Clinical trial NCT03337477
Conditions: Hyperkalemia
Sponsor: AstraZeneca
Start date: 2018-02-13; Completion date: 2018-12-21
Enrollment: 70 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study is designed to determine if ZS 10g administered up to three times over 10h added to insulin and glucose in patients presenting with hyperkalemia will prove tolerable and efficacious. Patients will receive ZS or Placebo on top of standard of care treatment with insulin and glucose.

Detailed description:

Arms: arm 1: ZS will be administered in addition to insulin and glucose. Insulin and glucose is the current standard of care to treat serum potassium ≥5.8mmol/L. arm 2: Placebo will be administered in addition to insulin and glucose. Insulin and glucose is the current standard of care to treat serum potassium ≥5.8mmol/L.
Interventions: intervention 1: Placebo intervention 2: Sodium Zirconium Cyclosilicate(ZS) intervention 3: Insulin intervention 4: Glucose intervention 5: Insulin intervention 6: Glucose
Intervention descriptions: intervention 1: Suspension administered orally for a treatment period of 24h. 2 sachets administered up to three times over 10h (at 0, 4 and 10h). intervention 2: Suspension administered orally for a treatment period of 24h. Single dose contains 2 sachets of ZS 5g. 10g administered up to three times over 10h (at 0, 4 and 10h). intervention 3: Insulin 0.1 units/kg administered as a bolus or for up to 30 minutes. intervention 4: Glucose 25g administered IV \<15 minutes before the insulin. intervention 5: Insulin 0.1 units/kg administered as a bolus or for up to 30 minutes. intervention 6: Glucose 25g administered IV \<15 minutes before the insulin.

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol - 2.0
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Clinical Study Protocol 
Drug Substance
Sodium Zirconium 
Cyclosilicate (ZS)
Study Code
D9480C00005
Version
2.0
Date
13 June 2018
A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled Study 
to Evaluate a Potassium Normalization Treatment Regimen Including Sodium 
Zirconium Cyclosilicate (ENERGIZE)
Sponsor: AstraZeneca AB, 151-85 Södertälje, Sweden
Regulatory Agency Identifying Number(s):
EudraCT number 2017-003955-50 


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VERSION HISTORY
Version 2.0 dated 13 June 2018
-
Time 0h redefined as time of first administration of ZS/placebo
-
Inclusion criterion 4 changed to allow enrolment of patients with S-K≥5.8 mmol/L
-
Exclusion criterion 5 re-worded to clarify requirements on co-existing conditions
-
Exclusion criterion 6 wording adjusted to only exclude patients with a high likelihood 
of dialysis within 4h
-
Exclusion criterion 8 changed to enable sites to enrol selected patients treated with 
insulin and glucose 
-
Changes in the CSP body to match above-mentioned changes in eligibility criteria
-
Changes in statistical considerations to reflect changes in eligibility criteria
-
IP preparation instruction changed – required volume of water is 45 mL (Table 4)
-
Concomitant medication requirements updated (list of pH-dependent bioavailability 
drugs in Table 6)
-
Minor changes in procedure descriptions to eliminate ambiguity
-
Typographical errors corrected
-
Statistical considerations (section 9) updated – statistical hypotheses, sample size 
determination and efficacy analyses revised
-
Synopsis statistical methods updated to align with the revised section 9
Version 1.0 dated 29 Sep 2017
Initial creation
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures.  The Clinical Study Protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.


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TABLE OF CONTENTS
TITLE PAGE.......................................................................................................................1
VERSION HISTORY ..........................................................................................................2
TABLE OF CONTENTS.....................................................................................................3
1.
PROTOCOL SUMMARY ...................................................................................6
1.1
Schedule of Activities (SoA)................................................................................6
1.2
Schema ..............................................................................................................12
2.
INTRODUCTION .............................................................................................13
2.1
Study rationale ...................................................................................................13
2.2
Benefit/risk assessment ......................................................................................14
3.
OBJECTIVES AND ENDPOINTS ....................................................................15
4.
STUDY DESIGN...............................................................................................17
4.1
Overall design....................................................................................................17
4.2
Scientific rationale for study design....................................................................17
4.3
Justification for doses.........................................................................................18
4.4
End of study definition.......................................................................................18
5.
STUDY POPULATION.....................................................................................18
5.1
Inclusion criteria ................................................................................................19
5.2
Exclusion criteria ...............................................................................................19
5.3
Lifestyle restrictions...........................................................................................21
5.4
Screen failures....................................................................................................21
6.
STUDY TREATMENTS ...................................................................................21
6.1
Treatments administered ....................................................................................22
6.2
Preparation/handling/storage/accountability .......................................................22
6.3
Measures to minimise bias: randomisation and blinding .....................................23
6.4
Treatment compliance ........................................................................................23
6.5
Concomitant therapy..........................................................................................24
6.5.1
Background medication......................................................................................24
6.5.2
Other concomitant treatment ..............................................................................25
6.5.3
Additional treatment for hyperkalaemia..............................................................25
6.5.4
Oral medications with gastric pH-dependent bioavailability ...............................26
6.6
Dose modification..............................................................................................27
6.7
Treatment after the end of Visit 1.......................................................................27


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7.
DISCONTINUATION OF TREATMENT AND SUBJECT WITHDRAWAL...27
7.1
Discontinuation of study treatment.....................................................................27
7.1.1
Procedures for discontinuation of study treatment ..............................................28
7.2
Lost to follow-up................................................................................................29
7.3
Withdrawal from the study.................................................................................29
8.
STUDY ASSESSMENTS AND PROCEDURES...............................................29
8.1
Efficacy assessments..........................................................................................30
8.1.1
Potassium Assessments ......................................................................................30
8.2
Safety assessments .............................................................................................31
8.2.1
Clinical safety laboratory assessments................................................................31
8.2.2
Glucose assessments ..........................................................................................32
8.2.3
Physical examinations ........................................................................................32
8.2.4
Vital signs, height and weight.............................................................................32
8.2.5
Electrocardiograms ............................................................................................33
8.2.6
Other safety assessments ....................................................................................33
8.3
Collection of adverse events...............................................................................33
8.3.1
Method of detecting AEs and SAEs....................................................................33
8.3.2
Time period and frequency for collecting AE and SAE information ...................33
8.3.3
Follow-up of AEs and SAEs...............................................................................34
8.3.4
Adverse event data collection.............................................................................34
8.3.5
Causality collection............................................................................................35
8.3.6
Adverse events based on signs and symptoms ....................................................35
8.3.7
Adverse events based on examinations and tests.................................................35
8.3.8
Hy’s law.............................................................................................................36
8.4
Safety reporting and medical management .........................................................36
8.4.1
Reporting of serious adverse events....................................................................36
8.4.2
Pregnancy ..........................................................................................................36
8.4.3
Overdose............................................................................................................37
8.4.4
Medication error.................................................................................................37
8.5
Pharmacokinetics ...............................................................................................38
8.6
Pharmacodynamics ............................................................................................38
8.7
Genetics .............................................................................................................38
8.8
Biomarkers.........................................................................................................38
8.9
Medical Resource Utilization and Health Economics .........................................38
8.10
Demography and medical history.......................................................................38
9.
STATISTICAL CONSIDERATIONS................................................................38
9.1
Sample size determination..................................................................................38
9.2
Populations for analyses.....................................................................................38
9.3
Statistical analyses .............................................................................................39


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9.3.1
Efficacy analyses................................................................................................39
9.3.2
Safety analyses...................................................................................................40
9.3.3
Other analyses....................................................................................................40
9.3.4
Methods for multiplicity control.........................................................................40
9.4
Interim analyses .................................................................................................40
9.4.1
Data monitoring committee (DMC)....................................................................41
10.
REFERENCES ..................................................................................................42
11.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS .........................................................................................43
LIST OF TABLES
Table 1
Study Assessments..................................................................................7
Table 2
Objectives and Endpoints ........................................................................9
Table 3
Study objectives ....................................................................................15
Table 4 
Investigational products.........................................................................22
Table 5
Restricted medications ..........................................................................24
Table 6
Drugs with pH-dependent absorption ....................................................27
Table 7
Laboratory safety variables....................................................................32
LIST OF FIGURES
Figure 1
Study design..........................................................................................12
LIST OF APPENDICES
Appendix A
Regulatory, ethical and study oversight considerations ..........................43
Appendix B
Adverse event definitions and additional safety information..................47
Appendix C
Handling of Human Biological Samples................................................51
Appendix D
Actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s Law .........................................................................53
Appendix E
Abbreviations........................................................................................58


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1.
PROTOCOL SUMMARY
1.1
Schedule of Activities (SoA)


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Table 1
Study Assessments
Visit
1
2
Details in CSP section or Appendix
Day
1
8c
Assessment/Task
Screening
0ha
1h +/-
15 
min
2h +/-
15 min
4h +/-
15 min
6h +/-
15 min
8hb +/-
30 min
10hb +/-  
30 min
12hb +/-  
30 min
24hb +/-  
2h 
(EOT)
+/-  2 
days
Informed consent 
Xd
Appendix A, Section A 3
Inclusion /exclusion 
criteria
X
Section 5.1 and 5.2
Clinical procedures
Demography
X
Section 8.10
Physical examination
X
X
Section 8.2.3
Medical history and 
comorbid conditions
X
Section 8.10
Vital signs
X
X
X
X
Section 8.2.4
Heighte
Xe
Section 8.2.4
Weight
X
Section 8.2.4
Concomitant medication
X
X
X
X
X
X
X
X
X
X
X
Section 6.5
Safety measurements
Adverse events
X
X
X
X
X
X
X
X
X
X
X
Section 8.3
ECG 
X
X
X
Section 8.2.5
Pregnancy test (serum or 
urine)
X
Section 5.1
Safety laboratory 
assessments (clinical 
chemistry, haematology)
X
X
Section 8.2.1
Efficacy measurements


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Potassium and glucose by 
i-STAT and Central lab
X
X
X
X
X
X
X
X
X
X
Study treatment administration
Randomisation
X
Section 6.3
Study treatment 
administered
Xa
X
X
Section 6.1
Administration of insulin 
and glucose
Xa
Section 6.5.1
a)
Time 0h is defined as the time at which ZS/placebo is first administered. For patients consented before insulin administration, insulin and glucose should be 
administered as soon as logistically possible after the start of screening. For all patients, ZS/placebo should be administered as close in time to the administration of 
insulin and glucose as logistically possible, but not more than 30 min after.  Once patients are randomized, ZS/placebo must be administered even if outside of the 30 
minutes time window.
b)
If medically appropriate patients may leave the study site between the 12h and 24h assessments, as long as they return for the 24h assessment. Patients treated with 
dialysis during Visit 1 should have the 24h / EoT assessment performed before initiation of dialysis, and will not undergo any further assessments during Visit 1.
Patients unwilling to participate in all assessments should have the 24h / End of Treatment assessment performed before leaving the site.
c)
The Day 8 Visit can be performed as a phone call.
d)
Informed consent can be signed after administration of insulin (see Exclusion 8 and Section 6.5.1 for details), but must always be signed before any study specific 
procedures that are not part of standard care.
e)
Height can be assessed at any time during Visit 1, and only needs to be assessed once.


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Synopsis
International co-ordinating investigator
 
Protocol Title: 
A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate a 
Potassium Normalization Treatment Regimen Including Sodium Zirconium Cyclosilicate 
(ENERGIZE)
Rationale: 
Elevated serum potassium (S-K) is potentially life threatening, and is frequently seen in 
emergency departments. Insulin and glucose is the standard of care among patients with 
S-K ≥6.0 due to a rapid onset of action. As insulin is a temporizing agent with a short duration of 
effect, additional clinical benefits may be achieved when ZS is added to insulin and glucose. 
ZS rapidly binds and eventually displaces potassium from the body, while insulin merely shifts 
S-K to the intracellular space. The purpose of this phase 2 study is to compare the effect of 
ZS 10g administered up to three times over 10 hours versus placebo added to insulin and glucose 
in the emergency department setting.
Table 2
Objectives and Endpoints
Primary objective:
Endpoint/variable:
To assess the effect of ZS vs placebo when 
added to insulin and glucose on the reduction of 
potassium at 4 hours after start of dosing
Mean absolute change in S-K from baseline until 
4h after start of dosing with ZS/placebo
Secondary objectives:
Endpoint/variable:
To assess the effect of ZS vs placebo when 
added to insulin and glucose on the response to 
therapy
Fraction of patients responding to therapy with 
responders to therapy defined as
•
S-K <6.0mmol/L between 1 and 4h and 
S-K <5.0mmol/L at 4h
AND
•
No additional therapy administered for 
hyperkalaemia from 0 to 4h with exception of 
the initial insulin treatment administered
To assess the effect of ZS vs placebo when 
added to insulin and glucose on the change in 
serum potassium at 1h and 2h after start of 
dosing
Mean absolute change in S-K from baseline to 1 
and 2h after start of dosing with ZS/placebo
Redacted


