Clinical trial NCT05347693: Continuing Sodium Zirconium Cyclosilicate (SZC) After Discharge Study
Official title: An Open-Label, Randomised, Phase 4 Study of Continuing Sodium Zirconium Cyclosilicate (SZC) After Discharge in Participants With Chronic Kidney Disease Treated for Hyperkalaemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Hyperkalaemia
Chronic Kidney Disease
Keywords: sodium zirconium cyclosilicate
Hyperkalaemia after discharge at the hospital
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2022-04-26
Enrollment: 186
Sex: ALL
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This is a Phase 4, randomised, controlled, open-label, parallel-group, multicentre study in participants with CKD treated for HK whilst in hospital.

* During the in-hospital phase, participants will be treated with SZC as per local label
* At discharge, NK participants who have been treated with SZC for between 1 and 21 days whilst in hospital and are started on SZC maintenance dose will be randomised in a 1:1 ratio to one of the following arms:

  * Arm A: Participants discharged with SZC, as per local label, to manage HK until the end of the outpatient phase
  * Arm B: Participants discharged with SoC, as per local practice, to manage HK until the end of study. Note: Participants intended to be discharged with a K+ binder (as per the site routine medical practice) will not be randomised and will be discontinued from the study.
* The total duration of the study for each participant will be up to approximately 6 months.
Primary purpose: TREATMENT

Brief summary: This is an open-label, randomised study in participants with chronic kidney disease (CKD) treated for hyperkalaemia (HK) whilst in hospital. The study will compare SZC to standard of care (SoC) with the goal of determining:

* If continued use of SZC maintains normokalaemia (NK) better than SoC after participant discharge from the hospital.
* If continued use of SZC after discharge will reduce HK related healthcare resource utilisation compared to SoC.

Detailed description: This is a Phase 4, randomised, controlled, open-label, parallel-group, multicentre study in participants with CKD treated for HK whilst in hospital.

* Participants from 30 to 50 sites in 4 to 7 countries will be screened for enrolment. In total, up to a maximum of 163 participants will be enrolled, resulting in approximately 130 participants discharged and randomised and 104 evaluable participants (52 per arm).
* The study plans to enrol approximately equal numbers of participants with mild HK (K+ between \> 5.0 and ≤ 5.5 mmol/L) and with moderate/severe HK (K+ between \> 5.5 and ≤ 6.5 mmol/L), with a minimum of 30% of the enrolled participants in either group.
* During the in-hospital phase, participants will be treated with SZC as per local label, starting at baseline and based on local K+ measurement obtained within 24 hours of treatment initiation:).

  * Participants with HK (K+ between \> 5.0 and ≤ 6.5 mmol/L):

    1. stop current K-binder if any
    2. start SZC correction dose (note: participants currently on SZC should continue SZC correction dose, up to 72 hours).
  * Participants currently receiving any treatment for the current episode of HK and are already NK at baseline (K+ ≤ 5.0 mmol/L): 1) stop any current K-binder, 2) start SZC maintenance dose (note: participants currently on SZC maintenance dose should continue SZC maintenance dose).
  * All treatment decisions, including modification of the ongoing therapy for HK must be based on the investigator's medical judgement of the participant's best interest.
* At discharge, NK participants who have been treated with SZC for between 1 and 21 days whilst in hospital and are started on SZC maintenance dose will be randomised in a 1:1 ratio to one of the following arms:

  * Arm A: Participants discharged with SZC, as per local label, to manage HK until the end of the outpatient phase
  * Arm B: Participants discharged with SoC, as per local practice, to manage HK until the end of study. Note: Participants intended to be discharged with a K+ binder (as per the site routine medical practice) will not be randomised and will be discontinued from the study. Still, participants randomised into Arm B may have a K-binder prescribed at Day 7 post-discharge, (or after Day 7 post-discharge), to treat confirmed HK or in case there is an increase in K+ level since discharge that, in the investigator's opinion, requires therapy.
* The total duration of the study for each participant will be up to approximately 6 months.
* Study visit schedule is as follows:

In-hospital phase: - The screening visit will occur while the participant is at the hospital (up to 21 days before discharge; medical monitor's approval may be sought for allowing longer duration hospital stays for specific participants) in order to check eligibility criteria

* Inpatient phase: o The baseline visit (can occur the same day as the screening visit) where treatment with SZC will be initiated

  o The discharge visit, 1 to 20 days after baseline; medical monitor's approval may be sought for allowing longer duration hospital stays for specific participants). Randomisation will occur at day of discharge.
* Outpatient phase: - Visits will occur at 7, 30, 60, 90, 120, 150, and 180 (EOT, End of Trial) days after randomisation. Only visits at 7, 90 and 180 days after randomisation will be on-site visits, the remaining being telephone visits. If dose titration occurs at any time during the outpatient phase, unscheduled dispensation visits will be performed.

