of SZC at discharge.

pazienti malattia renale cronica (MRC) trattati per iperkaliemia durante il ricovero in ospedal, che sono normokalemici e stabilizzati con dose di mantenimento di SZC fino alla dimissione.

E.1.1.1

Medical condition in easily understood language

Hyperkalemia means that the potassium level in the blood is higher than normal

Iperkaliemia significa che il livello di potassio nel sangue è più alto del normale

E.1.1.2

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10020646
E.1.2	Term	Hyperkalaemia
E.1.2	System Organ Class	10027433 - Metabolism and nutrition disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the efficacy of continuing SZC as part of the discharge medications, compared to SoC, in maintaining NK

Valutare l’efficacia della prosecuzione di SZC nell’ambito dei farmaci somministrati alla dimissione, rispetto a SoC, nel mantenimento della NK.

E.2.2

Secondary objectives of the trial

To evaluate the effect of continuing SZC as part of the discharge medications, compared to SoC:
1. in reducing the incidence of the composite outcome of hospital admissions or ED visits with HK as a contributing factor, all-cause death, or use of rescue-therapy for HK
2. in reducing the incidence of the composite outcome of hospital admissions with HK as a contributing factor, all-cause death, or use of rescue therapy for HK
3. in reducing the incidence of ED visits with HK as a contributing factor, all-cause death, or use of rescue therapy for HK
4. in reducing the incidence of the composite outcome of hospital admissions or ED visits with HK as a contributing factor or all-cause death
5. in reducing the incidence of hospital admissions with HK as a contributing factor or all-cause death
6. in reducing the incidence of ED visits with HK as a contributing factor or all-cause death

Valutare l’effetto della prosecuzione di SZC nell’ambito dei farmaci somministrati alla dimissione, rispetto a SoC:
1. nel ridurre l’incidenza dell’esito composito dei ricoveri ospedalieri o delle visite al pronto soccorso (PS) con l’HK come fattore contribuente, del decesso per qualsiasi causa o dell’uso di terapia di soccorso per l’HK.
2. Valutare l’effetto della prosecuzione di SZC nell’ambito dei farmaci somministrati alla dimissione, rispetto a SoC, nel ridurre l’incidenza dell’esito composito dei ricoveri ospedalieri con l’HK come fattore contribuente, del decesso per tutte le cause o dell’uso di terapia di soccorso per l’HK.
3. Valutare l’effetto della prosecuzione di SZC nell’ambito dei farmaci somministrati alla dimissione, rispetto a SoC, nel ridurre l’incidenza delle visite in PS con l’HK come fattore contribuente, del decesso per tutte le cause o dell’uso di terapia di soccorso per l’HK.
4. [...] Si prega di far riferimento al protocollo

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1 Must be 18 years of age or older, at the time of signing the informed consent
2 Admitted to hospital (inpatient care; directly or from ED)
3 With:
- diagnosed stage 3b to 5 CKD
And/or
- eGFR < 45 ml/min/1.73 m2 at, or within 3 months of, study screening, based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (Levey et al, 2009). Note: Race/ethnicity should not be included in CKD-EPI equation calculation.
4 Most recent recorded K+ measurement, either for this admission or at ED visit leading to this admission, should be between 5.5 and 6.5 mmol/L, inclusive
5 Male or female
6 Capable and willing of giving signed informed consent as described in Appendix A which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol.