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To assess the effect of ZS vs placebo when 
added to insulin and glucose on achieving 
normokalaemia
The fraction of patients achieving 
normokalaemia 1, 2 and 4h after start of dosing 
with ZS/placebo
To assess the effect of ZS vs placebo when 
added to insulin and glucose on achieving S-K 
<5.5mmol/l and <6.0mmol/l
The fraction of patients achieving S-K 
<5.5mmol/l and <6.0mmol/l 1, 2, and 4h after 
start of dosing with ZS/placebo
To assess the need for additional therapies for 
hyperkalaemia between ZS and placebo when 
added to insulin and glucose
The fraction of patients administered additional 
potassium lowering therapy due to 
hyperkalaemia from 0 to 4h. The considered 
therapies are:
•
2nd dose of insulin
•
Beta-agonists
•
Diuretics
•
Dialysis
•
Sodium bicarbonate
•
Potassium binders
Safety objective:
Endpoint/variable:
To characterize the safety of ZS when added to 
insulin and glucose
Adverse events (AEs) and serious AEs (SAEs)
Changes in vital signs (VS), physical 
examinations, and ECGs
Changes in clinical laboratory parameters, 
including assessment of hypokalaemia using 
S-K measurements and of hypoglycaemia using 
P-glucose measurements
Exploratory objectives:
Endpoint/variable:
To assess the effect of ZS vs placebo when 
added to insulin and glucose on the change in S-
K over time
Mean absolute change in S-K from baseline to 6, 
8, 10, 12, and 24h after start of dosing with 
ZS/placebo
To assess the effect of ZS vs. placebo when 
added to insulin and glucose on achieving 
normokalaemia
The fraction of patients achieving 
normokalaemia 6, 8, 10, 12 and 24h after start of 
dosing with ZS/placebo
To assess the effect of ZS vs. placebo when 
added to insulin and glucose on achieving S-K 
<5.0mmol/l, <5.5mmol/l and <6.0mmol/l
The fraction of patients achieving S-K <5.0 
mmol/L; <5.5mmol/l and <6.0mmol/l 6, 8, 10, 
12 and 24h after start of dosing with ZS/placebo


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To assess the need for additional therapies due to 
hyperkalaemia between ZS and placebo when 
added to insulin and glucose
The fraction of patients administered additional 
potassium lowering therapy due to 
hyperkalaemia from 4 to 24h. The considered 
therapies are:
•
2nd dose of insulin
•
Beta-agonists
•
Diuretics
•
Dialysis
•
Sodium bicarbonate
•
Potassium binders
To assess the time and disposition of patients 
when leaving the treating department between 
ZS and placebo when added to insulin and 
glucose
Time from randomization until leaving the 
treating department, and disposition after leaving 
the treating department
To compare the effect between ZS and placebo 
when added to insulin and glucose on duration 
of hospitalization
Time from randomization until discharge
Overall design:
The study is designed to determine if ZS 10g administered up to three times over 10h added to 
insulin and glucose in patients presenting with hyperkalaemia will prove tolerable and 
efficacious by performing a multicentre, international, randomized, double-blind, placebo-
controlled, prospective, parallel-group study.
Study Period:
Estimated date of first patient enrolled Q4 2017. 
Estimated date of last patient completed Q4 2018.
Number of Subjects: approximately 132.
Treatments and treatment duration: All patients will be treated with insulin and glucose. In 
addition, each patient will be treated with ZS or placebo for up to 10 hours.
Statistical methods
The study will employ a 1:1 randomization scheme. Based on ZS-004 and patients treated with 
medications only in ZS-007, the standard deviation for S-K change from baseline at 4 hours is 
assumed to be 0.7 mmol/L. With 66 patients per group a two-sided 95% confidence interval for 
the mean difference in S-K change will extend 0.239 mmol/L from the observed difference in 
means.


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1.2
Schema
The general study design is summarised in Figure 1.
Figure 1
Study design
Day/Hour 
1                                  1/0h                                                                                                                         8
Screening
R 
1:1
ZS at 0h, 4h, 
10h
placebo at 0h, 4h, 
10h
EoT
Insulin+glucose
F-U
Day/Hour 
1                                  1/0h                                                                                                                          8
Screening
R 
1:1
ZS at 0h, 4h, 
10h
placebo at 0h, 4h, 
10h
EoT
Insulin+glucose
F-U
OR (if patient is enrolled before insulin):


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2.
INTRODUCTION
2.1
Study rationale
This study is a first step in the development of ZS as a treatment to manage hyperkalaemia in the 
emergency department setting, where achievement of normokalaemia in a relatively short period 
is of particular importance. Insulin and glucose is the standard of care among patients with 
S-K ≥6.0 due to a rapid onset of action. As insulin is a temporizing agent with a short duration of 
effect additional clinical benefits may be achieved when ZS is added to insulin and glucose. ZS 
rapidly binds and eventually displaces potassium from the body, while insulin merely shifts S-K 
to the intracellular space. The purpose of this phase 2 study is to compare the effect of ZS 10 g 
administered up to three times over 10h versus placebo added to insulin and glucose.
Hyperkalaemia is defined as an abnormally high serum potassium (S-K) concentration, usually 
greater than 5.0 mmol/L.  The prevalence has been reported to 3-4% in hospitalized patients, and 
the risk is considerably increased in persons with advanced chronic kidney disease, heart failure, 
diabetes and/or treatment with renin angiotensin-aldosterone inhibitors (Einhorn et al 2009, Fleet 
et al 2012, Kovesdy 2015).  Hyperkalaemia often presents without symptoms or with non-
specific symptoms including malaise, confusion, muscle weakness or signs of cardiac 
arrhythmias (Henneman 2016).  The risk of fatal cardiac arrhythmias is increased especially at 
S-K levels above 6.0 mmol/L, and the mortality risk is increased even with mild elevations of 
S-K (S-K > 5.0 mmol/L), but a causal relationship remains to be established (Einhorn 2009, 
Collins 2014, Nakhoul 2015).
Current management of hyperkalaemia with S-K above 6.0 mmol/L at the emergency department 
has not been well studied previously (Rossignol 2016), but frequently includes administration of 
insulin and glucose to shift extracellular potassium to the intracellular space. The effect is rapid 
and substantial, but only lasts for 4 to 6 hours, and therefore further therapies are required, e.g. 
hemodialysis or potassium binding drugs. The use of insulin and glucose as the mainstay of 
therapy is recommended by clinical guidelines such as the American Heart Association 
guidelines from 2005, and in recent literature (Rossignol 2016, Kovesty 2015, Li and Vijayan 
2014).
Sodium zirconium cyclosilicate (ZS) is a non-absorbed, inorganic crystalline compound that 
selectively captures potassium ions in exchange for sodium and hydrogen ions in the 
gastrointestinal tract after oral administration. Thereby, potassium is removed from the blood 
stream, decreasing the serum potassium concentration and then removing the potassium from the 
body through faecal excretion. A global clinical programme including more than 1800 patients 
with hyperkalaemia demonstrated the efficacy of ZS compared with placebo for correction 
of hyperkalaemia, with 88% of patients reaching normal S-K after 48 hours of treatment with 
ZS 10 g three times a day (TID). A detailed description of the chemistry, pharmacology, 
efficacy, and safety of ZS are given in the Investigators’ Brochure.
The onset of action of ZS is slower than for insulin and glucose, but statistically significant 
lowering of S-K has been demonstrated at 1 hour. The efficacy of ZS, measured as change in 
S-K, appears to increase with higher baseline S-K. Combining insulin and glucose with ZS may 


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therefore provide enhanced short term as well as longer term lowering of S-K in the emergency 
department setting.
2.2
Benefit/risk assessment
Hyperkalaemia with S-K≥6.0 mmol/L is a potentially life-threatening condition. The primary 
potential benefit for patients randomized to ZS, insulin and glucose is a more pronounced and 
prolonged decrease of S-K compared with patients randomized to placebo, insulin and glucose. 
For patients with hyperkalaemia requiring emergency therapy this may significantly decrease the 
need for additional treatment for hyperkalaemia (including but not limited to additional insulin 
and glucose, beta-agonists, or potassium binding resins).
All randomized patients will receive standard of care treatment for hyperkalaemia and may 
benefit from close medical monitoring. Additional therapies will be administered whenever 
clinically warranted.
Patients with S-K ≥6.0 mmol/L may require rapid therapy to minimize the risk of arrhythmias. 
The study is therefore designed to allow rapid assessment, randomization and standard of care 
treatment of patients to minimize arrhythmia risk. Furthermore, intravenous calcium may be 
administered at the discretion of the treating physician to minimize the risk of dangerous 
arrhythmias.
Insulin and glucose therapy has been reported to be associated with a significant rate of 
hypoglycaemia. The weight based dosing of insulin together with the monitoring schedule was 
selected in order to minimize the risk of hypoglycaemia, and to detect and correct any 
hypoglycaemia if it were to occur.
Hypokalaemia has been reported at a low rate in prior studies with ZS. In this study, subjects will 
receive also insulin and glucose, which could increase the risk of hypokalaemia. However this 
study recruits patients with higher S-K (≥5.8 mmol/L) compared with earlier ZS studies 
(generally >5.0mmol/L), which decreases the risk of hypokalaemia. Furthermore, the peak effect 
of insulin and glucose is expected to wear off after 4-6 hours, by which time the effect of ZS is 
still limited to a fraction of the full ZS effect. Hence, the risk for hypokalaemia is limited.
Detailed information about the known and expected benefits and risks and reasonably expected 
adverse events of ZS may be found in the ZS Investigator’s Brochure.
The management of hyperkalaemia is poorly researched with few prospective randomized trials 
performed previously (Rossignol et al 2016). ZS may represent a helpful addition to insulin and 
glucose to manage emergent hyperkalaemia. This study therefore has potential to improve the 
scientific basis for the clinical management of hyperkalaemia irrespective of outcome by 
properly documenting the effects of the insulin and glucose regimen used, and to improve the 
clinical management of hyperkalaemia if successful. Hence, the limited risk the recruited patients 
will be exposed to is deemed acceptable considering the expected benefits of performing the 
trial.


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3.
OBJECTIVES AND ENDPOINTS
Table 3
Study objectives
Primary objective:
Endpoint/variable:
To assess the effect of ZS vs placebo when 
added to insulin and glucose on the reduction of 
potassium at 4 hours after start of dosing
Mean absolute change in S-K from baseline until 
4h after start of dosing with ZS/placebo
Secondary objectives:
Endpoint/variable:
To assess the effect of ZS vs placebo when 
added to insulin and glucose on the response to 
therapy
Fraction of patients responding to therapy with 
responders to therapy defined as
•
S-K <6.0mmol/L between 1 and 4h and 
S-K <5.0mmol/L at 4h
AND
•
No additional therapy administered for 
hyperkalaemia from 0 to 4h with exception of 
the initial insulin treatment administered
To assess the effect of ZS vs placebo when 
added to insulin and glucose on the change in 
serum potassium at 1h and 2h after start of 
dosing
Mean absolute change in S-K from baseline to 
1h and 2h after start of dosing with ZS/placebo
To assess the effect of ZS vs placebo when 
added to insulin and glucose on achieving
normokalaemia
The fraction of patients achieving 
normokalaemia 1, 2 and 4h after start of dosing 
with ZS/placebo
To assess the effect of ZS vs placebo when 
added to insulin and glucose on achieving S-K 
<5.5mmol/l and <6.0mmol/l
The fraction of patients achieving S-K 
<5.5mmol/l and <6.0mmol/l 1, 2, and 4h after 
start of dosing with ZS/placebo
To assess the need for additional therapies for 
hyperkalaemia between ZS and placebo when 
added to insulin and glucose
The fraction of patients administered additional 
potassium lowering therapy due to 
hyperkalaemia from 0 to 4h. The considered 
therapies are:
•
2nd dose of insulin
•
Beta-agonists
•
Diuretics
•
Dialysis
•
Sodium bicarbonate
•
Potassium binders


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Safety objective:
Endpoint/variable:
To characterize the safety of ZS when added to 
insulin and glucose
Adverse events (AEs) and serious AEs (SAEs)
Changes in vital signs (VS), physical 
examinations, and ECGs
Changes in clinical laboratory parameters, 
including assessment of hypokalaemia using S-
K measurements and of hypoglycaemia using P-
glucose measurements
Exploratory objectives:
Endpoint/variable:
To assess the effect of ZS vs placebo when 
added to insulin and glucose on the change in S-
K over time
Mean absolute change in S-K from baseline to 6, 
8, 10, 12, and 24h after start of dosing with 
ZS/placebo
To assess the effect between ZS and placebo 
when added to insulin and glucose on achieving 
normokalaemia
The fraction of patients achieving 
normokalaemia 6, 8, 10, 12 and 24h after start of 
dosing with ZS/placebo
To compare the effect between ZS and placebo 
when added to insulin and glucose on achieving 
S-K <5.0mmol/l, <5.5mmol/l and <6.0mmol/l
The fraction of patients achieving S-K <5.0 
mmol/L, <5.5mmol/l and <6.0mmol/l 6, 8, 10, 
12 and 24h after start of dosing with ZS/placebo
To assess the need for additional therapies due to 
hyperkalaemia between ZS and placebo when 
added to insulin and glucose
The fraction of patients administered additional 
potassium lowering therapy due to 
hyperkalaemia from 4 to 24h. The considered 
therapies are:
•
2nd dose of insulin
•
Beta-agonists
•
Diuretics
•
Dialysis
•
Sodium bicarbonate
•
Potassium binders
To assess the time and disposition of patients 
when leaving the treating department between 
ZS and placebo when added to insulin and 
glucose
Time from randomization until leaving the 
treating department, and disposition after leaving 
the treating department
To compare the effect between ZS and placebo 
when added to insulin and glucose on duration 
of hospitalization
Time from randomization until discharge


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4.
STUDY DESIGN
4.1
Overall design
The study is designed to determine if ZS 10g administered up to three times over 10h added to 
insulin and glucose in patients presenting with hyperkalaemia will prove tolerable and 
efficacious by performing a multicentre, international, randomized, double-blind, placebo-
controlled, prospective, parallel-group study. 
The study will recruit patients with S-K ≥5.8 mmol/L. Eligible patients fulfilling all of the 
inclusion criteria and none of the exclusion criteria will be randomised in a 1:1 ratio to ZS or 
placebo.
The study includes a single treatment visit no longer than 24h followed by a single follow up 
contact 7 days later. 
For a graphical overview of the study design see Figure 1, Section 1.2. 
4.2
Scientific rationale for study design
A prospective, randomized, double-blind, placebo-controlled, prospective, parallel arm design 
remains the gold standard to minimize potential biases. The use of multiple study sites increases 
the chances of recruiting a broad and representative patient population.
The inclusion and exclusion criteria were set to be as broad as possible without jeopardizing the 
safety of recruited subjects, and ensuring only patients for which insulin and glucose is the 
currently best standard of care therapy would be recruited. 
Insulin and glucose were chosen as background therapy based on guidelines (eg. the American 
Heart Association guidelines from 2005) and current practice in most US and European 
emergency departments.
The study design (adding ZS or placebo to insulin and glucose) is consistent with recent 
publications describing the acute treatment of hyperkalaemia in the emergency department 
(Rossignol et al 2016).
The primary endpoint (S-K at 4h) was selected as lowering S-K is of paramount interest in 
hyperkalaemic patients, and as the vast majority of patients receiving placebo on top of insulin 
and glucose is not expected to require additional therapy to maintain S-K in an acceptable range 
for the first 4 hours following the initial therapy. A key concern is the risk that any benefit in 
terms of S-K of ZS is erased if the control arm were to be administered significantly more 
additional therapies to manage hyperkalaemia. Sites will therefore be instructed to minimize the 
additional hyperkalaemia therapies for the first 4h without sacrificing patient safety.
Additional therapies are increasingly more likely to be administered to the control arm at time-
points beyond 4h, and any imbalance in the administration of additional therapies would be 
expected to increase beyond 4h, as the ZS effect is expected to become more pronounced over 
time. Hence, all measurements beyond the 4h time-point may be biased and are considered 


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exploratory in nature. Furthermore, not all data beyond the 4h time-point is likely to be collected, 
as subjects are increasingly likely to receive dialysis therapy or leave the emergency department 
over time.
4.3
Justification for doses
All randomized patients will be treated with insulin and glucose. The insulin and glucose therapy 
administered in the trial will consist of 0.1 units/kg of insulin administered IV as a bolus or for 
up to 30 minutes together with 25g of glucose administered just before (<15 minutes) the insulin. 
Glucose will be withheld for patients with plasma glucose > 400mg/dl. Additional glucose may 
be administered at the discretion of the treating physician, and as medically appropriate.
The insulin and glucose treatment regimen is based on the American Heart Association (AHA) 
guidelines from 2005 and the UK Renal Association guidelines from 2014, but with 
modifications based on more recently published treatment protocols. In particular the use of 
0.1 units/kg of insulin rather than administering 10 units to all patients is intended to minimize 
the risk of hypoglycaemia and to minimize variability in post treatment S-K measurements (Li 
and Vijayan 2014), thereby improving patient safety and the precision of S-K based endpoints in 
the trial.
The dose of ZS used in the study (10g administered at 0, 4 and 10h) is based on the results of 
prior dose-finding studies, and has been used in the Correction Phase of all phase III studies 
performed with ZS to date. ZS 10g three times per day (TID) is the expected dose to be 
recommended for the Correction Phase once ZS is approved by healthcare authorities globally. 
See the ZS Investigator’s Brochure for details on the dose of ZS explored in all prior studies and 
the associated safety and efficacy results.
4.4
End of study definition
The end of study is defined as the last expected visit or telephone contact of the last subject 
undergoing the study.
A subject is considered to have completed the study when he/she has completed Visit 2.
5.
STUDY POPULATION
The target study subject population consists of patients with S-K ≥5.8 mmol/L for whom 
treatment with insulin and glucose to manage hyperkalaemia has been determined medically 
appropriate by the Investigator.
Each subject should meet all of the inclusion criteria and none of the exclusion criteria for this 
study in order to be randomised to a study intervention. Under no circumstances can there be 
exceptions to this rule. Subjects who do not meet the entry requirements are screen failures, refer 
to section 5.4.


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In this protocol, “enrolled” subjects are defined as those who sign informed consent.  
“Randomized” subjects are defined as those who undergo randomization and receive a 
randomization number.
For procedures for withdrawal of subjects see Section 7.3.
5.1
Inclusion criteria
Subjects are eligible to be included in the study only if all of the following inclusion criteria and 
none of the exclusion criteria apply:
Informed consent
1.
Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this 
protocol.
2.
Provision of signed and dated, written informed consent form prior to any mandatory 
study specific procedures, sampling, and analyses. 
The ICF process is described in Appendix A 3
Age
3.
≥ 18 years of age at the time of signing the informed consent form.
Type of subject and disease characteristics
4.
S-K ≥5.8 mmol/L, as determined using an i-STAT device. Patients with S-K 5.8 or 5.9 
mmol/L can be included only if treatment of the patient with insulin and glucose is in 
accordance with the local standard of care. S-K measured by a local laboratory prior to 
insulin administration may replace S-K measured by i-STAT for assessment against 
this inclusion criterion for patients having received insulin before signing the informed 
consent form.
5.
Ability to have repeated blood draws or effective venous catheterization.
5.2
Exclusion criteria 
Medical conditions
1.
Possible pseudohyperkalaemia as assessed by the investigator, e.g. secondary to 
hemolyzed blood specimen. See section 7.1.1 for details on how to handle suspected 
hemolyzed samples.
2.
Hyperkalaemia caused by any condition for which a therapy directed against the 
underlying cause of hyperkalaemia would be a better treatment option than treatment 
with insulin and glucose. This includes, but is not limited to, hyperkalaemia 
reasonably likely to be caused by physical injury, intoxication, pre-renal kidney 
failure, substance abuse, diabetic ketoacidosis, and rhabdomyolysis.


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3.
Life-threatening cardiac arrhythmias requiring immediate treatment before an 
informed consent can be collected.
4.
Any condition representing a contra-indication to treatment with the rapid acting 
insulin to be used, e.g. allergy to any of the constituents of the insulin product to be 
used, or hypoglycaemia at study entry.
5.
Presence of any other acute or chronic medical condition which, in the opinion of the 
investigator, places the patient at undue risk due to the severity of illness or potentially 
jeopardizes patients’ ability to follow study procedures due to required interventions, 
investigations or procedure in the acute setting. Patients having any acute or chronic 
medical condition other than hyperkalaemia that would alone require immediate 
treatment in the hospital setting at Visit 1 are not eligible for the study
6.
Dialysis session expected within 4h after randomization.
Prior/concomitant therapy
7.
Treated with sodium polystyrene sulfonate (SPS, Kayexalate, Resonium), calcium 
polystyrene sulfonate (CPS, Resonium calcium) or patiromer (Veltassa) within the 
past 24h.
8.
Treated with any therapy intended to lower S-K between arriving at the hospital and 
randomization during Visit 1, with exception of patients meeting the following 
criteria:
•
Treated with no more than one course of insulin since arriving at the hospital
•
S-K measured by i-STAT device or local laboratory prior to administration of insulin. 
S-K must have met Inclusion criterion 4.
•
Reasonably likely to randomize, have screening and 0h assessments done, and dose the 
patient with ZS/placebo within 30 minutes of the start of administration of insulin.
Prior/concurrent clinical study experience
9.
Known hypersensitivity or previous anaphylaxis to ZS or to components thereof.
Reproduction
10.
Known pregnancy or actively attempting to become pregnant. A pregnancy test (urine 
or serum, analysed by a local laboratory) will be collected during screening for female 
subjects of childbearing potential, but randomization can take place before the result is 
available. If the pregnancy test is positive the patient will discontinue therapy (see 
sections 7.1and 8.4.2). 


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Other exclusions
11.
Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site).
12.
Judgment by the investigator that the subject should not participate in the study as the 
subject is unlikely to comply with study procedures, restrictions or requirements.
13.
Previous randomisation in the present study.
5.3
Lifestyle restrictions
Not applicable.
5.4
Screen failures
Screen failures are defined as subjects who signed the informed consent form to participate in the 
clinical study but are not subsequently randomly assigned to Study treatment. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure subjects to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and 
to respond to queries from regulatory authorities. Minimal information includes the reason for 
failing screening, demography, eligibility criteria, and any SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. Rescreened subjects should be assigned the same subject number as for the initial 
screening. However, rescreening should be documented so that its effect on study results, if any, 
can be assessed. During rescreening all assessments are to be performed again.
6.
STUDY TREATMENTS
Study treatment is defined as any investigational product(s) (including marketed product 
comparator and placebo) or medical device(s) intended to be administered to a study participant 
according to the study protocol. Study treatment in this study refers to Sodium Zirconium 
Cyclosilicate (ZS), placebo, insulin and glucose. Investigational Products (IPs) in this study 
refers to ZS and placebo. Insulin and glucose are considered background therapy, and thus are 
non-IPs (NIPs).


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6.1
Treatments administered
Table 4 
Investigational products
Study Treatments
Treatment 1
Treatment 2
Study treatment name:
Sodium Zirconium Cyclosilicate 
(ZS) 5g
Placebo
Dosage formulation:
Powder for oral suspension in a 
sachet
Powder for oral suspension in a 
sachet
Route of administration:
Oral use
Oral use
Dosing instructions:
  
Single dose contains two sachets 
that should be suspended in 
45 mL of water by patient.
Single dose contains two sachets 
that should be suspended in 
45 mL of water by patient.
Packaging and labelling:
  
Study treatment will be provided 
in sachets packed in a box. Each 
sachet and box will be labelled in 
accordance with Good 
Manufacturing Practice (GMP) 
Annex 13 and per country 
regulatory requirement.
Study treatment will be provided 
in sachets packed in a box. Each 
sachet and box will be labelled in 
accordance with Good 
Manufacturing Practice (GMP) 
Annex 13 and per country 
regulatory requirement.
Provider:
AstraZeneca
AstraZeneca
6.2
Preparation/handling/storage/accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported and 
resolved before use of the study treatment.
Only subjects enrolled in the study may receive study treatment and only authorised site staff 
may supply or administer study treatment.  All study treatments must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labelled storage conditions with access limited to the investigator and authorised site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (i.e., 
receipt, reconciliation, and final disposition records).
The randomized treatment phase will have a double-blind design. Patients will take by mouth 
assigned dose from the sachet(s) containing either ZS or placebo. Individual sachets are enclosed 


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in a carton with a tamper evident seal intended to be broken exclusively by patients just before 
taking the study drug.
Further guidance and information for the final disposition of unused study treatment will depend 
on local regulations in a given study country.
6.3
Measures to minimise bias: randomisation and blinding
All subjects will be centrally assigned to randomised study treatment using an interactive 
voice/web response system (IVRS/IWRS). Before the study is initiated, the telephone number 
and call-in directions for the IVRS and/or the log-in information and directions for the IWRS 
will be provided to each site. Randomization will be stratified by country.
If a subject withdraws from the study, then his/her enrolment/randomisation code cannot be 
reused. Withdrawn subjects will not be replaced. 
The IVRS/IWRS will provide to the Investigator(s) or pharmacists the kit identification number 
to be allocated to the patient at the dispensing visit.
Routines for this will be described in the IVRS/IWRS user manual that will be provided to each 
centre.
AstraZeneca retains the right to break the code for SAEs that are unexpected and are suspected to 
be causally related to an investigational product and that potentially require expedited reporting 
to regulatory authorities.
The IVRS/IWRS will be programmed with blind-breaking instructions. The blind may be broken 
if, in the opinion of the investigator, it is in the subject’s best interest for the investigator to know 
the study treatment assignment. The sponsor must be notified before the blind is broken unless 
identification of the study treatment is required for a medical emergency in which the knowledge 
of the specific blinded study treatment will affect the immediate management of the subject’s 
condition. In this case, the sponsor must be notified within 24 hours after breaking the blind. The 
date and reason that the blind was broken must be recorded in the source documentation and 
eCRF, as applicable.
Study unblinding should not occur until database lock and all decisions on the evaluability of the 
data from each individual subject have been made and documented.
6.4
Treatment compliance
Any change from the dosing schedule, such as dose discontinuations, should be recorded in
patient’s medical notes and eCRF.
The Investigator or designee is responsible for managing the IP from receipt by the study site 
until the destruction or return of all unused IP.


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6.5
Concomitant therapy
Any medication or vaccine including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements that the subject is receiving at the time of enrolment or receives 
during the study must be recorded along with:
•
Reason for use
•
Dates of administration including start and end dates
•
Dosage information including dose and frequency
Table 5
Restricted medications
Medication/class of drug:
Usage (including limits for duration permitted and 
special situations in which it’s allowed ):
Potassium lowering drugs (e.g. potassium 
binders, beta agonists)
See section 6.5.3
Potassium substitution (e.g. KCl)
All treatments for hypokalaemia to be withheld from 
enrolment to Visit 1 discharge
Antidiabetics
See section 6.5.2
Drugs with pH dependent absorption (see 
section 6.5.4 for details)
Drugs with pH-dependent absorption should be 
administered at least 2 hours before or 2 hours after 
ZS to mitigate the risk of drug interactions.
6.5.1
Background medication
All randomized patients will be treated with insulin and glucose. The insulin and glucose therapy 
administered in the trial will consist of 0.1 units/kg of insulin administered IV as a bolus or for 
up to 30 minutes together with 25g of glucose administered just before (<15 minutes) the insulin.
At the discretion of the treating physician additional glucose may be administered, e.g. as a slow 
infusion, if medically appropriate.
Glucose will be withheld for patients with plasma glucose > 400mg/dl or if any contraindication 
for treatment with glucose exists in the opinion of the investigator.
Insulin and glucose are NIPs, and will not be provided by AstraZeneca. The brand of insulin to 
be used is up to each study site, but the insulin brand used must belong to the “rapid acting” class 
of insulins including among others insulin lispro, insulin aspart and insulin glulisine.
The brand of glucose to be used and how to prepare it for administration is determined by each 
study site.


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Both insulin and glucose can be administered as a bolus or as a rapid infusion, as long as glucose 
administration is completed within 15 minutes before the insulin therapy is started, and as long 
as the administration of both insulin and glucose takes no longer than 30 minutes.
For patients consented before insulin administration, insulin and glucose should be administered 
as soon as logistically possible after the start of screening. For all patients, ZS/placebo should be 
administered as close in time to the administration of insulin and glucose as logistically possible, 
but not more than 30 min after.  Once patients are randomized, ZS/placebo must be administered 
even if outside of the 30 minutes time window.
Each site must complete a worksheet detailing their procedure for administering insulin and 
glucose with regards to the brand of insulin and glucose to use, how the insulin and glucose will 
be prepared for administration, and at what speed the insulin and glucose will be administered. 
The worksheet should also describe when ZS is to be administered, which should occur as 
closely as logistically possible to when the insulin therapy is started. The completed worksheet 
must be available to site staff when subjects are randomized to minimize variations in how the 
background therapy is administered at each site.
The flexibility provided in this section is intended to allow as many sites as possible to 
administer insulin and glucose as per their current standard of care for hyperkalaemia.
6.5.2
Other concomitant treatment
Medication other than described above, but considered necessary for the subject’s safety and 
wellbeing, may be given at the discretion of the Investigator and recorded in the appropriate 
sections of the eCRF, including start and stop time.
Calcium salts may be administered (intravenously) to patients with ECG changes or as deemed 
appropriate by the treating physician.
Administration of sodium bicarbonate may be considered for patients with blood pH < 7.2 or 
critically low plasma bicarbonate.
Investigators will monitor patients with diabetes mellitus as per the local standard of care. 
Antidiabetic therapies may be administered to patients at the discretion of the treating physician. 
Concomitant medications administered to maintain metabolic control will not be considered 
additional treatment for hyperkalaemia.
6.5.3
Additional treatment for hyperkalaemia
The study site will administer additional therapies to lower potassium if required for the safety of 
the patient. Additional potassium lowering therapies will not be provided by AstraZeneca.  
Although the use of additional potassium lowering therapies is allowed, the use of such therapies 
should be delayed, if at all possible without jeopardizing the safety of the patient, until after the 
4h S-K samples have been collected for analysis of the primary endpoint in the trial.


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The date and time of additional potassium lowering therapy administration as well as the name 
and dosage regimen of the therapy must be recorded, as for any other concomitant medications.
Examples of when additional potassium lowering therapy may be administered, also before 4h 
after ZS/placebo administration, are when:
Whole blood potassium measured with i-STAT is found to be higher than at baseline at any time 
>1h after the administration of insulin
Whole blood potassium measured with i-STAT is >6.5mmol/L at any time >1h after the 
administration of insulin
ECG changes likely to be related to hyperkalaemia develop or worsen significantly.
If additional potassium lowering therapy needs to be administered the first choice should be to 
administer an additional course of insulin and glucose therapy, assuming it would be medically 
appropriate to do so.
For patients receiving routine renal replacement therapy with either hemo- or peritoneal dialysis 
the preferred additional therapy will be a dialysis session, if available. Before dialysis is initiated 
all assessments planned for the end of treatment (24h time-point in the Schedule of Assessments) 
must be performed. Following the initiation of dialysis no further study assessments or 
procedures should be performed with the exception of the Day 8 follow up.
6.5.4
Oral medications with gastric pH-dependent bioavailability
When co-administered with ZS, some oral medications with gastric pH-dependent bioavailability 
may exhibit a clinically meaningful increase or decrease in their bioavailability. Therefore, these 
drugs should be administered at least 2 hours before or 2 hours after study treatment to mitigate 
the risk of drug interactions. 


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Drugs that should be taken 2 hours before or after study treatment to avoid a possible raised 
gastric pH drug interaction are listed below:
Table 6
Drugs with pH-dependent absorption
Class of Drug
Drugs
Azole antifungals
Ketoconazole, itraconazole, posaconazole, 
voriconazole 
Anti-HIV drugs
Amprenavir, atazanavir, delaviridine, 
fosamprenavir, nelfinavir, indinavir, ritonavir, 
saquinavir, raltegravir, ledipasvir, rilpivirine
Antibiotics
Cefditoren, clarithromycin
Antiepileptics
Gabapentin. phenytoin
Bisphosphonates
Risedronic acid
Cardiac glycosides
Digoxin
Immunosupressants
Methotrexate, mycophenolate mophetil, 
mycophenolic acid, tacrolimus
Intestinal anti-inflammatory agents
Mesalazine
Iron preparations
Iron salts
Tyrosine kinase inhibitors
Erlotinib, dasatinib, nilotinib
6.6
Dose modification
Not applicable.
6.7
Treatment after the end of Visit 1
After the 24h time-point, the initiation of dialysis, or discontinuation of study assessments, 
patients should be administered standard of care therapy as needed, at the discretion of the 
Investigator.
7.
DISCONTINUATION OF TREATMENT AND SUBJECT
WITHDRAWAL 
7.1
Discontinuation of study treatment 
Subjects may be discontinued from investigational product (IP) in the following situations. 
Note that discontinuation from study treatment is NOT the same thing as a complete withdrawal 
from the study.
•
Subject decision. The subject is at any time free to discontinue treatment, without 
prejudice to further treatment


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•
Adverse Event precluding further dosing in the opinion of the investigator or sponsor
•
A subject is determined to have met one or more of the exclusion criteria or failed to 
meet all of the inclusion criteria for study participation at the time of screening
•
Severe non-compliance with the Clinical Study Protocol
•
Pregnancy (see section 8.4.2)
•
Dialysis administered (see section 6.5.3)
•
Whole blood potassium <3.5mmol/L as measured with i-STAT before the administration 
of ZS at 10h.
7.1.1
Procedures for discontinuation of study treatment
A subject who decides to discontinue study treatment will always be asked about the reason(s) 
and the presence of any AEs. The date and time of last intake of study treatment should be 
documented in the eCRF. Subjects discontinuing study treatment should be given locally 
available standard of care therapy, at the discretion of the investigator (see section 6.7).
Discontinuation of study treatment, for any reason, does not impact on the subject´s participation 
in the study. Data collection should continue according to the study protocol, with the exception 
of patients discontinuing due to dialysis (see section 6.5.3). If the subject does not agree to 
continue assessments as scheduled, a modified follow-up can be arranged to maximize the 
collection of endpoints and safety information. This could be a telephone contact with the 
subject, a contact with a relative or treating physician, or information from medical records. The 
approach taken should be recorded in the medical records. A subject who agrees to modified 
follow-up is not considered to have withdrawn consent or to have withdrawn from the study.
Any subject leaving the study site before the 24h assessment should always have the 24h / End 
of Treatment assessment performed before departing if at all possible and acceptable to the 
patient. 
Alternatively, the patient can return to the study site at 24h to have the assessments performed. It 
will not constitute a protocol deviation if a patient leaves the study site after the 12h assessment 
during Visit 1, as long as the patient returns in time to have the 24h assessment performed as per 
the protocol.
The time and date that the patient leaves the treating department (the department or ward 
administering insulin, glucose and ZS or placebo) will be recorded, as well as the disposition of 
patients from the treating department.
The first time and date that the patient is discharged (i.e. told to leave) from the hospital after 
randomization will be recorded. If the patient decides to leave the hospital before being 
discharged, the time and date that the patient leaves the hospital will be recorded.


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7.2
Lost to follow-up
A subject will be considered potentially lost to follow-up if he or she is unable to be contacted by 
the study site.  
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit:
•
The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible
•
Before a subject is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the subject or next of kin by e.g. repeat telephone 
calls, certified letter to the subject´s last known mailing address or local equivalent 
methods. These contact attempts should be documented in the subject’s medical 
record
•
Should the subject be unreachable at the end of the study the subject should be 
considered to be lost to follow up with unknown vital status at end of study.
7.3
Withdrawal from the study
A subject may withdraw from the study (eg, withdraw consent), at any time at his/her own 
request, without prejudice to further treatment.
If the subject withdraws consent for disclosure of future information, the sponsor may retain and 
continue to use any data collected before such a withdrawal of consent.
If a subject withdraws from the study, he/she may request destruction of any samples taken, and 
the investigator must document this in the site study records.  
A subject who withdraws consent will always be asked about the reason(s) and the presence of 
any adverse events (AEs). The Investigator will follow up subjects as medically indicated. 
A subject who withdraws consent during Visit 1 will be asked if they would agree to undergo 
minimal follow up, e.g. all or part of the 24h / EoT assessment (see Table 1 for details) before 
leaving the site during Visit 1.
8.
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarised in the Table 1. 
The investigator will ensure that data are recorded on the eCRF. The Web Based Data Capture 
(WBDC) system Rave will be used for data collection and query handling.
The investigator ensures the accuracy, completeness and timeliness of the data recorded and of 
the provision of answers to data queries according to the Clinical Study Agreement.  
The investigator will sign the completed eCRF.  A copy of the completed eCRFs will be 
archived at the study site.


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Immediate safety concerns should be discussed with the sponsor immediately upon occurrence or 
awareness to determine if the subject should continue or discontinue study treatment.
Adherence to the study design requirements, including those specified in the Table 1, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential subjects 
meet all eligibility criteria.  The investigator will maintain a screening log to record details of all 
subjects screened and to confirm eligibility or record reasons for screening failure, as applicable.  
Procedures conducted as part of the subject’s routine clinical management (eg, blood count) and 
obtained before signing of the ICF may be utilised for screening or baseline purposes provided 
the procedures met the protocol-specified criteria and were performed within the time frame 
defined in the Table 1.
The maximum amount of blood collected from each subject over the duration of the study, 
including any extra assessments that may be required, will not exceed 60 mL. Repeat or 
unscheduled samples may be taken for safety reasons or for technical issues with the samples.
8.1
Efficacy assessments 
All efficacy endpoints are entirely or partially based on S-K measurements, and whole blood 
potassium measured by i-STAT is the main safety parameter to monitor in recruited patients. The 
proper collection and analysis of S-K and whole blood potassium is therefore of exceptional 
importance for the successful assessment of efficacy in the study, and for keeping recruited 
patients safe.
8.1.1
Potassium Assessments
Blood samples for determination of potassium and glucose will be taken at the times indicated in 
the Schedule of Assessments (see Table 1). Whole blood samples will be analyzed locally using 
i-STAT devices for the purposes of study inclusion and monitoring. Samples drawn at the same 
time-points will be prepared and shipped to the Central Laboratory for analysis of S-K.
All blood samples should be examined and any hemolyzed samples must be redrawn. In the 
event that hemolysis or other artefacts are suspected based on the reported i-STAT result the 
blood samples must be re-drawn to confirm the result. Only the confirmatory sample result needs 
to be reported in the eCRF.
See the laboratory manual for details on drawing, preparation and analysis of blood samples.
Blood glucose will be assessed simultaneously with the potassium assessments. See section 8.2.2


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8.2
Safety assessments 
Planned time-points for all required safety assessments are provided in Table 1.
8.2.1
Clinical safety laboratory assessments
See Table 7 for the list of clinical safety laboratory tests to be performed and see Table 1 for the 
timing and frequency. All protocol-required laboratory assessments, as defined in the table, must 
be conducted in accordance with the laboratory manual and the Table 1.
The Investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities.  The laboratory results should be signed and dated and retained at centre 
as source data for laboratory variables.  
For information on how AEs based on laboratory tests should be recorded and reported, see 
Section 8.3.7.
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator, and will then be analysed at a local laboratory on or near the study site if required 
for the appropriate monitoring and medical management of the patient. 
Analysis of clinical chemistry and haematology will be performed at a central laboratory.


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Table 7
Laboratory safety variables
Haematology/Haemostasis (whole blood)
Clinical Chemistry (serum or plasma)
B-Haemoglobin (Hb)
S-Creatinine
B-Leukocyte count
S-Bilirubin, total
B-Leukocyte differential count (absolute count, %)
S-Alkaline phosphatise (ALP)
B-Platelet count
S-Aspartate transaminase (AST)
S-Alanine transaminase (ALT)
S-Albumin
S-Potassium
S-Calcium, total
S-Sodium
S-C-reactive protein (CRP)
S-Bicarbonate
S-Phosphorous
S-Blood Urea Nitrogen (BUN)
S-Magnesium
S-Lactate dehydrogenase
S-Creatine kinase (CK)
NB. In case a subject shows an AST or ALT ≥3xULN together with total bilirubin ≥2xULN 
please refer to Appendix D ‘Actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s Law’, for further instructions.
8.2.2
Glucose assessments
Blood glucose will be assessed at each time-point when potassium is assessed using the i-STAT 
device, as indicate in Table 1. The i-STAT device will report both potassium and glucose at the 
same time using the same whole blood sample for both analyses. See section 8.1.1.
8.2.3
Physical examinations
A physical examination will be performed at screening and end of treatment/24h, and include an 
assessment of the following: general appearance, respiratory, cardiovascular (including signs of 
volume overload), and abdomen.
Investigators should pay special attention to clinical signs related to previous or concurrent 
serious illnesses. New or worsening abnormalities may qualify as adverse events, see Section 
8.3.7 for details.
8.2.4
Vital signs, height and weight
Temperature, pulse rate, respiratory rate, systolic and diastolic blood pressure and weight will 
ideally be assessed before blood collection for laboratory tests. Height may be measured at any 


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time during Visit 1. Patient reported dry weight should be used for patients receiving regular 
hemodialysis whenever available. Patient reported weight is acceptable also for non-dialysis 
patients, but measured weight is preferred.
Blood pressure and pulse measurements will be assessed with a completely automated device. 
Manual techniques will be used only if an automated device is not available.
8.2.5
Electrocardiograms
Single 12-lead ECG will be obtained as outlined in the Table 1 using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals.
8.2.6
Other safety assessments
Patients may present at an emergency department with hyperkalaemia due to a diverse range of 
causes. Additional safety assessments should be added as appropriate based on the suspected 
underlying cause of hyperkalaemia. Participation in the study will not replace or prevent any 
such additional assessment or investigation to diagnose, monitor or manage the underlying cause 
of hyperkalaemia or any concurrent conditions. Any diagnoses made and any additional signs, 
symptoms or laboratory results from such assessments or investigations will be reported on the 
AE eCRF page if appropriate.
8.3
Collection of adverse events
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
The definitions of an AE or SAE can be found in Appendix B.
AE will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or the 
subject's legally authorized representative).  
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE. For information on how to follow/up AEs see 
section 8.3.3.  
8.3.1
Method of detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrences.  
8.3.2
Time period and frequency for collecting AE and SAE information 
Adverse Events (including SAEs) will be collected from time of signature of informed consent 
form throughout the treatment period and including the follow-up period (Visit 2 or last contact).
All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as indicated 
in Appendix B.  The investigator will submit any updated SAE data to the sponsor within 24 
hours of it being available.


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Investigators are not obligated to actively seek AE or SAE in former study subjects. However, if 
the investigator learns of any SAE, including a death, at any time after a subject’s last visit and 
he/she considers the event to be reasonably related to the Study treatment or study participation, 
the investigator may notify the sponsor.
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix B.
8.3.3
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each subject at 
subsequent visits/contacts. All AE, will be followed until resolution, stabilization, the event is 
otherwise explained, or the subject is lost to follow-up.
Any AEs that are unresolved at the subject’s last visit in the study are followed up by the 
Investigator for as long as medically indicated, but without further recording in the eCRF. 
AstraZeneca retains the right to request additional information for any subject with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary.
8.3.4
Adverse event data collection
The following variables will be collect for each AE:
•
AE (verbatim)
•
The date and time (time required for Day 1 only) when the AE started and stopped
•
Maximum intensity
•
Whether the AE is serious or not
•
Investigator causality rating against the Investigational Product(s) (yes or no)
•
Action taken with regard to Investigational Product(s)
•
AE caused subject’s withdrawal from study (yes or no)
•
Outcome.
In addition, the following variables will be collected for SAEs:
•
Date AE met criteria for serious AE
•
Date Investigator became aware of serious AE
•
AE is serious due to
•
Date of hospitalisation
•
Date of discharge


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•
Probable cause of death
•
Date of death
•
Autopsy performed
•
Causality assessment in relation to Study procedure(s)
•
Causality assessment to other medication.
8.3.5
Causality collection
The Investigator will assess causal relationship between Investigational Product and each 
Adverse Event, and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a 
reasonable possibility that the event may have been caused by the investigational product?’
For SAEs, causal relationship will also be assessed for other medication and study procedures. 
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix B to the Clinical 
Study Protocol.
8.3.6
Adverse events based on signs and symptoms
All AEs spontaneously reported by the subject or reported in response to the open question from 
the study site staff: ‘Have you had any health problems since the previous visit/you were last 
asked?’, or revealed by observation will be collected and recorded in the eCRF. When collecting 
AEs, the recording of diagnoses is preferred (when possible) to recording a list of signs and 
symptoms. However, if a diagnosis is known and there are other signs or symptoms that are not 
generally part of the diagnosis, the diagnosis and each sign or symptom will be recorded 
separately.
8.3.7
Adverse events based on examinations and tests
The results from the Clinical Study Protocol mandated laboratory tests and vital signs will be 
summarised in the Clinical Study Report. Deterioration as compared to baseline in protocol-
mandated laboratory values and vital signs should therefore only be reported as AEs if they fulfil 
any of the SAE criteria or are the reason for discontinuation of treatment with the investigational 
product.
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign will 
be considered as additional information.  Wherever possible the reporting Investigator uses the 
clinical, rather than the laboratory term (e.g., anaemia versus low haemoglobin value).  In the 
absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s).


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Any new or aggravated clinically relevant abnormal medical finding at a physical examination as 
compared with the baseline assessment will be reported as an AE unless unequivocally related to 
the disease under study.
8.3.8
Hy’s law
Cases where subject shows elevations in liver biochemistry may require further evaluation and 
occurrences of AST or ALT ≥ 3xULN together with total bilirubin ≥ 2xULN may need to be 
reported as SAEs.  Please refer to Appendix D for further instruction on cases of increases in 
liver biochemistry and evaluation of Hy’s Law
8.4
Safety reporting and medical management
8.4.1
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s).  All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel inform the 
appropriate AstraZeneca representatives within one day i.e., immediately but no later than 
24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening adverse events where important or relevant information is missing, 
active follow-up is undertaken immediately.  Investigators or other site personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE within 
one calendar day i.e., immediately but no later than 24 hours of when he or she becomes aware 
of it.
Once the Investigators or other site personnel indicate an AE is serious in the eCRF, 
an automated email alert is sent to the designated AstraZeneca representative.
If the eCRF is not available, then the Investigator or other study site staff reports a SAE to the 
appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the Investigator/study site staff how to proceed.  
Investigators or other site personnel send relevant eCRF modules by fax to the designated 
AstraZeneca representative.
For further guidance on the definition of a SAE, see Appendix B of the Clinical Study Protocol.
8.4.2
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca unless the 
pregnancy is discovered before the study subject has received any study drug.


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If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of learning 
of the pregnancy. Abnormal pregnancy outcomes (eg, spontaneous abortion, foetal death, 
stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs.
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product under study may have interfered with the effectiveness of a contraceptive 
medication.  Congenital abnormalities/birth defects and spontaneous miscarriages should be 
reported and handled as SAEs.  Elective abortions without complications should not be handled 
as AEs.  The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth or congenital abnormality) should be followed up and documented even 
if the subject was discontinued from the study.
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1 day i.e., immediately but no later 
than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all relevant 
information is provided to the AstraZeneca Patient Safety data entry site within 1 or 5 calendar 
days for SAEs (see Section 8.4.1) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
8.4.3
Overdose
For this study, any dose of ZS greater than 30g within 1 day will be considered an overdose.
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the relevant AE 
modules in the eCRF and on the Overdose eCRF module.
An overdose without associated symptoms is only reported on the Overdose eCRF module
If an overdose on an AstraZeneca study drug occurs in the course of the study, then the 
Investigator or other site personnel inform appropriate AstraZeneca representatives immediately, 
or no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all relevant 
information is provided to the AstraZeneca Patient Safety data entry site.
For overdoses associated with a SAE, the standard reporting timelines apply (see Section 8.4.1).  
For other overdoses, reporting must occur within 30 days.
8.4.4
Medication error
If a medication error occurs in the course of the study, then the Investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day i.e., immediately but 
no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all relevant 
information is completed within 1 (Initial Fatal/Life-Threatening or follow up Fatal/Life-


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Threatening) or 5 (other serious initial and follow up) calendar days if there is an SAE associated 
with the medication error (see Section 8.3.2) and within 30 days for all other medication errors.
The definition of a Medication Error can be found in Appendix B.
8.5
Pharmacokinetics
PK parameters are not evaluated in this study.
8.6
Pharmacodynamics
Not applicable.
8.7
Genetics
Not applicable.
8.8
Biomarkers
Biomarkers are not evaluated in this study.
8.9
Medical Resource Utilization and Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are not 
evaluated in this study.
8.10
Demography and medical history
Demographic parameters to be collected from patients include sex, date of birth, race, and ethnic 
group.
Medical history parameters to be included include relevant medical and surgical history. 
In addition information about prior dialysis therapy will be collected.
9.
STATISTICAL CONSIDERATIONS 
9.1
Sample size determination 
The study will employ a 1:1 randomization scheme. Based on ZS-004 and patients treated with 
medications only in ZS-007, the standard deviation for S-K change from baseline at 4 hours is 
assumed to be 0.7 mmol/L. With 66 patients per group a two-sided 95% confidence interval for 
the mean difference in S-K change will extend 0.239 mmol/L from the observed difference in 
means.
9.2
Populations for analyses
For purposes of analysis, the following populations are defined: 
The full analysis set will be used for all efficacy analyses. Patients will be analysed according to 
their randomised study medication.


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The safety analysis set will be used for all safety analyses. Erroneously treated patients (eg, those 
randomised to ZS but actually given placebo or vice versa) will be accounted for in the actual 
treatment group. A patient who in error has received both ZS and placebo will be accounted for 
in the randomised treatment group.
Population
Description
Enrolled 
All subjects who sign the ICF.
Full analysis set
All randomised subjects.
Safety analysis set
All subjects randomly assigned to Study treatment and who take at 
least 1 dose of IMP.  
9.3
Statistical analyses
All personnel involved with the analysis of the study will remain blinded until database lock and 
Clinical Study Protocol deviations identified.  
Analyses will be performed by AstraZeneca or its representatives. A comprehensive statistical 
analysis plan will be developed and finalised before database lock and will describe the subject 
populations to be included in the analyses, and procedures for accounting for missing, unused, 
and spurious data. This section is a summary of the planned statistical analyses of the primary 
and secondary endpoints. Any deviations from this plan will be reported in the clinical study 
report.
Demographics and patient characteristics, relevant medical history, prior medications and patient 
disposition will be summarised by treatment group using frequency and percentages 
(for categorical variables) and descriptive statistics of mean, standard deviation, minimum, 
median, and maximum (for continuous variables) using the full analysis set.
Exposure will be summarised by treatment group using frequency and percentage of patients 
receiving 1, 2 and 3 doses using the safety analysis set.
9.3.1
Efficacy analyses
For all analyses of potassium with the exception of sensitivity analyses, the central laboratory 
S-K will be used. If central laboratory data is missing, i-STAT will be used instead, adding the 
average difference between the central lab S-K and i-STAT in those subjects with both values 
available at the relevant time point.
The primary and secondary variables of mean absolute change from baseline (the measurement 
at 0h) in S-K to different time points will be analysed using a linear model including treatment 
group, baseline S-K, time from the start of dosing insulin to the start of dosing ZS/placebo and 
the dose (units/kg) of the first course of insulin as covariates. The difference in least square 
means between treatment groups with associated 95% confidence intervals will be presented in 
addition to the mean absolute changes and standard deviations. For subjects with both S-K and i-
STAT missing, data will be imputed using last observation carried forward. If both S-K and i-


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STAT is missing at baseline the measurement at screening will be used as baseline. Sensitivity 
analyses, to be further defined in the SAP, will be performed using different assumptions for 
subjects with missing data for the primary variable as well as using i-STAT instead of S-K.
Secondary variables of fraction of patients will be analysed using logistic regression models 
including the same covariates as the primary analysis. Odds ratios and 95% confidence intervals 
will be presented in addition to frequency and percentages.
For the first secondary objective patients with any missing potassium value from 1h to 4h 
inclusive will be treated as non-responders.
9.3.2
Safety analyses
All safety analyses will be performed on the Safety Population.
Adverse events will be coded using the MedDRA dictionary. Number of subjects with events 
and percentages will be tabulated by preferred term and system organ class. Adverse events will 
also be summarised by intensity/severity and separately, by causality/relatedness (as determined 
by the investigator). Serious AEs, AEs leading to discontinuation will be summarised in a 
generally similar manner. Adverse events, SAEs, AEs leading to death, and AEs leading to study 
discontinuation will be summarised for each treatment group as applicable. AEs occurring 
between 0h to 24 h and AEs occurring after 24 h will be summarised separately.
Laboratory data will be summarised by presenting shift tables using normal ranges (baseline to 
most extreme post-baseline value) and by presenting summary statistics of observed and change 
from baseline values (means, medians, quartiles, ranges). The incidence of clinically notable lab 
abnormalities will be summarised.
Vital sign data will be summarised by presenting summary statistics of observed and change 
from baseline values. The incidence of clinically notable vital sign abnormalities will be 
summarised.
ECG intervals will be summarised by presenting summary statistics of observed and change 
from baseline values. The incidence of clinically notable ECG abnormalities will be summarised.
9.3.3
Other analyses 
Exploratory objectives will be presented using summary statistics. Further details will be 
described in the SAP.
9.3.4
Methods for multiplicity control
There will be no adjustment for multiplicity, except for the primary analysis, p-values will be 
considered exploratory and confidence intervals used as a measure of precision.
9.4
Interim analyses 
There are no planned interim analyses in this study.


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9.4.1
Data monitoring committee (DMC)
No data monitoring committee will be utilized for this study, as the study does not meet any of 
the criteria proposed by the FDA to be used to identify studies requiring a DMC in the guidance 
document "The Establishment and Operation of Clinical Trial Data Monitoring Committees for 
Clinical Trial Sponsors".


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10.
REFERENCES
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing clinical 
evaluation’
Einhorn, L. M., et al. (2009). "The frequency of hyperkalemia and its significance in chronic 
kidney disease." Arch Intern Med 169(12): 1156-1162.
Fleet JL, Shariff SZ, Gandhi S, et al. Validity of the International Classification of Diseases 10th 
revision code for hyperkalaemia in elderly patients at presentation to an emergency department 
and at hospital admission. BMJ Open 2012;2:e002011
Nakhoul, G. N., et al. (2015). "Serum Potassium, End-Stage Renal Disease and Mortality in 
Chronic Kidney Disease." Am J Nephrol 41(6): 456-463.
Henneman, A., et al. (2016). "Emerging therapies for the management of chronic hyperkalemia 
in the ambulatory care setting." Am J Health Syst Pharm 73(2): 33-44.
Kovesdy, C. P. (2015). "Management of Hyperkalemia: An Update for the Internist." Am J Med 
128(12): 1281-1287.
Li, T., and Vijayan, A. (2014) “Insulin for the treatment of hyperkalemia: a double-edged 
sword?” Clin Kidney J. 7(3):239-41.
Rossignol, P, et al (2016) “Emergency management of severe hyperkalemia: Guideline for 
bestpractice and opportunities for the future” Pharmacol Res. 113(Pt A):585-591.
FDA Guidance for Clinical Trial Sponsors “Establishment and Operation of Clinical Trial Data 
Monitoring Committees”


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11.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
Appendix A
Regulatory, ethical and study oversight considerations
A 1
Regulatory and ethical considerations
This study will be conducted in accordance with the protocol and with the following:
•
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines
•
Applicable ICH Good Clinical Practice (GCP) Guidelines
•
Applicable laws and regulations
•
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.  
•
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study subjects.  
The investigator will be responsible for the following:
•
Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC
•
Notifying the IRB/IEC of S AEs or other significant safety findings as required by 
IRB/IEC procedures
•
Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
studies (if applicable), and all other applicable local regulations
•
The study will be performed in accordance with the AstraZeneca policy on Bioethics and 
Human Biological Samples.
A 2
Financial disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities.  Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study.


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A 3
Informed consent process
The investigator or his/her representative will explain the nature of the study to the subject or 
his/her legally authorised representative and answer all questions regarding the study.  
Subjects must be informed that their participation is voluntary. Subjects or their legally 
authorised representative will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study centre. 
The medical record must include a statement that written informed consent was obtained before 
the subject was enrolled in the study and the date and time the written consent was obtained.  
Both subject and authorised person obtaining the informed consent must sign and date the ICF.
Subjects must be re-consented to the most current version of the ICF(s) during their participation 
in the study.  
A copy of the ICF(s) must be provided to the subject or the subject’s legally authorised 
representative.  
Subjects who are rescreened are required to sign a new ICF.
A 4
Data protection
Each subject will be assigned a unique identifier by the sponsor.  Any subject records or data sets 
transferred to the sponsor will contain only the identifier; subject names or any information 
which would make the subject identifiable will not be transferred.  
The subject must be informed that his/her personal study-related data will be used by the sponsor 
in accordance with local data protection law.  The level of disclosure must also be explained to 
the subject.  
The subject must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorised personnel appointed by the sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities.
A 5
Committees structure
The safety of all AstraZeneca clinical studies is closely monitored on an on-going basis by 
AstraZeneca representatives in consultation with Patient Safety.  Issues identified will be 
addressed.
A 6
Dissemination of clinical study data
A description of this clinical trial will be available on clinicaltrails.gov as will the summary of 
the study results when they are available. The clinical trial and/or summary of main study results 
may also be available on other websites according to the regulations of the countries in which the 
study is conducted.


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A 7
Data quality assurance
All subject data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data).  The investigator is 
responsible for verifying that data entries are accurate and correct by physically or electronically 
signing the CRF.  
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
The investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents.  
The sponsor or designee is responsible for the data management of this study including quality 
checking of the data.  
Study monitors will perform ongoing source data verification and source data review to confirm 
that data entered into the CRF by authorised site personnel are accurate, complete, and verifiable 
from source documents; that the safety and rights of subjects are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
Records and documents, including signed and dated ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 15 years after study completion unless local regulations 
or institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor. 
A 8
Source documents
Source documents provide evidence for the existence of the subject and substantiate the integrity 
of the data collected.  Source documents are filed at the investigator’s site.
Data reported on the CRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained.  The investigator may need to 
request previous medical records or transfer records, depending on the study.  Also, current 
medical records must be available.
A 9
Publication policy
The results of this study may be published or presented at scientific meetings.  If this is foreseen, 
the investigator agrees to submit all manuscripts or abstracts to the sponsor before submission.  
This allows the sponsor to protect proprietary information and to provide comments.  
The sponsor will comply with the requirements for publication of study results.  In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 
multicentre studies only in their entirety and not as individual site data.  In this case, a 
coordinating investigator will be designated by mutual agreement.


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Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements.


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Appendix B
Adverse event definitions and additional safety information
B 1
Definition of adverse events
An adverse event is the development of any untoward medical occurrence in a subject or clinical 
study subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment.   An AE can therefore be any unfavourable and unintended sign 
(e.g.  an abnormal laboratory finding), symptom (for example nausea, chest pain), or disease 
temporally associated with the use of a medicinal product, whether or not considered related to 
the medicinal product.  
The term AE is used to include both serious and non-serious AEs and can include a deterioration 
of a pre-existing medical occurrence.  An AE may occur at any time, including run-in or washout 
periods, even if no Study treatment has been administered.
B 2
Definitions of serious adverse event
A serious adverse event is an AE occurring during any study phase (i.e., run-in, treatment, 
washout, follow-up), that fulfils one or more of the following criteria:
•
Results in death
•
Is immediately life-threatening
•
Requires in-subject hospitalisation or prolongation of existing hospitalisation 
•
Results in persistent or significant disability or incapacity.  
•
Is a congenital abnormality or birth defect
•
Is an important medical event that may jeopardise the subject or may require medical 
treatment to prevent one of the outcomes listed above.
B 3
Life threatening
‘Life-threatening’ means that the subject was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the subject’s 
death.  ‘Life-threatening’ does not mean that had an AE occurred in a more severe form it might 
have caused death (e.g., hepatitis that resolved without hepatic failure).
B 4
Hospitalisation
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons for 
it may be (e.g., bronchospasm, laryngeal oedema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.
B 5
Important medical event or medical treatment


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Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardize the subject or may require 
medical treatment to prevent one or more outcomes listed in the definition of serious.  These 
should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.
Angioedema not severe enough to require intubation but requiring iv hydrocortisone treatment.
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with N-
acetylcysteine.
Intensive treatment in an emergency room or at home for allergic bronchospasm.
Blood dyscrasias (e.g., neutropenia or anaemia requiring blood transfusion, etc.) or convulsions 
that do not result in hospitalisation.
Development of drug dependency or drug abuse.
B 6
Intensity rating scale:
1.
mild (awareness of sign or symptom, but easily tolerated)
2.
moderate (discomfort sufficient to cause interference with normal activities)
3.
severe (incapacitating, with inability to perform normal activities)
It is important to distinguish between serious and severe AEs.  Severity is a measure of intensity 
whereas seriousness is defined by the criteria in Appendix B 2. An AE of severe intensity need 
not necessarily be considered serious.  For example, nausea that persists for several hours may be 
considered severe nausea, but not a SAE unless it meets the criteria shown in Appendix B 2. On 
the other hand, a stroke that results in only a limited degree of disability may be considered a 
mild stroke but would be a SAE when it satisfies the criteria shown in Appendix B 2.
B 7
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there is 
a ‘reasonable possibility’ that an AE may have been caused by the drug.
Time Course.  Exposure to suspect drug.  Has the subject actually received the suspect drug?  
Did the AE occur in a reasonable temporal relationship to the administration of the suspect drug?
Consistency with known drug profile.  Was the AE consistent with the previous knowledge of 
the suspect drug (pharmacology and toxicology) or drugs of the same pharmacological class? Or 
could the AE be anticipated from its pharmacological properties?


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De-challenge experience.  Did the AE resolve or improve on stopping or reducing the dose of the 
suspect drug?
No alternative cause.  The AE cannot be reasonably explained by another aetiology such as the 
underlying disease, other drugs, other host or environmental factors.
Re-challenge experience.  Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped? AstraZeneca would not normally recommend or support a re-challenge.
Laboratory tests.  A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:
Is this a recognized feature of overdose of the drug?
Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case.  The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are facts 
(evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough information 
to make an informed judgment.  With limited or insufficient information in the case, it is likely 
that the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of effect 
should be classified as no reasonable possibility.
B 8
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study drug that either causes harm to the participant or 
has the potential to cause harm to the participant.  
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant.
Medication error includes situations where an error:  
•
occurred
•
was identified and intercepted before the participant received the drug
•
did not occur, but circumstances were recognized that could have led to an error


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Examples of events to be reported in clinical studies as medication errors:
•
Drug name confusion
•
Dispensing error e.g.  medication prepared incorrectly, even if it was not actually given to 
the participant
•
Drug not administered as indicated, for example, wrong route or wrong site of 
administration
•
Drug not taken as indicated e.g.  tablet dissolved in water when it should be taken as a 
solid tablet 
•
Drug not stored as instructed e.g.  kept in the fridge when it should be at room 
temperature 
•
Wrong participant received the medication (excluding IVRS/IWRS errors)
•
Wrong drug administered to participant (excluding IVRS/IWRS errors)
Examples of events that do not require reporting as medication errors in clinical studies:
•
Errors related to or resulting from IVRS/IWRS - including those which lead to one of the 
above listed events that would otherwise have been a medication error 
•
Participant accidentally missed drug dose(s) e.g.  forgot to take medication
•
Accidental overdose (will be captured as an overdose)
•
Participant failed to return unused medication or empty packaging
•
Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AZ product 
•
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.


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Appendix C
Handling of Human Biological Samples
C 1
Chain of custody of biological samples
A full chain of custody is maintained for all samples throughout their lifecycle.
The Investigator at each centre keeps full traceability of collected biological samples from the 
subjects while in storage at the centre until shipment or disposal (where appropriate).
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of arrival.
AstraZeneca will keep oversight of the entire life cycle through internal procedures, monitoring 
of study sites, auditing or process checks, and contractual requirements of external laboratory 
providers.
Samples retained for further use will be stored in the AZ-assigned biobanks and will be 
registered by the AstraZeneca Biobank Team during the entire life cycle.
C 2
Withdrawal of Informed Consent for donated biological samples 
If a subject withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented.  If samples are already analysed, AstraZeneca 
is not obliged to destroy the results of this research.
As collection of the biological sample(s) is an integral part of the study, then the subject is 
withdrawn from further study participation. 
The Investigator:
•
Ensures subjects’ withdrawal of informed consent to the use of donated samples is 
notified immediately to AstraZeneca
•
Ensures that biological samples from that subject, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented
•
Ensures the organization(s) holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed of/destroyed, the action documented 
and the signed document returned to the study site
•
Ensures that the subject and AstraZeneca are informed about the sample disposal.
AstraZeneca ensures the organizations holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed of/destroyed and the action documented and 
returned to the study site.
C 3
International Airline Transportation Association (IATA) 6.2 
Guidance Document


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LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation Association (IATA) classifies biohazardous agents into 3 
categories 
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.htm). For 
transport purposes the classification of infectious substances according to risk groups was 
removed from the Dangerous Goods Regulations in the 46th edition (2005). Infectious 
substances are now classified either as Category A, Category B or Exempt. There is no direct 
relationship between Risk Groups and Categories A and B.
Category A Infectious Substances are infectious substances in a form that, when exposure to it 
occurs, is capable of causing permanent disability, life-threatening or fatal disease in otherwise 
healthy humans or animals. Category A pathogens are eg, Ebola, Lassa fever virus:
are to be packed and shipped in accordance with IATA Instruction 602.
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are eg, Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus types 1 and 2. They are assigned the following UN number and 
proper shipping name:
UN 3373 – Biological Substance, Category B
are to be packed in accordance with UN3373 and IATA 650
Exempt - all other materials with minimal risk of containing pathogens
Clinical trial samples will fall into Category B or exempt under IATA regulations
Clinical trial samples will routinely be packed and transported at ambient
temperature in IATA 650 compliant packaging 
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.htm)
Biological samples transported in dry ice require additional dangerous goods specification 
for the dry-ice content
IATA compliant courier and packaging materials should be used for packing and transportation 
and packing should be done by an IATA certified person, as applicable.
Samples routinely transported by road or rail are subject to local regulations which require that 
they are also packed and transported in a safe and appropriate way to contain any risk of 
infection or contamination by using approved couriers and packaging/containment materials at 
all times. The IATA 650 biological sample containment standards are encouraged wherever 
possible when road or rail transport is used.


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Appendix D
Actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s Law
D 1
Introduction
This Appendix describes the process to be followed in order to identify and appropriately report 
cases of Hy’s Law.  It is not intended to be a comprehensive guide to the management of 
elevated liver biochemistries. 
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry.  The Investigator is responsible for determining whether a subject meets potential 
Hy’s Law (PHL) criteria at any point during the study.
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria 
are met.  HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than drug induced liver injury (DILI) caused by the investigational medicinal 
product (IP).  
The Investigator is responsible for recording data pertaining to PHL/HL cases and for reporting 
AE and SAE according to the outcome of the review and assessment in line with standard safety 
reporting processes.
D 2
Definitions
Potential Hy’s Law (PHL)
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 3× upper limit of normal 
(ULN) together with total bilirubin (TBL) ≥ 2×ULN at any point during the study following the 
start of study medication  irrespective of an increase in alkaline phosphatase (ALP).  
Hy’s Law (HL)
AST or ALT ≥ 3 × ULN  together with TBL ≥ 2 ×ULN, where no other reason, other than the 
IMP, can be found to explain the combination of increases, eg, elevated ALP indicating 
cholestasis, viral hepatitis, another drug.  
For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified time frame within which the elevations 
in transaminases and TBL must occur.
D 3
Identification of potential Hy’s Law cases
In order to identify cases of PHL it is important to perform a comprehensive review of laboratory 
data for any subject who meets any of the following identification criteria in isolation or in 
combination:
ALT ≥ 3 × ULN
AST ≥ 3 × ULN


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TBL ≥ 2 × ULN
When a subject meets any of the identification criteria, in isolation or in combination, the central 
laboratory will immediately send an alert to the Investigator (and also to the AstraZeneca 
representative).  
The Investigator will also remain vigilant for any local laboratory reports where the 
identification criteria are met, where this is the case the Investigator will:
•
Notify the AstraZeneca representative
•
Request a repeat of the test (new blood draw) by the central laboratory
•
Complete the appropriate unscheduled laboratory CRF module(s) with the original local 
laboratory test result
When the identification criteria are met from central or local laboratory results the Investigator 
will without delay:
•
Determine whether the subject meets PHL criteria (see Appendix D 2 for definition) by 
reviewing laboratory reports from all previous visits (including both central and local 
laboratory results)
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will:
•
Notify the AstraZeneca representative
•
Determine whether the subject meets PHL criteria (see Appendix D 2 for definition) by 
reviewing laboratory reports from all previous visits
•
Promptly enter the laboratory data into the laboratory CRF
D 4
Follow-up
D 4.1
Potential Hy’s Law criteria not met
If the subject does not meet PHL criteria the Investigator will:
•
Inform the AstraZeneca representative that the subject has not met PHL criteria.
•
Perform follow-up on subsequent laboratory results according to the guidance provided 
in the Clinical Study Protocol.
D 4.2
Potential Hy’s Law criteria met


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If the subject does meet PHL criteria the Investigator will:
•
Determine whether PHL criteria were met at any study visit prior to starting Study 
treatment (See Section 8.4 Safety Reporting)
•
Notify the AstraZeneca representative who will then inform the central Study Team 
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study subjects’ follow-up and the continuous review of data.  Subsequent to this 
contact the Investigator will:
•
Monitor the subject until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically indicated 
•
Investigate the aetiology of the event and perform diagnostic investigations as discussed 
with the Study Physician.  For studies using a central laboratory add: This includes 
deciding which the tests available in the Hy’s law lab kit should be used.
•
Complete the three Liver CRF Modules as information becomes available 
If at any time (in consultation with the Study Physician) the PHL case meets serious criteria, 
report it as an SAE using standard reporting procedures.
D 5
Review and assessment of potential Hy’s Law cases
The instructions in this section should be followed for all cases where PHL criteria are met.
No later than 3 weeks after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether there 
is an alternative explanation for meeting PHL criteria other than DILI caused by the IMP.  The 
AstraZeneca Global Clinical Lead or equivalent and Global Safety Physician will also be 
involved in this review together with other subject matter experts as appropriate.  
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE:
•
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF
•
If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF accordingly 
and follow the AZ standard processes
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP:


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Report an SAE (report term ‘Hy’s Law’) according to AstraZeneca standard processes.  

The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply

As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned.
If there is an unavoidable delay of over 3 weeks in obtaining the information necessary to assess 
whether or not the case meets the criteria for HL, then it is assumed that there is no alternative 
explanation until such time as an informed decision can be made:
•
Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and causality 
assessment as per above
•
Continue follow-up and review according to agreed plan.  Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are met.  Update the SAE report according to the outcome of the 
review amending the reported term if an alternative explanation for the liver biochemistry 
elevations is determined.
D 6
Actions required when potential Hy’s Law criteria are met before and 
after starting study treatment
This section is applicable to subjects who meet PHL criteria on Study treatment having 
previously met PHL criteria at a study visit prior to starting Study treatment.
At the first on-study treatment occurrence of PHL criteria being met, the Investigator will 
determine if there has been a significant change in the subjects’ condition# compared with the 
last visit where PHL criteria were met. 
If there is no significant change, no action is required.
If there is a significant change, notify the AstraZeneca representative, who will inform the 
central Study Team, then follow the subsequent process described in Appendix B 5.
A ‘significant’ change in the subject’s condition refers to a clinically relevant change in any of 
the individual liver biochemistry parameters (ALT, AST or total bilirubin) in isolation or in 
combination, or a clinically relevant change in associated symptoms.  The determination of 
whether there has been a significant change will be at the discretion of the Investigator, this may 
be in consultation with the Study Physician if there is any uncertainty.
D 7
Actions required for repeat episodes of potential Hy’s Law
This section is applicable when a subject meets PHL criteria on study treatment, and has already 
met PHL criteria at a previous on study treatment visit.


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The requirement to conduct follow-up, review, and assessment of a repeat occurrence(s) of PHL 
is based on the nature of the alternative cause identified for the previous occurrence.  
The investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question:
Was the alternative cause for the previous occurrence of PHL criteria being met found to be the 
disease under study (eg, chronic or progressing malignant disease, severe infection or liver 
disease), 
If No: Follow the process described in Appendix D 4.1.
If Yes: Determine if there has been a significant# change in the subject’s condition compared 
with when PHL criteria were previously met.
If there is no significant change, no action is required.
If there is a significant change, follow the process described in Appendix D 4.
A ‘significant’ change in the subject’s condition refers to a clinically relevant change in any of 
the individual liver biochemistry parameters (ALT, AST or total bilirubin) in isolation or in 
combination, or a clinically relevant change in associated symptoms.  The determination of 
whether there has been a significant change will be at the discretion of the Investigator; this may 
be in consultation with the Study Physician if there is any uncertainty.


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Appendix E
Abbreviations 
Abbreviation or 
special term
Explanation
AE
adverse event
CONSORT
Consolidated Standards of Reporting Trials
eCRF
electronic case report form 
CSA
clinical study agreement
CSR
clinical study report
CTCAE
Common Terminology Criteria for Adverse Event
DAE
discontinuation of investigational product due to adverse event
DNA
deoxyribonucleic acid 
EC
ethics committee, synonymous to institutional review board (IRB) and 
independent ethics committee (IEC)
EOT
End of treatment
EOS
End of study
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HL
Hy’s law
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
International 
Co-ordinating 
investigator
If a study is conducted in several countries the International Co-ordinating 
Investigator is the Investigator co-ordinating the investigators and/or 
activities internationally.  
IP
Investigational Product
IV
Intravenous(ly)
IVRS
interactive voice response system
IWRS
interactive web response system
LSLV
last subject last visit
LIMS
laboratory information management system
MedDRA
Medical Dictionary for Regulatory Activities
NIP
Non-Investigational procduct
OAE
other significant adverse event
PHL
Potential Hy’s law
PI
principal investigator 
SAE
serious adverse event 


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Abbreviation or 
special term
Explanation
SAP
statistical analysis plan
SoA
Schedule of Activities
S-K
Serum potassium
WBDC
web based data capture


SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d9480c00005-csp-v2
Document Title:
D9480C00005 Clinical Study Protocol version 2
Document ID:
Doc ID-003614013
Version Label:
2.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
14-Jun-2018 13:54 UTC
Content Approval
14-Jun-2018 11:47 UTC
Author Approval
14-Jun-2018 11:56 UTC
Content Approval
14-Jun-2018 11:55 UTC
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
Redacted
Redacted
Redacted
Redacted

SAP_001.pdf: 
Statistical Analysis Plan, ANGEL
Version number 4.0
Form Doc Number: LDMS_001_00026934
Parent Doc Number: 
Statistical Analysis Plan
Study Code
D9480C00005
Edition Number
0.7
Date
09/Nov/18
A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled 
Study to Evaluate a Potassium Normalization Treatment Regimen 
Including Sodium Zirconium Cyclosilicate (ENERGIZE)


Redacted


Redacted


Statistical Analysis Plan 
Study Code D9480C00005
Edition Number 0.7
Date 09/Nov/18
4
TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................................1
SIGNATURE OF STUDY STATISTICIAN........................................................................2
SIGNATURE OF GLOBAL PRODUCT STATISTICIAN ..................................................3
TABLE OF CONTENTS.....................................................................................................4
LIST OF ABBREVIATIONS ..............................................................................................6
AMENDMENT HISTORY..................................................................................................7
1.
STUDY DETAILS...............................................................................................8
1.1
Study objectives...................................................................................................8
1.2
Study design ........................................................................................................9
1.3
Number of subjects ..............................................................................................9
2.
ANALYSIS SETS ...............................................................................................9
2.1
Definition of analysis sets ....................................................................................9
2.2
Violations and deviations .....................................................................................9
3.
PRIMARY AND SECONDARY VARIABLES...................................................9
3.1
Primary variable.................................................................................................10
3.2
Secondary variables ........................................................................................... 10
3.3
Exploratory variables ......................................................................................... 10
3.4
Safety variables..................................................................................................11
3.4.1
AEs.................................................................................................................... 11
3.4.2
Vital signs..........................................................................................................11
3.4.3
Physical examinations........................................................................................ 11
3.4.4
ECGs ................................................................................................................. 11
3.4.5
Clinical laboratory parameters............................................................................12
4.
ANALYSIS METHODS.................................................................................... 12
4.1
General principles.............................................................................................. 12
4.2
Analysis methods............................................................................................... 12
4.2.1
Efficacy analysis................................................................................................ 12
4.2.2
Safety analysis ...................................................................................................13
4.2.3
Exploratory analysis........................................................................................... 13
5.
INTERIM ANALYSES ..................................................................................... 13


Statistical Analysis Plan 
Study Code D9480C00005
Edition Number 0.7
Date 09/Nov/18
5
6.
CHANGES OF ANALYSIS FROM PROTOCOL ............................................. 13
7.
REFERENCES ..................................................................................................14
8.
APPENDIX .......................................................................................................14


Statistical Analysis Plan 
Study Code D9480C00005
Edition Number 0.7
Date 09/Nov/18
6
LIST OF ABBREVIATIONS
Abbreviation or 
special term
Explanation
AE
Adverse Event
CI
Confidence Interval
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CTMS
Clinical Trial Management System
ECG
Electrocardiography
ICF
Informed Consent Form
IP
Investigational Product
IPD
Important Protocol Deviation
ITT
Intention to Treat
MedDRA
Medical Dictionary for Regulatory Activities
PE
Physical Examination
SAE
Serious Adverse Event
SD
Standard Deviation
VS
Vital Signs
SZC
Sodium Zirconium Cyclosilicate


Statistical Analysis Plan 
Study Code D9480C00005
Edition Number 0.7
Date 09/Nov/18
7
AMENDMENT HISTORY
Date
Brief description of change
N/A


Statistical Analysis Plan 
Study Code D9480C00005
Edition Number 0.7
Date 09/Nov/18
8
1.
STUDY DETAILS
1.1
Study objectives
The primary objective in this study is to assess the effect of SZC vs placebo when added to 
insulin and glucose on the reduction of potassium at 4 hours after start of dosing.
Secondary objectives include the following:

To assess the effect of SZC vs placebo when added to insulin and glucose on the 
response to therapy. 

To assess the effect of SZC vs placebo when added to insulin and glucose on the 
change in serum potassium at 1h and 2h after start of dosing. 

To assess the effect of SZC vs placebo when added to insulin and glucose on achieving 
normokalaemia. 

To assess the effect of SZC vs placebo when added to insulin and glucose on achieving 
S-K <5.5mmol/l and <6.0mmol/l. 

To assess the need for additional therapies for hyperkalaemia between SZC and 
placebo when added to insulin and glucose.
Safety objective is to characterize the safety of SZC when added to insulin and glucose.
In addition, there are several exploratory objectives to be considered as follows: 

To assess the effect of SZC vs placebo when added to insulin and glucose on the 
change in SK over time. 

To assess the effect between SZC and placebo when added to insulin and glucose on 
achieving normokalaemia. 

To compare the effect between SZC and placebo when added to insulin and glucose on 
achieving S-K <5.0mmol/l, S-K <5.5mmol/l and <6.0mmol/l. 

To assess the need for additional therapies due to hyperkalaemia between SZC and 
placebo when added to insulin and glucose. 

To assess the time and disposition of patients when leaving the treating department 
between SZC and placebo when added to insulin and Glucose. 

To compare the effect between SZC and placebo when added to insulin and glucose on 
duration of hospitalization.


Statistical Analysis Plan 
Study Code D9480C00005
Edition Number 0.7
Date 09/Nov/18
9
1.2
Study design
The study is designed to determine if SZC 10g administered up to three times over 10h added 
to insulin and glucose in patients presenting with hyperkalaemia will prove to be tolerable and 
efficacious by performing a multicentre, international, randomized, double-blind, placebo-
controlled, prospective, parallel-group study. The study will recruit patients with S-K ≥5.8 
mmol/L. Eligible patients fulfilling all of the inclusion criteria and none of the exclusion 
criteria will be randomised in a 1:1 ratio to SZC or placebo. The study includes a single 
treatment visit no longer than 24h followed by a single follow up contact 7 days later.
1.3
Number of subjects
Approximately 132 patients are planned to be included in the study. Based on ZS-004 and 
patients treated with medications only in ZS-007, the SD for S-K change from baseline at 4 
hours is assumed to be 0.7 mmol/L. With 66 patients per group a two-sided 95% confidence 
interval for the mean difference in S-K change will extend 0.239 mmol/L from the observed 
difference in means.
2.
ANALYSIS SETS
2.1
Definition of analysis sets
The full analysis set, including all randomised subjects, will be used for the primary objective, 
secondary objectives and exploratory objectives. Patients will be analysed according to their 
randomised study medication.
The safety analysis set includes all subjects who were randomly assigned to study treatment 
and ingested at least 1 dose of IP. The safety objective will be analysed using the safety 
analysis set, according to patients’ randomised study medication, except that erroneously 
treated patients (e.g., those randomised to SZC but actually given placebo or vice versa) will 
be accounted for in their actual treatment group, while patients who in error have received 
both SZC and placebo will be accounted for in their randomised treatment group. 
2.2
Violations and deviations
The IPDs are described in Appendix A1. Whether they will be programmatically identified is 
also specified. There will be no IPDs leading to exclusion in primary analysis, which will be 
implemented upon full analysis set per ITT principle, regardless of protocol deviations. 
3.
PRIMARY AND SECONDARY VARIABLES
To derive analysis variables, several terms need to be clarified.
Baseline is defined as the measurement at 0h. Time point 0h is defined as the start of the 
administration of SZC/placebo. 


Statistical Analysis Plan 
Study Code D9480C00005
Edition Number 0.7
Date 09/Nov/18
10
The central laboratory S-K will be used. If central laboratory data is missing, i-STAT will be 
used instead, adding the average difference between the central lab S-K and i-STAT at the 
relevant time point. The difference between central lab S-K and i-STAT will be estimated 
from the mean difference in those subjects with both values available at the relevant time 
point. For subjects with both S-K and i-STAT missing, regardless of whether the subjects 
discontinued the study, data will be imputed using last observation carried forward up to 4h 
inclusive, unless otherwise established. If both S-K and i-STAT is missing at baseline, the 
measurement at screening will be used as baseline. 
The additional therapies administered for lowering potassium are defined as 2nd dose of 
insulin, Beta-agonists, Diuretics, Dialysis, Sodium bicarbonate and Potassium binders when 
administered with the expressed intent to lower S-K.
3.1
Primary variable
The primary efficacy variable is mean absolute change in S-K from baseline until 4h.   
3.2
Secondary variables

Proportion of patients whose S-K <6.0mmol/L at 1h or 2h, S-K <5.0mmol/L at 4h, and 
no additional therapy administered for hyperkalaemia from 0h to 4h inclusive. Patients 
who have any missing potassium value from 1h to 4h inclusive will be treated as non-
responders.

Mean absolute change in S-K from baseline to 1h and 2h, respectively.

The fraction of patients achieving normokalaemia (S-K 3.5-5.0mmol/L) at 1, 2 and 4h, 
respectively.

The fraction of patients achieving S-K <5.5mmol/l at 1, 2, and 4h, respectively.

The fraction of patients achieving S-K<6.0mmol/l at 1, 2, and 4h, respectively.

The fraction of patients administered additional potassium lowering therapy due to 
hyperkalaemia from 0 to 4h inclusive.
3.3
Exploratory variables
All the exploratory variables will be reported in CSR.

Mean absolute change in S-K from baseline to 6, 8, 10, 12 and 24h

The fraction of patients achieving normokalaemia (S-K 3.5-5.0mmol/L) at 6, 8, 10, 12 
and 24h

The fraction of patients achieving S-K <5.0mmol/L, S-K <5.5mmol/l and S-K 
<6.0mmol/l respectively at 6, 8, 10, 12 and 24h


Statistical Analysis Plan 
Study Code D9480C00005
Edition Number 0.7
Date 09/Nov/18
11

The fraction of patients administered additional potassium lowering therapy due to 
hyperkalaemia from 4 to 24h

Time from randomization until leaving the treating department. Time will be presented 
in hours with one decimal place, converted from minutes.

Disposition after leaving the treating department. Disposition in this variable means 
where patients will go right after leaving the initial treatment department within visit 1 
period. Disposition options include going home, going to dialysis and other treating 
departments. Only the first destination will be analysed if there is more than one move 
after leaving the initial treatment department. 

Time from randomization until discharge from hospitalization. Time will be presented 
in hours with one decimal place, converted from minutes.
3.4
Safety variables
3.4.1
AEs
AEs, including SAEs, will be collected from time of signature of informed consent form 
throughout the treatment period and including the follow-up period (visit 2 or last contact). 
However, AE/SAEs occurring between 0h to 24h and AE/SAEs occurring after 24h (time 
calculated from the start of the administration of insulin) will be analysed separately. 
3.4.2
Vital signs
Temperature, pulse rate, respiratory rate and systolic blood pressure and diastolic blood 
pressure will be collected at screening, 4, 10 and 24h time points. The safety variable of each 
of these VS is the change from baseline to each available time point. Baseline is defined as the 
measurement at screening.
3.4.3
Physical examinations
Physical examinations will be performed at screening and 24h. The change in a physical 
examination from screening will be examined through any new or aggravated clinically 
relevant abnormal medical finding, which will be reported as an AE unless unequivocally 
related to the disease under study. Therefore, there will be no separate safety variables and 
analyses for PEs.
3.4.4
ECGs
ECGs will be collected at screening, 4h and 24h time points, using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTcF intervals. The 
safety variable of each of these ECG measurements is the change from baseline to each 
available time point. Baseline is defined as the measurement at screening.


Statistical Analysis Plan 
Study Code D9480C00005
Edition Number 0.7
Date 09/Nov/18
12
3.4.5
Clinical laboratory parameters
The laboratory parameters to be included in the safety analyses are defined in Table 7 in CSP. 
Central laboratory value will be used for assessments of clinical chemistry and haematology. 
These data (except potassium) will be collected at screening and 24h only. The safety variable 
of each of these laboratory parameters is the change from screening.
However, potassium and glucose measurements will be collected at all scheduled time points 
from screening until 24h, and only i-STAT data will be collected for glucose. The change in 
potassium and glucose from baseline to each time point, hypokalaemia based on S-K 
<3.5mmol/L and hypoglycaemia based on blood glucose <70mg/dL will be assessed.
4.
ANALYSIS METHODS
4.1
General principles
The denominator used in percentage should be the total number of subjects in treatment group, 
unless otherwise specified in programming specification.
4.2
Analysis methods
4.2.1
Efficacy analysis
All efficacy analyses will be performed on full analysis set.
The primary objective is to assess the effect of SZC vs placebo when added to insulin and 
glucose on the reduction of potassium at 4 hours after start of dosing SZC/placebo. To 
examine the primary objective, a linear regression model, including treatment group, baseline 
S-K, time from the start of dosing insulin to the start of dosing SZC/placebo and the dose 
(units/kg) of the first course of insulin as covariates, will be employed. The difference in least 
square means between treatment groups with associated 95% CIs will be presented in addition 
to the mean absolute changes and standard deviations.
The secondary variables of mean absolute change from baseline in S-K to different time 
points will be analysed, similarly to the analysis for the primary variable. 95% CIs of the least 
square mean difference will be presented in addition to mean and SD of the absolute change. 
Secondary variables of fraction of patients will be analysed for the full analysis set using 
logistic regression including the same covariates as the primary analysis. Odds ratio and its 
95% CIs will be presented in addition to frequency and percentages. Secondary variables are 
declared supportive, thus, there is no need for multiplicity adjustment. 
Sensitivity analysis will be performed for the primary variable, where only those subjects with 
non-missing central lab potassium data at both baseline and 4h will be included, therefore, 
there will be no missing data imputation in the sensitivity analysis. An analysis will also be 
performed using i-STAT data rather than central lab data, where only subjects with non-
missing i-STAT data at baseline and 4h will be included in the analysis. 


Statistical Analysis Plan 
Study Code D9480C00005
Edition Number 0.7
Date 09/Nov/18
13
4.2.2
Safety analysis
All safety analyses will be performed on safety analysis set, i.e. including all patients who 
have received at least one dose of study drug. 
AEs will be coded using the MedDRA dictionary. AEs occurring between 0h to 24 h and AEs 
occurring after 24 h will be analysed separately. Number of subjects with events and 
percentages will be tabulated by preferred term and system organ class. AEs, SAEs, AEs 
leading to discontinuation of IP and AEs with outcome of death will be summarised for each 
treatment group as applicable. AEs will also be summarised by intensity and separately, by 
causality (as determined by the investigator). SAEs and AEs leading to discontinuation of IP 
will also be summarised by causality. Number of AEs and SAEs will also be summarized by 
preferred term and system organ class, respectively. 
Laboratory data will be summarised by presenting shift tables using normal ranges (baseline 
to most extreme post-baseline value) and by presenting summary statistics of observed and 
change from baseline values (means, medians, quartiles, ranges). The incidence of clinically 
notable lab abnormalities will be summarised. The frequency and percentages of 
hypokalaemia and hypoglycaemia will be tabulated.
VS data will be summarised by presenting summary statistics of observed and change from 
baseline values. The incidence of clinically notable VS abnormalities will be summarised.
ECG data will be summarised by presenting summary statistics of observed and change from 
baseline values. The incidence of clinically notable ECG abnormalities will be summarised.
4.2.3
Exploratory analysis
Exploratory objectives will be presented using summary statistics. Mean, SD, median, min 
and max will be provided for the variable of absolute change in S-K. 
Frequency and percentages will be provided for proportions, and additionally, 95% Clopper–
Pearson CI of the proportion in each treatment group will be presented separately. P-values 
are not applicable in these exploratory analyses.
Disposition after leaving the initial treating department will be summarized by frequency and 
percentages. The summary of time from randomization will be based on statistics mean, SD, 
min and max.
5.
INTERIM ANALYSES
N/A.
6.
CHANGES OF ANALYSIS FROM PROTOCOL
N/A.


Statistical Analysis Plan 
Study Code D9480C00005
Edition Number 0.7
Date 09/Nov/18
14
7.
REFERENCES
N/A.
8.
APPENDIX
Appendix A1 Important Protocol Deviation
Code
Description
IPD
Programmable
IPD
1.1
Informed consent not obtained prior to any mandatory 
study specific procedures, sampling, and analyses
Yes
Yes
1.2
<18 years of age at the time of signing the informed 
consent form
Yes
Yes
1.3
Whole blood potassium < 5.8 mmol/L
Yes
Yes
1.4
Inability to have repeated blood draws or effective 
venous catheterization
Yes
Yes
2.1
Possible pseudohyperkalaemia as assessed by the            
investigator, e.g. secondary to hemolyzed blood 
specimen
Yes
Yes
2.2
Hyperkalaemia caused by any condition for which a 
therapy directed against the underlying cause of 
hyperkalaemia would be a better treatment option than 
treatment with insulin and glucose. This includes 
hyperkalaemia reasonably likely to be caused by 
physical injury, intoxication, pre-renal kidney failure, 
substance abuse, diabetic ketoacidosis, and 
rhabdomyolysis
Yes
Yes
2.3
Life-threatening cardiac arrhythmias requiring 
immediate treatment before an informed consent can be 
collected
Yes
Yes
2.4
Any condition representing a contra-indication to 
treatment with the rapid acting insulin to be used, e.g. 
allergy to any of the constituents of the insulin product 
to be used, or hypoglycaemia at study entry
Yes
Yes


Statistical Analysis Plan 
Study Code D9480C00005
Edition Number 0.7
Date 09/Nov/18
15
2.5
Presence of any other acute or chronic medical 
condition which, in the opinion of the investigator, 
places the patient at undue risk due to the severity of 
illness or potentially jeopardizes patients’ability to 
follow study procedures due to required interventions, 
investigations or procedure in the acute setting. Patients 
having any acute or chronic medical condition other 
than hyperkalaemia that would alone require immediate
treatment in the hospital setting at Visit 1 are not 
eligible for the study.
Yes
Yes
2.6
Dialysis session expected within 4h after randomization
Yes
Yes
2.7
Treated with sodium polystyrene sulfonate (SPS, 
Kayexalate, Resonium), calcium polystyrene sulfonate 
(CPS, Resonium calcium) or patiromer (Veltassa) 
within the past 24h
Yes
Yes
2.8
Treated with any therapy intended to lower S-K 
between arriving at the hospital and randomization 
during Visit 1
with exception of patients meeting the following
criteria:
• Treated with no more than one course of insulin since 
arriving at the hospital
• S-K measured by i-STAT device or local laboratory 
prior to administration of insulin.
S-K must have met Inclusion criterion 4.
• Reasonably likely to randomize, have screening and 0h 
assessments done, and dose the
patient with IP within 30 minutes of the start of 
administration of insulin.
Yes
Yes
2.9
Known hypersensitivity or previous anaphylaxis to ZS 
or to components thereof
Yes
Yes
2.10
Known pregnancy or actively attempting to become 
pregnant
Yes
Yes
2.11
Involvement in the planning and/or conduct of the study 
(applies to both AstraZeneca staff and/or staff at the 
study site)
Yes
Yes
2.12
Judgment by the investigator that the subject should not 
participate in the study as the subject is unlikely to 
comply with study procedures, restrictions or 
Yes
Yes


Statistical Analysis Plan 
Study Code D9480C00005
Edition Number 0.7
Date 09/Nov/18
16
requirements
2.13
Previous randomization in the present study
Yes
Yes
3.1
Patient withdrawal of consent not handled correctly
Yes
Yes
3.2
Adverse Event precluding further dosing in the opinion 
of the investigator or sponsor
Yes
Yes
3.3
Severe non-compliance to the study protocol
Yes
Yes
3.4
Patient became pregnant (screening pregnancy test 
positive), but not discontinued from study drug
Yes
Yes
3.5
Whole blood potassium <3.5mmol/L as measured with 
i-STAT before the administration of ZS at 10h
Yes
Yes
3.6
Dialysis administered
Yes
Yes 
4.2
Use of expired study drug or drug affected by 
temperature excursion 
Yes
No
4.3
Received wrong type of study drug (i.e. not the one 
patient was randomized to)
Yes
Yes
4.4
Received incorrect dose or wrong frequency of 
investigational product
Yes
Yes
5.1
Additional potassium lowering drugs (eg insulin, beta 
agonists, potassium binders) administered with the 
intent to lower potassium before 4h (except in cases 
where it was allowed by protocol (one dose of insulin) 
or necessary for the safety of the patient).
Yes
No
5.2
Potassium substitution (e.g. KCl).
All treatments for hypokalemia not withheld from 
enrolment to Visit 1 discharge
Yes
Yes
5.3
Gastric pH-dependent bioavailability drugs were 
administered/taken within +/- 2 hours of IP /ZS
Yes
Yes
6.1
Visit or procedures not done within the timeframe 
defined by the CSP
No
N/A
6.2
Visit procedure not done according to description in the
CSP
No
N/A


Statistical Analysis Plan 
Study Code D9480C00005
Edition Number 0.7
Date 09/Nov/18
17
6.3
Defined order of the visit’s procedures required by the 
CSP not followed
No
N/A
6.4
Study drug storage temperature and/or documentation of 
monitoring is inadequate
No
N/A
6.5
Storage area security / accessibility inadequate
No
N/A
6.6
Study drug disposition not documented
No
N/A
6.7
Significant compliance issues 
Yes
No
6.8
iStat Cartridges not stored at the correct temperature, 
temperature excursion occurred.
No
N/A
8.1
Delay of SAE reporting (initial or follow-up)
Yes
Yes
9.1
Delay of pregnancy reporting
Yes
No
9.2
Delay of IP overdose reporting (initial or follow-up)
Yes
No
9.3
Other safety issues not specified in the deviations 
described above
Yes
No
7.1
Examinations/assessments for the study were not done 
according to GCP.
Yes
No
7.2
Other GCP deviations e.g. failure to report changes in 
the consent form to an IEC.
Patient consented with obsolete version of ICF.
Patient not re-consented with updated ICF version at 
next patient’s visit. 
Not signed any OC form.
Failure to notify GP of subject participation (if
applicable)
Yes
No