Follow-up phase: - A follow-up on-site visit (end of study visit) will occur approximately 7 days after EOT. • Data will be collected at on-site visits, via telephone visits and medical chart reviews.

• An adjudication committee will be involved in the study.

Eligibility criteria: Inclusion Criteria:

* Must be 18 years of age or older, at the time of signing the informed consent
* Admitted to hospital (inpatient care; directly or from ED)
* With:

  1. Diagnosed CKD (any stage) or
  2. eGFR \< 90 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.

* Local laboratory K+ measurement within 24 hours of baseline visit (visit 2), where result is either:
* Hyperkalaemic as defined by site's local practice and K+ ≤ 6.5 mmol/L.
* Or, normokalaemic: K+ between ≥ 3.5 and ≤ 5.0 mmol/L, where patient started and is receiving treatment for this episode of HK
* Male or female
* 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 this protocol.

Exclusion Criteria:

* Hospitalisation for an acute cardiovascular event within 12 weeks prior to screening
* Unable to take oral SZC drug mix
* With a life expectancy of less than 6 months
* Any medical condition that, in the opinion of the investigator makes the participant not suitable for inclusion
* QT interval corrected by the Fridericia method (QTcF) \> 550 msec
* History of QT prolongation associated with other medications that required discontinuation of that medication
* Congenital long QT syndrome
* Clinically significant arrythmias as judged by the investigator
* Ongoing treatment with SZC or patiromer before current ED visit/hospital admission (ongoing treatment with other K-binders before current ED visit/hospital admission is allowed).

Note: Initiation of any SZC or patiromer during the current ED visit/hospitalisation preceding enrolment is allowed.

* Chronic haemodialysis or peritoneal dialysis or the recipient of or scheduled date for a kidney transplant. Note: Emergency/unscheduled haemodialysis to treat HK during the current ED visit/hospitalisation preceding enrolment is allowed.
* Participation in another clinical study with an investigational medicinal product (IMP) administered during the month before screening.
* Known hypersensitivity to SZC or any of the excipients of the product
* Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
* 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
* Previous randomisation in the present study
* For women only: Women of child-bearing potential (WOCBP; ie, those who are not chemically or surgically sterilised or who are not post-menopausal) who are not willing to use one of the methods of contraception described hereafter, or who are not stable on the contraception method for the last one month, from the time of signing the informed consent throughout the study and 7 days after the last dose: (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 (d) Intrauterine hormone-releasing system (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.
* For WOCBP only: Women who have a positive pregnancy test at screening OR women who are breastfeeding.