E.4

Principal exclusion criteria

1 Myocardial infarction, stroke, seizure, or a thrombotic/thromboembolic event (eg, deep vein thrombosis or pulmonary embolism, but excluding vascular access thrombosis) within 12 weeks prior to screening
2 Unable to take oral SZC drug mix
3 Recipient of or scheduled date for living donor kidney transplant
4 With a life expectancy of less than 6 months
5 Any medical condition (including active, clinically significant infection) that, in the opinion of the investigator or sponsor, may pose a safety risk to the participant in this study, which may confound safety or efficacy assessments and jeopardise the quality of data, or may interfere with study participation
6 Presence of cardiac arrhythmias or conduction defects that require immediate treatment
7 QT interval corrected by the Fridericia method (QTcF) > 550 msec
8 History of QT prolongation associated with other medications that required discontinuation of that medication
9 Congenital long QT syndrome
10 Symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Participant with atrial fibrillation controlled by medication is permitted.
11 Evidence of Coronavirus disease 2019 (COVID-19) within 2 weeks prior to screening (see Appendix C)
12 History of alcohol or drug abuse within 2 years prior to screening
13 Ongoing treatment with any K-binder at index hospital admission (initiation of SZC during ED visit immediately preceding the index hospital admission is allowed)
14 Renal replacement therapy, including chronic haemodialysis and peritoneal dialysis
15 Participation in another clinical study with an investigational product (IP) administered during the month before screening. Note: Participant vaccinated with COVID-19 vaccine whilst still under Emergency Use Utilisation will not be excluded from the study.
16 Known hypersensitivity to SZC or any of the excipients of the product
17 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
18 Judgment by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements
19 Previous randomisation in the present study
20 For women only: Women of child-bearing potential (WOCBP; ie, those who are not chemically or surgically sterilised or who are not postmenopausal) who are not willing to use one of the methods of contraception described hereafter, from the time of signing the informed consent throughout the study and 4 weeks thereafter:
(a) Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, transdermal
(b) Progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable, implantable
(c) Intrauterine device (IUD)
(d) Intrauterine hormone-releasing system (IUS)
(e) Bilateral tubal occlusion
(f) Vasectomised partner (vasectomised partner is a highly effective birth control method provided that partner is the sole sexual partner of the WOCBP participant and that the vasectomised partner has received medical assessment of the surgical success
(g) Sexual abstinence: it is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant.
21 For WOCBP only: Women who have a positive pregnancy test at screening OR women who are breastfeeding.

E.5 End points

E.5.1

Primary end point(s)

Occurrence (yes/no) of NK (K+ between 3.5 and 5.0 mmol/L, inclusive) at 180 days post-discharge.

Occorrenza (sì/no) della NK (potassio [K+] tra 3,5 e 5,0 mmol/l, inclusi) a 180 giorni dopo la dimissione.

E.5.1.1

Timepoint(s) of evaluation of this end point

Up to 180 days post-discharge

a 180 giorni dopo la dimissione.

E.5.2

Secondary end point(s)

Time to first occurrence of:
1. hospital admissions or ED visits with HK as a contributing factor, use of rescue therapy for HK, or all-cause death (composite outcome)
2. hospital admission with HK as a contributing factor, all-cause death, or use of rescue therapy for HK
3. ED visits with HK as a contributing factor, all-cause death, or use of rescue therapy for HK
4, 5 and 6: either component of the composite outcome in point 1

Tempo alla prima occorrenza di:
1. ricoveri ospedalieri o visite in PS con l’HK come fattore contribuente, al decesso per qualsiasi causa o all’uso di terapia di soccorso per l’HK in qualsiasi momento successivo alla dimissione fino a 180 giorni.
2. ricovero ospedaliero con l’HK come fattore contribuente, al decesso per qualsiasi causa o all’uso di terapia di soccorso per l’HK in qualsiasi momento successivo alla dimissione fino a 180 giorni.
3. di visite al PS con l’HK come fattore contribuente, al decesso per qualsiasi causa o all’uso di terapia di soccorso per l’HK in qualsiasi momento successivo alla dimissione fino a 180 giorni.
4, 5 e 6. di uno dei componenti dell’esito composito in qualsiasi momento successivo alla dimissione fino a 180 giorni.

E.5.2.1

Timepoint(s) of evaluation of this end point

At any time post-discharge up to 180 days.

In qualsiasi momento dopo la dimissione fino a 180 giorni.

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

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)

E.7.4

Therapeutic use (Phase IV)

Yes

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

Yes

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

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Local standard of care

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in 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

Information not present in EudraCT

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

Belgium

France

Germany

Italy

Netherlands

Spain

United Kingdom

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:

120

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

224

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

200

F.4.2

For a multinational trial

F.4.2.1

In the EEA

337

F.4.2.2

In the whole clinical trial

344

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)

No intervention will follow the end of the study. Decision to continue on SZC treatment or SoC will be at investigator's discretion.

Nessun intervento seguirà la fine dello studio. La decisione di continuare il trattamento con SZC o SoC sarà a discrezione dello sperimentatore.

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

2021-12-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-11-09

P. End of Trial
P.	End of Trial Status	Ongoing

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