A Study in Children With Hyperkalaemia Between Birth and <18 Years of Age to Evaluate Doses of Sodium Zirconium Cyclosilicate (SZC) for Correction of Hyperkalaemia and Effectiveness of Same Dose to Maintain Normokalaemia.

.Protocol title: A Phase 3, Dose-Escalating Study in Children With Hyperkalaemia Between
Birth and <18 Years of Age to Evaluate Increasing Doses of Sodium Zirconium Cyclosilicate
(SZC) Given Three Times Daily for the Correction of Hyperkalaemia and the Effectiveness of
the Same Dose of SZC Given Once Daily to Maintain Normokalaemia Among Those Requiring
Continuous

Treatment.Rationale:

Sodium zirconium cyclosilicate has been shown to be effective and safe in adults for the
treatment of hyperkalaemia, and therefore it is expected to be beneficial in children. This
study will evaluate the efficacy, safety and tolerability of sodium zirconium cyclosilicate
for the treatment of hyperkalaemia in children <18 years of age.

Primary Objective: Endpoint/Variable:28-day maintenance phase (MP) primary objective:

To compare the effect of SZC vs placebo on maintaining normokalaemia during the MP 28-day
maintenance phase (MP) primary endpoint (primary analysis endpoint):

The proportion of subjects in whom normokalaemia can be maintained throughout the MP.

Correction phase (CP) primary objective:

To evaluate SZC dose levels on achieving normokalaemia during the CP Correction phase (CP)
primary endpoint:The proportion of subjects in whom serum K decreases by ≥0.5 mmol/L and who
achieve normokalaemia at (by or before) 24, 48 and 72 hours during CP.

Secondary Objectives: Endpoint/Variable:

CP secondary objectives:

To evaluate SZC dose levels on achieving normokalaemia within the first 72 hours

CP secondary endpoints:

The proportion of subjects in whom serum K decreases by ≥0.5 mmol/L and who achieve
normokalaemia during the first 72 hours. To evaluate SZC dose levels on time to achieving
normokalaemia during the CP Time to first day achievement of normokalaemia To evaluate SZC
dose levels on the reduction of serum K levels during the CP Absolute and percent change from
baseline in serum K levels at all intervals of follow-up after dosing has been initiated To
evaluate SZC dose levels on time to reduction of serum K levels during the CP Time to
decrease of 0.5 mmol/L in serum K level To evaluate the acceptability and palatability of SZC
Proportion of patients per response category in Study Medication Palatability Assessment
questionnaires (self reported or observer assessment)

MP secondary objectives:

To evaluate the effect of SZC vs placebo on time from randomization to relapse of
hyperkalaemia.

MP secondary endpoints:

Time from randomization to relapse of hyperkalaemia (return to serum K level >5.0 mmol/L for
subjects 2 to <18 years and >6.0 mmol/L for subjects <2 years) in each treatment group To
evaluate the effect of SZC vs placebo on the proportion of subjects with normokalaemia per
visit over the MP Proportion of subjects within each treatment group who maintain normal
serum K levels (defined as serum K of ≥3.5 mmol/L and ≤5.0 mmol/L for subjects aged 2 to <18
years and serum K of ≥3.5 mmol/L and ≤6.0 mmol/L for subjects <2 years) per visit over the MP
To evaluate the effect of SZC vs placebo on the change in serum K levels over the MP Both
absolute and percent change from baseline in serum K levels post dose during the MP and at
any time point thereafter in each treatment group To evaluate the effect of SZC vs placebo on
time to increase in serum K during the MP Time to an increase in serum K concentration of 0.5
mmol/L in each treatment group To evaluate the effect of SZC vs placebo on proportion of days
of normokalaemia during the MP Number and percentage of days of normokalaemia To evaluate the
effect of SZC vs placebo on mean serum K during the MP The difference in mean of all serum K
values obtained during the MP in subjects receiving either SZC or placebo To evaluate the
effect of SZC vs placebo on the proportion of subjects experiencing hypoor hyperkalaemia
during the MP The number and percentage of subjects with hypo- (<3.0 mmol/L) or hyperkalaemia
(>6.0 mmol/L) in subjects receiving either SZC or placebo To evaluate the effect of SZC vs
placebo on serum aldosterone at the end of the MP Change from baseline in serum aldosterone
(S-Aldo) to end of the MP To evaluate the effect of SZC vs placebo on plasma electrolytes
(including bicarbonate) and spot urinary pH and electrolytes Change from baseline in plasma
electrolytes (including bicarbonate) and spot urinary pH and electrolytes to end of the MP To
evaluate the acceptability and palatability of SZC Proportion of patients per response
category in Study Medication Palatability Assessment