Primary outcomes:
measure: Occurrence (yes/no) of normokalaemia (NK) (potassium [K+] between 3.5 and 5.0 mmol/L, inclusive)
timeFrame: Up to 180 days post-discharge
Secondary outcomes:
measure: Time to first occurrence of all-cause hospital admissions or ED visits with HK as a contributing factor, all-cause death, or use of rescue therapy for HK
timeFrame: Up to 180 days post-discharge
measure: Time to first occurrence of all-cause hospital admission or ED visit, with HK as a contributing factor
timeFrame: Up to 180 days post-discharge
measure: Number of all-cause hospital admission or ED visits, with HK as a contributing factor
timeFrame: Up to 180 days post-discharge
measure: Time to first occurrence of hospital admission or ED visit with HK as a contributing factor between the SZC and SoC arms.
timeFrame: Up to 180 days post-discharge
measure: Incidence rate of hospital admission or ED visit with HK as a contributing factor between the SZC and SoC arms.
timeFrame: Up to 180 days post-discharge
measure: Time to first occurrence of RAASi down-titration (or discontinuation)
timeFrame: Up to 180 days post-discharge
Other outcomes:
measure: Adverse Events (AE)
timeFrame: From time of signature of the ICF, throughout the treatment period and including the follow-up period, 201 days maximum
measure: Weight in kilograms
timeFrame: From time of signature of the ICF, throughout the treatment period and including the follow-up period, 201 days maximum
measure: Height in centimeters
timeFrame: Height will be measured at screening visit
measure: Blood pressure (BP) in mmHg
timeFrame: From time of signature of the ICF, throughout the treatment period and including the follow-up period, 201 days maximum
measure: Pulse rate in beats/min
timeFrame: From time of signature of the ICF, throughout the treatment period and including the follow-up period, 201 days maximum
measure: Clinical safety laboratory tests
timeFrame: From time of signature of the ICF, throughout the treatment period and the follow-up period, 201 days maximum
measure: Electrocardiograms (ECG)
timeFrame: From time of signature of the ICF, throughout the treatment period and the follow-up period, 201 days maximum
measure: Time to first occurrence of any component of hospital admission or ED visit, both with HK as a contributing factor, or all-cause death
timeFrame: Up to 180 days post-discharge
measure: Time to first occurrence of either hospital admission with HK as a contributing factor or allcause death
timeFrame: Up to 180 days post-discharge
measure: Time to first occurrence of either ED visit with HK as a contributing factor or all-cause death
timeFrame: Up to 180 days post-discharge
measure: Time to first occurrence of any component of all-cause hospitalisations, ED visits, use of rescue therapy for HK or all-cause death in each arm
timeFrame: Up to 180 days post-discharge
measure: K+ level
timeFrame: Up to 180 days post-discharge
measure: Number of hospital admissions with HK as a contributing factor
timeFrame: Up to 180 days post-discharge
measure: Time to first occurrence of K-binder use in each arm
timeFrame: Up to 180 days post-discharge
measure: Frequency of the use of K-binder to treat HK in each arm
timeFrame: Up to 180 days post-discharge
measure: Time to first occurrence of rescue therapy use in each arm
timeFrame: up to 180 days post-discharge
measure: Time to first occurrence of all-cause hospitalisations, ED visits, or outpatient visits in each arm
timeFrame: up to 180 days post-discharge
measure: Rate of change in (slope) eGFR (estimated glomerular filtration rate) from inpatient phase
timeFrame: 90 and 180 days post-discharge
measure: Time to first occurrence of dialysis initiation in each arm
timeFrame: up to 180 days post-discharge
measure: Time to first occurrence of ICU (intensive care unit) admissions in each arm
timeFrame: up to 180 days post-discharge
measure: Frequency (%) of participants on RAASi (renin-angiotensin-aldosterone system inhibitor) at discharge who remained on / increased / decreased / initiated RAASi
timeFrame: 90 and 180 days post-discharge
Locations:
city: Bonheiden
country: Belgium
facility: Research Site
city: Leuven
country: Belgium
facility: Research Site
city: Annonay
country: France
facility: Research Site
city: Ars-Laquenexy
country: France
facility: Research Site
city: Nice
country: France
facility: Research Site
city: Saint-priest En Jarez
country: France
facility: Research Site
city: Bari
country: Italy
facility: Research Site
city: Foggia
country: Italy
facility: Research Site
city: Parma
country: Italy
facility: Research Site
city: Pavia
country: Italy
facility: Research Site
city: Eindhoven
country: Netherlands
facility: Research Site
city: Algeciras
country: Spain
facility: Research Site
city: Almería
country: Spain
facility: Research Site
city: Badajoz
country: Spain
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Burgos
country: Spain
facility: Research Site
city: Getafe
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Salamanca
country: Spain
facility: Research Site
city: San Sebastián de los Reyes
country: Spain
facility: Research Site
city: Sevilla
country: Spain
facility: Research Site
city: Talavera de la Reina
country: Spain
facility: Research Site
city: Zamora
country: Spain
facility: Research Site
city: Doncaster
country: United Kingdom
facility: Research Site
city: Hull
country: United Kingdom
facility: Research Site
city: Salford
country: United Kingdom
facility: Research Site
city: Stevenage
country: United Kingdom
facility: Research Site
Study officials:
References: