Clinical Trials Register

Summary
EudraCT Number:	2021-003527-14
Sponsor's Protocol Code Number:	D9480C00023
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-10-19
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

Spain - AEMPS

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

Estudio en fase IV, abierto, aleatorizado, del uso continuado de ciclosilicato de sodio y zirconio (CSZ) después del alta hospitalaria en participantes con nefropatía crónica tratados por hiperpotasemia

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

Estudio del uso continuado de ciclosilicato de sodio y zirconio (CSZ) después del alta hospitalaria

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.3.9.3	Other descriptive name	SODIUM ZIRCONIUM CYCLOSILICATE (SZC)
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.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.

Pacientes con nefropatía crónica tratados por hiperpotasemia mientras están en el hospital, y establecer una dosis de mantenimiento de CSZ al alta.

E.1.1.1

Medical condition in easily understood language

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

Hiperpotasemia significa que el nivel de potasio en la sangre es más alto de lo normal

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

Evaluar la eficacia de continuar el tratamiento con CSZ como parte de los medicamentos en el momento del alta hospitalaria, en comparación con el tratamiento estándar, en el mantenimiento de la 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

Evaluar el efecto de la continuación de la CSZ como parte de los medicamentos en el momento del alta hospitalaria, en comparación con el tratamiento estándar, en la reducción de la incidencia del criterio de valoración compuesto de ingresos hospitalarios o visitas al servicio de urgencias (SU) con HK como factor contribuyente, muerte por cualquier causa o uso de tratamiento de rescate para la HK.
2. reducción de la incidencia del criterio de valoración compuesto de ingresos hospitalarios con HK como factor contribuyente, muerte por cualquier causa o uso de tratamiento de rescate para la HK.
3. reducción de la incidencia de visitas al SU con HK
4. reducción de la incidencia del criterio de valoración compuesto de ingresos hospitalarios o visitas al SU con HK como factor contribuyente o la muerte por cualquier causa
5. reducción de la incidencia de ingresos hospitalarios con HK como factor contribuyente o la muerte por cualquier causa
6. reducción de la incidencia de visitas al SU

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.

1 Deben tener 18 años o más en el momento de firmar el formulario de consentimiento informado
2 Ingreso en el hospital (atención hospitalaria; directamente o desde el SU)
3 Con:
-NPC en estadio 3b a 5 diagnosticada
o
-TFGe <45 ml/min/1,73 m2 en el momento de la selección del estudio o en los 3 meses anteriores, según la ecuación de la Colaboración en epidemiología de la nefropatía crónica (CKD-EPI) (Levey et al, 2009). Nota: La raza/origen étnico no deben incluirse en el cálculo de la ecuación CKD-EPI.
4 La medición de K+ registrada más reciente, ya sea para este ingreso o en la visita al SU que provocó este ingreso, debe estar entre 5,5 y 6,5 mmol/l, ambos inclusive
5 Hombre o mujer
6 Capaz de, y dispuesto a, dar el consentimiento informado firmado, tal como se describe en el Apéndice A, que incluye el cumplimiento de los requisitos y las restricciones que se enumeran en el formulario de consentimiento informado (FCI) y en este protocolo.

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.