LTMP objective:

To evaluate long term maintenance of normokalemia during treatment with SCZ

LTMP secondary endpoints:

Proportion of subjects in whom normokalaemia can be maintained over the LTMP To evaluate long
term maintenance of normokalemia during treatment with SCZ Proportion of subjects who needed
dose escalation to higher dose levels during the LTMP To evaluate long term maintenance
ofnormokalemia during treatment with SCZ Proportion of subjects who needed dose deescalation
to lower dose levels during the LTMP To evaluate long term maintenance of normokalemia during
treatment with SCZ The number and percentage of subjects with hypo- (<3.0 mmol/L) or
hyperkalaemia (>6.0 mmol/L) during the LTMP To evaluate the acceptability and palatability of
SZC Proportion of patients per response category in Study Medication Palatability Assessment
questionnaires (self reported or observer assessment)

Safety Objective: Endpoint/Variable:

To evaluate the safety and tolerability of SZC in the 3 phases (CP, MP and the LTMP), and of
SZC in relation to placebo in the MP.

- Adverse events/serious adverse events

- Vital signs

- Electrocardiogram

- Clinical laboratory evaluations (urinalysis, serum clinical chemistry, and haematology
parameters)

- i-STAT-K and central laboratory K

- Physical examinations

Overall design:

Approximately 100 subjects will be enroled at approximately 40 sites in locations including
but not limited to Europe and North America for this study.

This study will enrol males and females aged birth to <18 years with hyperkalaemia, except
neonates with a gestational age less than 30 weeks or a birth weight less than 1500 g.

All subjects are eligible for open-label treatment with SZC during the Correction Phase, and
subjects aged 2 to <18 years who are eligible to participate in the Maintenance Phase will be
randomised in a 1:1 ratio to double-blinded treatment with SZC or matching placebo
comparator.

Subjects aged <2 years who require continuing treatment will participate in an open-label
Maintenance Phase. Only subjects aged 2 to <18 years may continue to the optional open-label
Long-Term Maintenance Phase.

Treatment will be stratified by the following age cohorts during the study:

- 12 to <18 years of age

- 6 to <12 years of age

- 2 to <6 years of age

- 0 to <2 years of age, except neonates with a gestational age less than 30 weeks or a
birth weight less than 1500 g.

- During the dose escalation period in the CP, treatment will first be initiated in
the oldest age cohort (12 to <18 years). The age cohort 6 to <12 years will start
as soon as study drug is available. Dosing may then be started sequentially in the
younger age cohorts, depending on the safety and efficacy data during the CP in the
older cohorts.

