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

Hyperkaliemia is a potentially life-threatening electrolyte disorder and is
primarily caused by renal dysfunction leading to reduced excretion of K+. The
incidence of HK in CKD patients has been reported to range between 7.7% and 73%.
In a study of approximately 36,000 patients with an estimated glomerular
filtration rate (eGFR) < 60 ml/min per 1.73 m2, HK was associated with
increased all-cause mortality.
Because HK can induce or worsen cardiac arrhythmias, it is associated with
significantly increased mortality.

Treatment of severe HK is then a medical emergency but it should be followed by
continuous long-term treatment to prevent recurrence. So far, the common
practice for managing chronic HK is focused on eliminating HK predisposing
factors. Patients are then advised to reduce high K+ intake in diets but also
to withdraw or reduce medications known to raise K+ levels.

Maintaining the use of these beneficial medications
(renin-angiotensin-aldosterone system inhibitors (RAASi), for example,) while
implementing various strategies to control K+ balance is desirable and could be
obtained by long-term use of K+ binders.
A treatment of up to 12 months with SZC utilising a dose titration scheme with
the starting dose of 5 or 10 g daily, titrated to a maximum of 15 g daily or a
minimum of 5 g every other day, was effective in maintaining NK in the majority
of subjects in a long-term study (Spinowitz et al, 2019). However, in the US,
only 0.1% of patients with a HK-related inpatient stay received a binder at
discharge (Davis et al, 2019).

Hyperkalaemia is reported in less than 5% of the population, worldwide (Lederer
and al, 2020), but may affect up to 10% of hospitalised patients
(Rossignol et al, 2016). In addition to clinical consequences, HK is associated
with increased health care costs and healthcare resource utilisation (HRU).
(protocol section 2.2)

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

Secondary:
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 all-cause hospital
admissions or ED visits with HK as a contributing factor, or all-cause death,
or use of rescue-therapy for HK.
2. in reducing the incidence of all-cause hospital admissions or ED visit with
HK as a contributing factor.
3. in reducing the number of all-cause hospital admissions or ED visits with HK
as a contributing factor.
4. in reducing the risk of renin angiotensi-aldosterone system inhibitors
(RAASi) down-titration (including discontinuation).
5. in reducing the incidence of hospital admissions or ED visits with HK as a
contributing factor.
6. in reducing the number of hospital admissions or ED visits with HK as a
contributing factor.

This is a Phase 4, randomised, controlled, open-label, parallel group,
multicentre study in participants with CKD treated for HK, whilst admitted to
the hospital. There will be 3 phases:
• The in-hospital phase
- screening visit
- The Inpatient phase
- clinical phase:
- baseline visit: correction treatment with SZC will be initiated.
- discharge visit: randomisation to one of the 2 parallel arms.
• The outpatient phase: treated with either SZC, as per local label, or SoC as
per local practice for 180 days.
• The follow-up phase: end of study visit 7 days after end of treatment

All participants will be treated with SZC as per local label (correction and
maintenance treatment) during the in-hospital phase. The duration of
in-hospital phase will be 2 to 21 days post-enrolment; medical monitor*s
approval may be sought for allowing longer duration hospital stays for specific
participants.
At discharge, participants who are NK (K+ between 3.5 and 5.0 mmol/L,
inclusive) and have been started on a maintenance dose for SZC will be
randomised in a 1:1 ratio to one of the following arms and subsequently enter
the outpatient phase:
• Arm A: Participants discharged with SZC, as per local label, to manage HK
until end of outpatient phase
• Arm B: Participants discharged with SoC, as per local practice, to manage HK
until end of the study.
Note: Participants intended to receive a K-binder at discharge (as per the site
routine medical practice) will not be randomised and will be discontinued from
the study. Still, it is allowed that participants randomised into Arm B have
any 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 duration of outpatient phase will be approximately 180 days.
After the outpatient phase, participants will enter into the follow-up phase
which will last 7 days. Study drug will be discontinued for participants in Arm
A. These participants will be treated as per local practice (SoC). Participants
in Arm B will continue SoC treatment.

The total study duration for each participant will then be approximately 6
months.

In the hospital:
- Screening visit
- baseline visit
- Treatment: 14 days in the hospital, with SZC for stabilizing potassium values.

At home:
Return to hospital 4 times for visit
Being called at home four times for a check-up

Type of examinations:
- physical examination
- ECG
- assess side effects
- blood collections, 5-9.5 mL per visit
- urine collection/handing in for pregnancy testing (if applicable)