1 Infarto de miocardio, accidente cerebrovascular, convulsiones o un acontecimiento trombótico/tromboembólico (p. ej., trombosis venosa profunda o embolia pulmonar, pero excluyendo trombosis de acceso vascular) en las 12 semanas anteriores a la selección
2 Incapaz de tomar la mezcla de fármaco CSZ por vía oral
3 Destinatario de, o con fecha programada para, un trasplante de riñón de donante vivo
4 Con una esperanza de vida de menos de 6 meses
5 Cualquier afección médica (incluida infección activa clínicamente significativa) que, en opinión del investigador o del promotor, pueda suponer un riesgo para la seguridad del participante en este estudio, lo que puede confundir las evaluaciones de la seguridad o la eficacia y poner en peligro la calidad de los datos, o pueda interferir con la participación en el estudio
6 Presencia de arritmias cardíacas o defectos de la conducción que requieran tratamiento inmediato
7 Intervalo QT corregido por el método Fridericia (QTcF) >550 ms
8 Antecedentes de prolongación del intervalo QT asociado con otros medicamentos que requirieron la interrupción de dicho medicamento.
9 Síndrome de QT largo congénito
10 Fibrilación auricular sintomática o no controlada a pesar del tratamiento, o taquicardia ventricular sostenida asintomática. Están permitidos los participantes con fibrilación auricular controlada con medicación.
11 Indicios de enfermedad por coronavirus 2019 (COVID-19) en las 2 semanas anteriores a la selección (véase el Apéndice C)
12 Antecedentes de abuso de alcohol o drogas en los 2 años anteriores a la selección
13 Tratamiento continuado con cualquier quelante de K en el momento del ingreso de referencia en el hospital (se permite el inicio del tratamiento con CSZ durante la visita al SU inmediatamente anterior al ingreso de referencia en el hospital)
14 Tratamiento sustitutivo renal, incluida hemodiálisis crónica y diálisis peritoneal
15 Participación en otro estudio clínico con un producto en fase de investigación (PEI) administrado durante el mes previo a la selección. Nota: Los participantes vacunados con una vacuna contra la COVID-19 mientras aún esté bajo la Autorización de Uso de Emergencia no se excluirán del estudio.
16 Hipersensibilidad conocida a CSZ o a cualquiera de los excipientes del producto.
17 Participación en la planificación y/o realización del estudio (aplicable al personal de AstraZeneca y/o al personal del centro del estudio).
18 Determinación por parte del investigador de que el participante no debe participar en el estudio si es poco probable que cumpla con los procedimientos, las restricciones y los requisitos del estudio.
19 Aleatorización previa en el presente estudio
20 Solo para mujeres: las mujeres en edad fértil (MEF; es decir, aquellas que no están esterilizadas química o quirúrgicamente o que no son posmenopáusicas) que no están dispuestas a utilizar uno de los métodos anticonceptivos descritos a continuación, desde el momento de la firma del consentimiento informado a lo largo del estudio y a las 4 semanas siguientes:
a Anticonceptivos hormonales combinados (que contengan estrógenos y gestágeno) asociados a inhibición de la ovulación: orales, intravaginales o transdérmicos.
b Anticonceptivos hormonales solo de gestágenos asociados a inhibición de la ovulación: orales, inyectables o implantables.
c Dispositivo intrauterino (DIU).
d Sistema intrauterino (SIU) liberador de hormonas.
e Oclusión tubárica bilateral.
f Pareja vasectomizada (la pareja vasectomizada es un método anticonceptivo altamente eficaz siempre que se trate de la única pareja sexual de la MEF participante y que se haya evaluado el éxito quirúrgico en la pareja vasectomizada.
(g) Abstinencia sexual: se considera un método anticonceptivo altamente eficaz solamente si se define como la abstinencia de mantener relaciones heterosexuales durante todo el periodo de riesgo asociado a los tratamientos del estudio. Debe evaluarse la fiabilidad de la abstinencia sexual en relación con la duración estudio clínico y el estilo de vida preferido y habitual del participante.
21 Para MEF solamente: mujeres con resultado positivo en una prueba de embarazo en la selección O mujeres en período de lactancia.

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.

Aparición (sí/no) de NK (potasio [K+] entre 3,5 y 5,0 mmol/l, ambos inclusive) 180 días después del alta hospitalaria.

E.5.1.1

Timepoint(s) of evaluation of this end point

Up to 180 days post-discharge

Hasta 180 días después del alta hospitalaria.

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

Tiempo hasta la primera incidencia:
1. ingresos hospitalarios o visitas al SU con HK como factor contribuyente, muerte por cualquier causa o uso de tratamiento de rescate para la HK en cualquier momento
2. primera incidencia de ingreso hospitalario con HK como factor contribuyente, muerte por cualquier causa o uso de tratamiento de rescate para la HK
3. de visitas al SU con HK como factor contribuyente, muerte por cualquier causa o uso de tratamiento de rescate para la HK
4,5 y 6: cualquiera de los componentes del resultado en el punto 1.

E.5.2.1

Timepoint(s) of evaluation of this end point

At any time post-discharge up to 180 days.

En cualquier momento después del alta hospitalaria hasta los 180 días.

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

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

UVUP

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.

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

2021-11-15

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-11-08

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

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