Study period:

Estimated date of first subject enroled Q3 2018 Estimated date of last subject completed Q1
2021

Number of subjects:

The study will enrol approximately 100 subjects into the CP in order to achieve randomisation
of at least 90 subjects into the MP. Of the 100 subjects enroled, ≥5 subjects should be in
the birth to <2 years cohort. Additionally, the 90 (or greater) subjects randomised into the
MP should include ≥30 subjects in the 12 to <18 years cohort, ≥30 subjects in the 6 to <12
years cohort, and ≥10 subjects in the 2 to <6 years cohort. At least 45 randomised subjects
should have a baseline potassium level (using the mean of the two consecutive i-STAT-K
measurements at Screening) of >5.5 mmol/L by i-STAT (i-STAT-K). A minimum number of 75
subjects must continue study drug throughout the MP (≥25 subjects in the 12 to <18 years
cohort, ≥25 subjects in the 6 to <12 years cohort, and ≥8 subjects in the 2 to <6 years
cohort). Hence, randomisation will continue until it can be predicted that 75 subjects
fulfilling the specific age cohort requirements will complete the MP without premature
discontinuation of study drug.

Based on data from adult study SZC-004, the proportion of responders (subject with maintained
normokalaemia, defined as i-STAT-K 3.5 to 5.0 mmol/L inclusive, throughout the MP) can be
assumed to be 37% and 12% in the SZC and placebo treatment groups, respectively. Forty-five
subjects per group will then provide 79% power using a chi-square test at 5% significance
level.

Treatments and treatment duration:

Treatment will include 3 phases: the CP, MP, and LTMP. Subjects from 2 to <18 years requiring
chronic treatment for hyperkalaemia are eligible to participate in all phases of the study.

Subjects <2 years of age requiring acute or chronic treatment for hyperkalaemia will be
included in the first 2 phases, as specified:

An open-label CP during which SZC is administered orally 3 times daily (TID) prior to
breakfast, lunch, and dinner for 1 to 3 days to achieve normokalaemia (i-STAT-K level

- 3.5 mmol/L and ≤5.0 mmol/L in subjects 2 to <18 years, and ≥3.5 mmol/L and

- 6.0 mmol/L in subjects from birth to <2 years) in subjects from birth to <18 years.

A 28-day MP during which SZC or placebo is administered in randomised, double-blind manner
orally once daily (QD) to maintain normokalaemia in subjects from 2 to <18 years. Subjects
aged <2 years will continue treatment in the MP with open-label QD oral SZC active treatment
if medically indicated by the treating physician. Dose titration will be allowed in this
phase for subjects aged <2 years in the case of hypokalaemia.

• An open-label LTMP during which SZC is administered QD for up to 22 weeks, to maintain
normokalaemia in subjects aged 2 to <18 years. Continuation into this phase is optional, and
will be determined by the Investigator based on the subject's need for long-term treatment.
Dose titration for individual subjects will be allowed in this phase.

Dose levels are derived from doses of SZC previously used in the adult population, by
adjusting for paediatric body weight.

Data Monitoring Committee:

An independent Data Monitoring Committee will be utilised for this study to evaluate emerging
safety data during the dose escalation part of the study.Statistical methods All efficacy
analyses will be based on the intent-to-treat (ITT) principle using the Full analysis set,
i.e., subjects that stop taking treatment, or are randomised but receive no treatment, are
still included in the analysis.

Safety analyses will similarly be primarily based on the ITT principle of including data
after premature discontinuation of study drug using the Safety analysis set. If the
proportion of treated subjects who discontinue study drug prematurely is larger than 15%, a
subset of the safety summaries as defined in the Statistical Analysis Plan (SAP) will be
produced using an on-treatment approach also. In general, CP data will be presented by dose.
MP data will be presented by treatment, denoted by SZC or placebo.

In the LTMP, the open-label SZC dose can be titrated. Summaries by dose will however be done
based on the dose the subject was initially on when starting the LTMP (which should be the
same dose at which the subject started the study, according to study design).

. Categorical variables will be summarised using frequency and percentages, where the
denominator for calculation is the underlying analysis set population unless otherwise
stated.

Continuous variables will be summarised with descriptive statistics of number of available
observations, mean, standard deviation, median, minimum and maximum, and quartiles where more
appropriate.

In instances where central laboratory K data is missing, the i-STAT-K value will be used
instead, adding the average difference between the central laboratory K and i-STAT-K in those
subjects with both values available at the relevant time point.

All point estimates will be presented together with 95% confidence intervals as measures of
precision. No interim analyses are planned for this study.

Inclusion Criteria:

1. Provision of written informed consent of the subject or legal representative, and
informed assent from the subject (as appropriate) as described in Appendix A 3.

2. Female or male from birth to <18 years of age.

3. Subjects requiring long-term treatment of hyperkalaemia (chronic hyperkalaemia) in the
age cohort ≥2 years, and subjects requiring either short- or long-term treatment for
hyperkalaemia (acute and chronic hyperkalaemia) in the age cohort <2 years.

4. Subjects must meet 1 of the following criteria for hyperkalaemia:

1. For subjects ≥2 years of age, mean i-STAT-K level >5.0 mmol/L at Screening. Two
consecutive i-STAT-K values, measured 60 (±15) minutes apart, both

≥5.0 mmol/L and measured within 1 day before the first dose of SZC on CP Study
Day 1.

2. For subjects <2 years of age, i-STAT-K level >6.0 mmol/L at Screening, measured
within 1 day before the first dose of SZC on CP Study Day 1.

Using digital ECG, QT interval corrected by Bazett's method (QTcB) must meet the
age-appropriate parameters at Screening:

1. For subjects aged 0 to ≤3 days after birth: <450 ms

2. For subjects aged >3 days to <12 years: <440 ms

3. For subjects ≥12 to <18 years: <450 ms (male), <460 ms (female) All QTcB values
outside the reference values specified in the protocol should be manually re-measured
and re-calculated, and if there is a difference in measurement between the automatic
and manual ECG, the manual measurement should always be considered correct. 6. Ability
to have repeated blood draws or effective venous catheterization. 7. Females of
childbearing potential must have a negative pregnancy test within 1 day prior to the
first dose of SZC on CP Study Day 1 and sexually active females of childbearing
potential must be using 2 forms of medically acceptable contraception with at least 1
being a barrier method

Exclusion Criteria:1. Neonates with a gestational age <30 weeks or a birth weight
<1500 g.

2. Subjects with pseudohyperkalaemia caused by excessive fist clenching to enable
venepuncture, by haemolysed blood specimens, or by severe leukocytosis or
thrombocytosis. 3. Subjects with hyperkalaemia due to soft-tissue damage from crush
injury or burns.

4. Subjects treated with lactulose, rifaximin (XIFAXAN™), or other nonabsorbed
antibiotics for hyperammonaemia within the last 7 days. 5. Subjects treated with
calcium polystyrene sulfonate (CPS), sodium polystyrene sulfonate (e.g., KAYEXALATE™),
or patiromer within the last 4 days. 6. Subjects with a life expectancy of less than 3
months. 7. Subjects who are known to have tested Human Immunodeficiency Virus (HIV)
positive. 8. Presence of any condition which, in the opinion of the Investigator,
places the subject at undue risk or potentially jeopardises the quality of the data to
be generated.

9. Known hypersensitivity or previous anaphylaxis to SZC or to components thereof.

10. Subjects with cardiac arrhythmias that require immediate treatment. 11. Subjects
with a family history of long QT syndrome. 12. Subjects on dialysis to exclude
subjects requiring acute or chronic renal replacement therapy. 13. Subjects with a
history of bowel obstruction. 14. Subjects with severe gastrointestinal disorder or
major gastrointestinal surgery (e.g., large bowel resection). 15. Involvement in the
planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff
at the study site). 16. Previous treatment with SZC. 17. Treatment with a drug or
device within the last 30 days that has not received regulatory approval at the time
of study entry. 18. Previous enrolment in the present study. 19. Females who are
pregnant, breastfeeding, or planning to become pregnant. 20. Judgment by the
Investigator that the subject should not participate in the study if the subject is
unlikely to comply with study procedures, restrictions and requirements.