Clinical trial NCT04550234
Conditions: Chronic Kidney Disease
Keywords: 3-period Crossover URAT1 inhibitor Xanthine oxidase inhibitor
Sponsor: AstraZeneca
Start date: 2021-04-13; Completion date: 2021-07-15
Enrollment: 25 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study is a single centre, randomised, open-label, single-dose, 5-period, 5-treatment, crossover study in healthy male and female subjects. This study is intended to assess the relative bioavailability between the fixed dose combination (FDC, i.e. verinurad/allopurinol FDC capsule 12/300 mg) and free combination formulations of verinurad (i.e. verinurad prolonged release Hydroxypropyl methylcellulose \[HPMC\] capsule 12 mg) and allopurinol (i.e. allopurinol table 300 mg) in fasted and fed conditions. The study will also assess the relative bioavailability between a formulation only containing verinurad (i.e. verinurad prolonged release gelatin capsule 12 mg) and the FDC capsule.

Detailed description:
The study comprises of:

* A Screening Period of maximum 28 days;
* Five treatment periods during which subjects will be resident from the morning of Day -2 until at least 72 hours after dosing in Treatment Period 5; discharged on the morning of Day 4 of Treatment Period 5; and
* A Follow-up Visit 7 to 14 days after the last dosing.

Each subject will receive 5 single dose treatments of verinurad and allopurinol or verinurad alone and subject will be involved in the study for 52 to 59 days.

Arms: arm 1: Subjects will receive verinurad prolonged release HPMC capsule and allopurinol tablet in fasted state on Day 1. arm 2: Subjects will receive verinurad/allopurinol FDC capsule in fasted state on Day 1. arm 3: Subjects will receive verinurad/allopurinol FDC capsule in fed state on Day 1. arm 4: Subjects will receive verinurad prolonged release HPMC capsule and allopurinol tablet in fed state on Day 1. arm 5: Subjects will receive verinurad prolonged release gelatin capsule in fasted state on Day 1.
Interventions: intervention 1: Verinurad prolonged release HPMC capsule intervention 2: Allopurinol Tablet intervention 3: Verinurad/Allopurinol FDC Capsule intervention 4: Verinurad prolonged release gelatin Capsule
Intervention descriptions: intervention 1: Randomized subjects will receive oral dose of verinurad HPMC capsule. intervention 2: Randomized subjects will receive oral dose of allopurinol tablet. intervention 3: Randomized subjects will receive oral dose of Verinurad/Allopurinol FDC capsule. intervention 4: Randomized subjects will receive oral dose of Verinurad gelatin capsule.

Protocol documents:
Prot_SAP_000.pdf: 
A Randomised, Single-dose, 3-period, 3-treatment, Crossover 
Study to Assess the Relative Bioavailability of 2 Different 
Formulations of Verinurad and Allopurinol in Healthy Subjects 
ClinicalTrials.gov Identifier: NCT04550234 
Original Protocol:  24 June 2020 (Version 1.0)
Amendment 1: 22 Feb 2021 (Version 2.0) 


Cli nical St u d y Pr ot oc ol
Astra Ze neca
V eri n ura d a n d A ll o p uri n ol - D 5 4 9 5 C 0 0 0 1 4
2 2 Fe br uar y 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y
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Cli nic al St u d y Pr ot oc ol
A R a n d o mise d, Si n gle -d ose, 5- peri o d, 5- tre at me nt, Cr oss o ver 
St u d y t o Assess t he Rel ati ve Bi o a v ail a bilit y of 4 D iffere nt 
F or m ul ati o ns of V eri n ur a d a n d All o p uri n ol i n He alt h y S u bjects
P are xel St u d y N o.:
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S p o ns or St u d y C o de:
D 5 4 9 5 C 0 0 0 1 4
E u dr a C T N o:
2 0 2 0- 0 0 2 7 2 0 - 3 6
St u d y T y pe:
Bi oa vaila bilit y
Test / Refere nce Pr o d uct:
Veri n ura d/all o p uri n ol F D C ca ps ule 1 2/ 3 0 0 m g
V eri n ura d pr ol o n ge d release gelati n ca ps ule 1 2 m g
V eri n ura d pr ol o n ge d release H P M C ca ps ule 1 2 m g
A ll o p uri n ol ta blet 3 0 0 m g
T her a pe utic I n dic ati o n:
C hr o nic ki d ne y disea se
P h ar m ac ol o gic al Cl ass:
U R A T 1 i n hi bit or
Xa nt hi ne o xi dase i n hi bit or
De vel o p me nt P h ase:
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St u d y Ce nt r e :
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T his cli nical st u d y will be c o n d ucte d acc or di n g t o t he pr ot oc ol a n d i n c o m plia nce wit h G o o d Cli nical 
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C o nfi de ntialit y State me nt
T his c o nfi de ntial d oc u me nt is t he pr o pert y of Astra Ze neca. N o u n p u blis he d i nf or mati o n c o ntai ne d 
her ei n ma y be discl ose d wit h o ut pri or writte n a p pr o val fr o m Astra Ze neca. Access t o t his d oc u me nt 
m ust be restricte d t o rele va nt parties.
P P D


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PROTOCOL AMENDMENTS
Protocol Amendment No. 1, dated 22 February 2021
The original protocol, Clinical Study Protocol Final 1.0 dated 24 June 2020, was amended for 
the following reasons:

To have in the same study the relative bioavailability of verinurad, allopurinol, and its
metabolite (oxypurinol) of both fixed-dose combinations (FDC, ie, verinurad/allopurinol
FDC capsule 12/300 mg) and free combinations of verinurad (ie, verinurad prolonged
release hydroxypropyl methylcellulose [HPMC] capsule 12 mg) and allopurinol (ie,
allopurinol tablet 300 mg) tested under both fasted and fed conditions. Therefore, a fourth
treatment period was added to evaluate the free combination formulations under fed
conditions.

Another capsule formulation containing only verinurad (verinurad prolonged release
gelatin capsule 12 mg) will be administered under fasted conditions. Consequently, with
the addition of Treatment 4 and Treatment 5, the sample size was increased to 25
randomized subjects to enable 20 evaluable subjects.

To learn more about the pharmacokinetics (PK)-pharmacodynamics (PD) relationship of
verinurad and allopurinol. Therefore, measurements of serum uric acid (sUA) were added
as PD outcome measures. Consequently, the admission to the study site has been shifted
from Day -1 to Day -2.

To update the naming of the study drug for uniform naming of the different formulations.

To implement corrections or clarifications of some study procedures.
The following sections were updated to reflect the addition of Treatment 4 (ie, verinurad 
prolonged release HPMC capsule 12mg and allopurinol tablet 300mg, as a free 
formulation combination, fed state) and Treatment 5 (ie, verinurad prolonged release 
gelatin capsule 12 mg, fasted state):

Title Page (Study Title), Protocol Synopsis (Study Title, Study Design),
Section 3.1 (Overall Study Design and Flow Chart), Study Flow Chart (Figure 3-1),
Section 5.4.3 (Dose and Treatment Regimens): Changed text from ‘3-period, 3-treatment’
to ‘5-period, 5-treatment’, from ‘3 single-dose treatments’ to ‘5 single-dose treatments’,
and from ‘Three/3 treatment periods’ to ‘Five/5 treatment periods’, where applicable.

Protocol Synopsis (Secondary Study Objectives), Section 2.2 (Secondary Objectives):
Added evaluation of Treatment 4 and Treatment 5 to objectives.

Protocol Synopsis (Study Rationale), Section 1.3 (Rationale for Conducting this Study),
Section 3.2.1 (Rationale for Study Design), Section 5.4.3 (Dose and Treatment
Regimens): Added wording ‘in fasted and fed conditions’.

Protocol Synopsis (Study Design, Investigational Medicinal Product), Section 3.1
(Overall Study Design and Flow Chart), Study Flow Chart (Figure 3-1), Section 5.4.1
(Table 5-1), Section 5.4.3 (Dose and Treatment Regimens): Added description of
Treatment 4 and Treatment 5.


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
Protocol Synopsis (Expected Duration of the Study), Section 3.1.3 (Expected Duration of 
the Study): Updated study duration from ‘46 to 53 days’ to ‘52 to 59 days’ to reflect the 
addition of Treatment Period 4 and Treatment Period 5.

Protocol Synopsis (Number of Subjects Planned, Study Design, Sample Size 
Determination), Section 3.1 (Overall Study Design and Flow Chart), Section 5.1.1
(Procedures for Randomisation), Section 11.4 (Determination of Sample Size): Revised 
text of randomised subjects from ‘15’ to ‘25’ and evaluable subjects from ‘12’ to ‘20’. 
Revised text of treatment sequences to reflect the addition of Treatment 4 and Treatment 
5.

Section 3.1 (Overall Study Design and Flow Chart): Added Treatment Period 4 and 5
(text box Figure 3-1, table heading Table 3-1). Added description of Treatment 4 and 
Treatment 5 in footnote (Figure 3-1). Updated definition of the residential period in 
footnotes (Table 3-1, Figure 3-1). 

Section 5.1.1 (Procedures for Randomisation): Updated randomisation ratio from ‘1:1:1’ 
to ‘1:1:1:1:1’. Updated text for reference capsule and tables to include mention of 
Treatment 4 and Treatment 5.

Protocol Synopsis (Presentation and Analysis of Pharmacokinetic Data), 
Section 11.2.7 (Inferential Statistical Analysis of Pharmacokinetic Data): Added text with 
regard to comparisons of relative bioavailability of the 5 treatments.

Section 10.1.1 (Adverse Events): Added text with regard to assignment of adverse events 
to Treatment Period 4 and Treatment Period 5.
The following sections were updated to reflect the addition of measurement of sUA:

Protocol Synopsis (Secondary Objectives, Statistical Methods), Section 2.2 (Secondary 
Objectives): Added new secondary objective and corresponding outcome measures, 
concerning PD of verinurad and allopurinol.

Protocol Synopsis (Study Design), Section 3.1 (Overall Study Design and Flow Chart), 
Study Flow Chart (Figure 3-1), Schedule of Assessments (Table 3-1), Section 4.2
(Restrictions During the Study), Section 10.1.2 (Laboratory Assessments): Admission 
changed from ‘Day -1’ to ‘Day -2’; some of the assessments that were previously 
scheduled for Day -1 of Treatment Period 1 were moved to Day -2 (Table 3-1).

Protocol Synopsis: Added headings and text for ‘Pharmacodynamic Endpoints’ and 
‘Presentation and Analysis of Pharmacodynamic Data’.

Section 3.1 (Overall Study Design and Flow Chart), Section 5.4.3 (Dose and Treatment 
Regimens): Revised text concerning the start of expected water intake from ‘Day -1’ to 
‘Day -2’, due to change in admission.

Schedule of Assessments (Table 3-1): Added assessment of sUA on Day -1 (Treatment 
Period 1) and Days 1 to 4 of each treatment period.

Section 3.1.1 (Order of Assessments): Added PD and safety blood sampling.

Section 3.2.1 (Rationale for the Study Design), Total Blood Volume (Table 7-1): Added 
sUA sample time, volume and number, updated sample numbers, updated total blood 
volume.


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
Section 10.1.1 (Laboratory Assessments): Revised definition of baseline for laboratory 
assessments due to change in admission.

Added Section 6.5 (Pharmacodynamics), Section 7.2.3 (Pharmacodynamic Samples): 
Added collection of the samples.

Added Section 10.3 (Pharmacodynamic Parameters), Section 11.1.3 (Pharmacodynamic 
Analyses Set), and Section 11.2.8 (Presentation and Statistical Analysis of 
Pharmacodynamic Data): Added presentation and analysis of the sUA data.
The following sections were updated for correction or clarification:

Protocol Synopsis (Targeted Study Population, Outcome Endpoints, Sample Size 
Determination), Section 11.4 (Determination of Sample Size): Added justification of 
sample size determination.

List of Abbreviations updated according to updated text.

Investigators and Study Administrative Structure: Telephone number for adverse event 
reporting was updated, details for Sponsor’s lead physician was updated.

Study Flow Chart (Figure 3-1): Removed text ‘Admission Day -1’ from text box of 
Treatment Period 3.

Schedule of Assessments (Table 3-1): Corrected placement of marks ‘X’ that indicate 
assessment time points of tympanic temperature.

Schedule of Assessments (Table 3-1), Section 4.2 (Restrictions During the Study), 
Section 10.1.2 (Laboratory Assessments): Added footnote that SARS-CoV-2 tests can be 
done unscheduled at the discretion of the investigator.

Section 4.1.2: Added exclusion of subjects who had or planned to have the COVID-19 
vaccination within 4 weeks prior to screening or during the study.

Section 5.4.2 (Supply of Investigational Medicinal Product): Updated supply of IMP to 
bulk bottles with open labels.

Section 0 (FDA Breakfast Menu): Corrected weight of hash-browned potatoes from ‘112 
g’ to ‘120 g’.

Section 5.7 (Discontinuation of Investigational Product and Withdrawal from Study): 
Revised the wording ‘drug-related’ to ‘IMP-related’ to indicate a potential relationship 
with verinurad as well as allopurinol.

Section 11.2.6 (Presentation of Pharmacokinetic Parameter Data): Removed the word 
‘period’ from ‘by treatment period’. Deleted reference to specific version of CPE TFL 
Corporate CSRHLD reporting standards, to cover if later version is used.

Throughout: The terms ‘Test’ and ‘Reference’ were removed to avoid confusion with 
‘Test product’ and ‘Reference product’.
The following sections were updated for uniform naming of the different formulations:

Title Page (Test/Reference Product), Synopsis (Study Rationale, Primary and Secondary 
Study Objectives, Study Design, Investigational Medicinal Product, Statistical Methods), 


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Section 1.3 (Rational for Conducting the Study). Section 2 (Study Objectives). 
Section 3.1 (Overall Study Design and Flow Chart), Section 3.2.1 (Rationale for Study 
Design), Section 5.1.1(Procedures for Randomisation), Section 5.4.1 (Table 5-1), 
Section 11.2.7 (Inferential Statistical Analysis of Pharmacokinetic Data): Updated the 
current study drug names to the proposed names for the clinical program as per below 
table.
Previous name in protocol
Proposed full name
12 mg verinurad ph2b capsule
Verinurad prolonged release HPMC capsule 12mg
N/A
Verinurad prolonged release gelatin capsule 12mg
12 mg verinurad + 300 mg allopurinol ph3 fixed-dose 
combination capsule
Verinurad/allopurinol FDC capsule 12/300 mg
300 mg allopurinol ph2b tablet
Allopurinol tablet 300mg 
N/A: not applicable
In addition, the study period has been updated and some minor editorial and formatting 
changes were made.


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PROTOCOL SYNOPSIS
Title of the Study
A Randomised, Single-dose, 5-period, 5-treatment, Crossover Study to Assess the Relative 
Bioavailability of 4 Different Formulations of Verinurad and Allopurinol in Healthy Subjects.
Principal Investigator (PI)
Thomas Kӧrnicke, MD
Study Centre
This study will be conducted at the Parexel Early Phase Clinical Unit Berlin.
Study Rationale
This study is intended to assess the relative bioavailability between the fixed-dose 
combination (FDC, ie, verinurad/allopurinol FDC capsule 12/300 mg) and free combination
formulations of verinurad (ie, verinurad prolonged release HPMC capsule 12 mg) and 
allopurinol (ie, allopurinol table 300 mg) in fasted and fed conditions. The study will also 
assess the relative bioavailability between a formulation only containing verinurad (ie, 
verinurad prolonged release gelatin capsule 12 mg) and the FDC capsule. For verinurad, all
formulations have prolonged release profile. For allopurinol, both formulations containing 
alopurinol have an immediate release profile.
Number of Subjects Planned
Twenty-five subjects will be randomised into this study to ensure at least 20 evaluable 
subjects complete the study.
Study Period
Estimated date of first subject enrolled: 2nd quarter of 2021 (signing of informed consent)
Estimated date of last subject completed: 3rd quarter of 2021
Study Objectives
The objectives of the study are:
Primary Objective:

To evaluate the relative bioavailability of verinurad, allopurinol and oxypurinol after 
dosing with the verinurad/allopurinol FDC capsule 12/300 mg and free combination 
formulations of verinurad (verinurad prolonged release hydroxypropyl methylcellulose 
[HPMC] capsule 12 mg) and allopurinol (allopurinol tablet 300 mg), under fasted 
conditions.
Secondary Objectives:

To evaluate the relative bioavailability of verinurad, allopurinol and oxypurinol after 
dosing with the verinurad/allopurinol FDC capsule 12/300 mg under fed and fasted 
conditions and with free combination formulations (verinurad prolonged release HPMC 
capsule 12 mg) and allopurinol (allopurinol tablet 300 mg), under fed and fasted 
conditions.


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
To evaluate the relative bioavailability of verinurad after dosing with the verinurad 
prolonged release gelatin capsule 12 mg and verinurad/allopurinol FDC capsule 
12/300 mg under fasted conditions.

To assess the pharmacokinetic profiles of verinurad, allopurinol and oxypurinol when 
administered as the verinurad/allopurinol FDC capsule 12/300 mg and free combination 
formulations of verinurad (verinurad prolonged release HPMC capsule 12 mg) and 
allopurinol (allopurinol tablet 300 mg) under fed and fasted conditions and of verinurad 
when administered as a prolonged release gelatin capsule 12 mg under fasted conditions.

To assess the safety of single doses of verinurad and allopurinol.

To assess the PD of verinurad, allopurinol and oxypurinol when administered as the 
verinurad/allopurinol FDC capsule 12/300 mg and free combination formulations of 
verinurad (verinurad prolonged release HPMC capsule 12 mg) and allopurinol
(allopurinol tablet 300 mg) under fed and fasted conditions and of verinurad when 
administered as a prolonged release gelatin capsule 12 mg under fasted conditions.
Study Design
This study will be a single-centre, randomised, open-label, single-dose, 5-period, 5-treatment, 
crossover study in healthy male and female subjects.
The study will comprise:

A Screening Period of maximum 28 days.

Five treatment periods during which subjects will be resident from the morning of Day -2
until at least 72 hours after dosing in Treatment Period 5; discharged on the morning of 
Day 4 of Treatment Period 5.

A Follow-up Visit 7 to 14 days after the last dosing.
There will be a minimum washout period of 5 days between each dose administration.
A total of 25 healthy male and female subjects will be randomised into one of 5 treatment 
sequences. Each subject will receive 5 single-dose treatments of verinurad and allopurinol or 
verinurad alone:

Treatment 1: verinurad prolonged release HPMC capsule 12mg and allopurinol tablet 
300mg, as a free combination, fasted state.

Treatment 2: verinurad/allopurinol FDC capsule 12/300 mg, fasted state.

Treatment 3: verinurad/allopurinol FDC capsule 12/300 mg, fed state.

Treatment 4: verinurad prolonged release HPMC capsule 12mg and allopurinol tablet 
300mg, as a free combination, fed state.

Treatment 5: verinurad prolonged release gelatin capsule 12 mg, fasted state.
Expected Duration of the Study
Each subject will be involved in the study for 52 to 59 days.
Targeted Study Population
This study will be conducted in healthy male and female subjects, 18 to 50 years of age.


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Investigational Medicinal Product
Supplier:
AstraZeneca
Formulations:
Verinurad prolonged release HPMC capsule 12 mg
Verinurad prolonged release gelatin capsule 12 mg
Verinurad/allopurinol FDC capsule 12/300 mg
Allopurinol tablet 300 mg
Strength/concentration:
Verinurad: 12 mg
Allopurinol: 300 mg
Dose:
Verinurad: 12 mg
Allopurinol: 300 mg
Route of administration:
Oral
Specific device for drug 
administration, if applicable:
Not applicable
Regimen:
Treatment 1: verinurad prolonged release HPMC capsule 12mg and 
allopurinol tablet 300mg, as a free combination, fasted state
Treatment 2: verinurad/allopurinol FDC capsule 12/300 mg, fasted state
Treatment 3: verinurad/allopurinol FDC capsule 12/300 mg, fed state
Treatment 4: verinurad prolonged release HPMC capsule 12mg and 
allopurinol tablet 300mg, as a free combination, fed state
Treatment 5: verinurad prolonged release gelatin capsule 12 mg, fasted 
state
Outcome Endpoints
Safety and Tolerability Endpoints:
Safety and tolerability variables will include:

Adverse events (AEs)

Laboratory assessments (haematology, clinical chemistry and urinalysis).

Physical examination

Electrocardiogram (ECG)

Vital signs (systolic and diastolic blood pressure, pulse, tympanic temperature)
Pharmacokinetic Endpoints:
The pharmacokinetic (PK) parameters will be determined for verinurad, allopurinol and 
oxypurinol using plasma concentrations.

Primary PK parameters:

Area under plasma concentration-time curve from time zero to infinity (AUCinf)

Area under the plasma concentration-time curve from time zero to time of last 
quantifiable concentration (AUClast)

Maximum observed plasma (peak) drug concentration (Cmax)

Secondary PK parameters:


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
Time to reach maximum observed plasma concentration following drug 
administration (tmax)

Time delay between drug administration and the first observed concentration in 
plasma (tlag)

Terminal elimination rate constantz)

Half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time 
curve (t½λz)

Mean residence time of the unchanged drug in the systemic circulation from zero to 
infinity (parent drug only) (MRTinf)

Apparent total body clearance of drug from plasma after extravascular administration 
(parent drug only) (CL/F)

Apparent volume of distribution during the terminal phase after extravascular 
administration (parent drug only) (Vz/F)

Volume of distribution (apparent) at steady state following extravascular 
administration (parent drug only) (Vss/F)
Additional PK parameters may be determined where appropriate.
Pharmacodynamic Endpoints:
The following PD variables will be assessed:

Observed values and percentage change from baseline (CB) (time-matched, Day -1) in 
sUA concentrations at each time point up to and including 72 hours following 
administration of verinurad and allopurinol in each treatment period

Emax, CB: Maximum percentage CB (time-matched, Day -1) in sUA concentrations up 
to and including 72 hours post-dose

tEmax, CB: Time of maximum percentage CB (time-matched, Day -1) in sUA
concentrations up to and including 72 hours post-dose
Statistical Methods
Presentation and Analysis of Safety and Eligibility Data:
All safety data will be presented in the data listings. Continuous variables will be summarised 
using descriptive statistics (n, mean, standard deviation [SD], minimum, median, maximum) 
by treatment. Categorical variables will be summarised in frequency tables (frequency and 
proportion) by treatment. The analysis of the safety variables will be based on the safety 
analysis set.
Adverse events will be summarised by Preferred Term and System Organ Class using Medical 
Dictionary for Regulatory Activities vocabulary.
Tabulations and listings of data for vital signs, clinical laboratory tests and ECGs (listings 
only) will be presented. Any new or aggravated clinically relevant abnormal medical physical 
examination finding compared to the baseline assessment will be reported as an AE.


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Out-of-range values for safety laboratory, vital signs and ECG will be flagged in individual 
listings as well as summarised descriptively using agreed standard reference ranges and/or 
extended reference ranges (eg, AZ, program, or laboratory ranges).
Presentation and Analysis of Pharmacokinetic Data:
Pharmacokinetic parameters will be summarised for each treatment using descriptive 
statistics. The descriptive statistics may include: n, geometric mean, geometric coefficient of 
variation, arithmetic mean, arithmetic SD, median, minimum and maximum. For tmax, only n, 
median, minimum and maximum will be presented.
The geometric mean ratios of Cmax, AUCinf and AUClast will be calculated for each
treatment comparison (Test treatment versus Reference treatment). Analyses will be 
performed using a linear mixed-effects analysis of variance model using the natural logarithm 
of Cmax, AUCinf and AUClast as the response variables, sequence, period and treatment as 
mixed-effects, subject nested within sequence as a random effect. Transformed back from the 
logarithmic scale, geometric means together with confidence intervals (CIs) (2-sided 95%) for 
Cmax, AUCinf and AUClast will be calculated and presented. Also, ratios of geometric means 
together with CIs (2-sided 90%) will be estimated and presented. Additionally, the 90% CI for 
the difference in tmax will be calculated and presented.
The following comparisons of relative bioavailability (Cmax, AUCinf and AUClast) for each 
analyte (verinurad, allopurinol and oxypurinol) will be performed:

Treatment 2 versus Treatment 1, ie, “verinurad/allopurinol FDC capsule, fasted” versus
“verinurad HPMC capsule and allopurinol tablet, free combination, fasted”.

Treatment 3 versus Treatment 2, ie “verinurad/allopurinol FDC capsule, fed” versus
“Verinurad/allopurinol FDC capsule. fasted”.

Treatment 4 versus Treatment 1, ie. “verinurad HPMC capsule and allopurinol tablet, free 
combination, fed” versus “verinurad HPMC capsule and allopurinol tablet, free 
combination, fasted”.

Treatment 3 versus Treatment 4, ie. “verinurad/allopurinol FDC capsule, fed” versus 
“verinurad HPMC capsule and allopurinol tablet, free combination, fed”.

Treatment 5 versus Treatment 2 (for verinurad only), ie., “verinurad gelatin capsule,
fasted” versus “verinurad/allopurinol FDC capsule, fasted”.
Presentation and Analysis of Pharmacodynamic Data:
Analyses of sUA will be based on log-transformed values (natural logarithm). Descriptive 
statistics will be presented for sUA observed and time-matched percentage change from 
baseline, Emax CB and tEmax CB by treatment. For observed and time-matched percentage 
change from baseline, the descriptive statistics will include n, geometric mean, geometric CV, 
arithmetic mean, arithmetic SD, median, minimum, and maximum. A listing of sUA sample 
collection times, as well as derived sampling time deviations will be provided.
Sample Size Determination
The sample size was chosen to obtain a reasonable assessment of relative bioavailability 
between different formulations of verinurad and allopurinol without exposing undue numbers 
of subjects to the compound at this phase of clinical development. It is estimated that 20 subjects 
randomised to 5 sequences in a reduced Latin square will provide a 90% CI within 0.7 and 1.43,


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with a probability of > 90% if the estimated treatment ratio is 1 for Cmax. This is based on an 
intra-subject variability of 24% for Cmax of verinurad in Study D5495C00001. Similarly, it is 
estimated that 20 subjects will provide a 90% CI within 0.8 and 1.25, with a probability of 
> 95% if the estimated treatment ratio is 1 for AUC. This is based on an intra-subject variability 
of 14.7% for AUC of verinurad in Study D5495C00001.
Twenty-five subjects will be equally randomised to 5 treatment sequences: 12345, 23451,
34512, 45123, and 51234 in order to ensure at least 20 evaluable subjects at the end of the last 
treatment period.


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TABLE OF CONTENTS
PROTOCOL AMENDMENTS............................................................................................. 2
Protocol Amendment No. 1, dated 21 Janaury 2021 .............................................................. 2
PROTOCOL SYNOPSIS...................................................................................................... 6
TABLE OF CONTENTS.................................................................................................... 12
List of Tables...................................................................................................................... 15
List of Figures..................................................................................................................... 15
List of Appendices.............................................................................................................. 16
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS.......................................... 17
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE............................. 22
1.
INTRODUCTION............................................................................................ 25
1.1.
Background Information................................................................................... 25
1.1.1.
Description of Verinurad .................................................................................. 25
1.2.
Background to COVID-19................................................................................ 26
1.3.
Rationale for Conducting this Study.................................................................. 26
2.
STUDY OBJECTIVES..................................................................................... 27
2.1.
Primary Objective............................................................................................. 27
2.2.
Secondary Objectives........................................................................................ 27
3.
STUDY DESIGN ............................................................................................. 28
3.1.
Overall Study Design and Flow Chart............................................................... 28
3.1.1.
Order of Assessments ....................................................................................... 35
3.1.2.
End of Study..................................................................................................... 35
3.1.3.
Expected Duration of the Study ........................................................................ 35
3.2.
Rationales for Study Design and Dose Selection............................................... 35
3.2.1.
Rationale for Study Design ............................................................................... 35
3.2.2.
Dose Rationale.................................................................................................. 35
3.3.
Risk-benefit Assessment................................................................................... 36
3.3.1.
Verinurad.......................................................................................................... 37
3.3.1.1.
Non-clinical Findings........................................................................................ 37
3.3.1.2.
Clinical Studies................................................................................................. 37
3.3.2.
Allopurinol ....................................................................................................... 37
3.3.3.
Risk Assessment for COVID-19 Pandemic ....................................................... 37
4.
STUDY POPULATION ................................................................................... 40
4.1.
Selection of Study Population ........................................................................... 40
4.1.1.
Inclusion Criteria .............................................................................................. 40
4.1.2.
Exclusion Criteria ............................................................................................. 41
4.2.
Restrictions During the Study ........................................................................... 43
4.2.1.
Reproductive Restrictions ................................................................................. 44
4.2.1.1.
Women of Non-childbearing Potential.............................................................. 44


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4.2.1.2.
Women of Childbearing Potential ..................................................................... 44
4.2.1.3.
Male Subjects ................................................................................................... 46
4.3.
Replacement of Subjects................................................................................... 46
5.
STUDY CONDUCT......................................................................................... 47
5.1.
Subject Enrolment and Randomisation.............................................................. 47
5.1.1.
Procedures for Randomisation .......................................................................... 47
5.2.
Procedures for Handling Incorrectly Randomised Subjects ............................... 48
5.3.
Blinding............................................................................................................ 48
5.4.
TREATMENTS................................................................................................ 48
5.4.1.
Identity of the Investigational Medicinal Product.............................................. 48
5.4.2.
Supply of Investigational Medicinal Product..................................................... 49
5.4.3.
Dose and Treatment Regimens.......................................................................... 49
5.4.4.
Other restrictions, including posture control are described in Section 4.2. Data 
of subjects may be excluded from the PK analysis set as described in 
Section 11.1.2.FDA Breakfast Menu................................................................. 50
5.4.5.
Labelling .......................................................................................................... 50
5.4.6.
Storage and Handling Procedures...................................................................... 50
5.5.
Concomitant and Post-study Treatment(s)......................................................... 50
5.6.
Treatment Compliance...................................................................................... 51
5.6.1.
Drug Accountability, Dispensing and Destruction............................................. 51
5.7.
Discontinuation of Investigational Product and Withdrawal from Study............ 51
5.7.1.
Procedures for Withdrawal of a Subject from the Study.................................... 52
5.8.
Premature Termination of the Study.................................................................. 52
6.
COLLECTION OF STUDY VARIABLES....................................................... 54
6.1.
Recording of Data............................................................................................. 54
6.2.
Enrolment and Screening Procedures................................................................ 54
6.3.
Safety and Eligibility Measurements................................................................. 54
6.3.1.
Adverse Events................................................................................................. 54
6.3.1.1.
Definition of Adverse Events............................................................................ 54
6.3.1.2.
Definitions of Serious Adverse Event ............................................................... 55
6.3.1.3.
Other Significant Adverse Events ..................................................................... 55
6.3.1.4.
Recording of Adverse Events............................................................................ 56
6.3.1.5.
Reporting of Serious Adverse Events................................................................ 58
6.3.1.6.
Regulatory Reporting Requirements for Serious Adverse Events ...................... 59
6.3.2.
Laboratory Assessments ................................................................................... 59
6.3.2.1.
Haematology .................................................................................................... 59
6.3.2.2.
Serum Clinical Chemistry................................................................................. 60
6.3.2.3.
Genotyping....................................................................................................... 60
6.3.2.4.
Urinalysis ......................................................................................................... 60
6.3.2.5.
Pregnancy Testing ............................................................................................ 60
6.3.2.6.
Viral Serology .................................................................................................. 61
6.3.2.7.
SARS-CoV-2 Virology..................................................................................... 61
6.3.2.8.
Drugs of Abuse, Alcohol, and Cotinine............................................................. 61


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6.3.3.
Physical Examination........................................................................................ 61
6.3.4.
Electrocardiograms........................................................................................... 61
6.3.4.1.
Resting 12-lead Electrocardiogram ................................................................... 61
6.3.5.
Vital Signs........................................................................................................ 62
6.4.
Pharmacokinetics.............................................................................................. 62
6.4.1.
Collection of Pharmacokinetic Samples ............................................................ 62
6.4.1.1.
Plasma Samples................................................................................................ 62
6.4.2.
Pharmacokinetic Drug Assays........................................................................... 62
6.5.
Pharmacodynamics........................................................................................... 63
6.5.1.
Collection of Pharmacodynamic Samples ......................................................... 63
7.
BIOLOGICAL SAMPLES PROCEDURES ..................................................... 63
7.1.
Total Blood Volume ......................................................................................... 63
7.2.
Handling, Storage and Destruction of Biological Samples................................. 64
7.2.1.
Safety Samples ................................................................................................. 64
7.2.2.
Pharmacokinetic Samples ................................................................................. 64
7.2.3.
Pharmacodynamic Samples............................................................................... 64
7.3.
Labelling and Shipment of Biohazard Samples ................................................. 64
7.4.
Chain of Custody of Biological Samples........................................................... 64
7.5.
Withdrawal of Informed Consent for Donated Biological Samples.................... 65
8.
ETHICAL AND REGULATORY REQUIREMENTS...................................... 66
8.1.
Ethical Conduct of the Study............................................................................. 66
8.2.
Subject Data Protection..................................................................................... 66
8.3.
Ethics and Regulatory Review .......................................................................... 66
8.4.
Insurance .......................................................................................................... 66
8.5.
Informed Consent ............................................................................................. 67
8.6.
Changes to the Protocol and Informed Consent Form........................................ 67
9.
DATA QUALITY ASSURANCE AND DATA MANAGEMENT................... 68
9.1.
Quality Control and Source Data Verification................................................... 68
9.2.
Audit/Inspections.............................................................................................. 68
9.3.
Study Monitoring.............................................................................................. 68
9.4.
Data Collection................................................................................................. 68
9.4.1.
Case Report Forms and Source Documents....................................................... 69
9.4.2.
Access to Source Documents ............................................................................ 69
9.5.
Data Management............................................................................................. 69
10.
EVALUATION AND CALCULATION OF VARIABLES .............................. 71
10.1.1.
Adverse Events................................................................................................. 71
10.1.2.
Laboratory Assessments ................................................................................... 72
10.1.3.
Physical Examination........................................................................................ 73
10.1.4.
Resting 12-lead Electrocardiogram ................................................................... 73
10.1.5.
Vital Signs........................................................................................................ 73
10.2.
Pharmacokinetic Parameters ............................................................................. 73


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10.2.1.
Plasma Parameters............................................................................................ 73
10.2.2.
Calculation or Derivation of Pharmacokinetic Parameters................................. 74
10.3.
Pharmacodynamic parameters........................................................................... 75
11.
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION.......... 75
11.1.
Description of the Analysis Sets........................................................................ 75
11.1.1.
Safety Analysis Set........................................................................................... 75
11.1.2.
Pharmacokinetic Analysis Set........................................................................... 75
11.1.3.
Pharmacodynamic Analysis Set ........................................................................ 76
11.1.4.
Randomised Set................................................................................................ 76
11.2.
Methods of Statistical Analyses ........................................................................ 76
11.2.1.
General Principles............................................................................................. 76
11.2.2.
Missing Data..................................................................................................... 77
11.2.3.
Subject Characteristics...................................................................................... 78
11.2.3.1.
Demographic and Baseline Data ....................................................................... 78
11.2.4.
Prior and Concomitant Medication and Drug Administration............................ 78
11.2.4.1.
Prior and Concomitant Medication.................................................................... 78
11.2.4.2.
Drug Administration......................................................................................... 79
11.2.5.
Safety and Tolerability...................................................................................... 79
11.2.7.
Inferential Statistical Analysis of Pharmacokinetic Data ................................... 80
11.2.8.
Presentation and Statistical Analysis of Pharmacodynamic Data ....................... 81
11.3.
Protocol Deviations........................................................................................... 81
11.4.
Determination of Sample Size........................................................................... 82
12.
LEGAL AND ADMINISTRATIVE ASPECTS................................................ 83
12.1.
Archiving of Study Documents......................................................................... 83
12.2.
Publication of Study Results ............................................................................. 83
12.3.
Clinical Study Report........................................................................................ 83
13.
REFERENCE LIST.......................................................................................... 84
14.
APPENDICES.................................................................................................. 86
List of Tables
Table 2-1
Primary Objective and Outcome Measures............................................... 27
Table 2-2
Secondary Objectives and Outcome Measures ......................................... 27
Table 3-1
Schedule of Assessments ......................................................................... 31
Table 5-1
Identity of the Investigational Medicinal Product..................................... 48
Table 7-1
Total Blood Volume ................................................................................ 63
List of Figures
Figure 3-1
Study Flow Chart..................................................................................... 30


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List of Appendices
Appendix A
Additional Safety Information.................................................................. 86
Appendix B
International Airline Transportation Association 6.2 Guidance Document89
Appendix C
Actions Required in Cases of Combined Increase of Aminotransferase 
and Total Bilirubin - Hy’s Law ................................................................ 90
Appendix D
Actions Required in Cases of a Renal-related or Urolithiasis 
Treatment-emergent Adverse Event or a Serum Creatinine Elevation ...... 95


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviation or 
special term
Explanation
AE
Adverse event (see definition in Section 6.3.1.1)
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUCextr
Extrapolated area under the curve from tlast to infinity, expressed as percentage of 
AUCinf
AUCinf
Area under plasma concentration-time curve from time zero to infinity
AUClast
Area under the plasma concentration-time curve from time zero to time of last 
quantifiable concentration
AV
Atrioventricular
BfArM
Bundesinstitut für Arzneimittel und Medizinprodukte (The Federal Institute for 
Drugs and Medical Devices)
BMI
Body mass index
BP
Blood pressure
bpm
Beats per minute
CB
Change from baseline
CI
Confidence interval 
CKD
Chronic Kidney Disease
CL/F
Apparent total body clearance of drug from plasms after extravascular 
administration (parent drug only)
ClinBase™
Parexel’s electronic source data capturing and information management system
Cmax
Maximum observed plasma (peak) drug concentration
COVID-19
Coronavirus disease 2019
CRF
Case report form
CRO
Contract research organization
CRP
C-reactive protein
CSP
Clinical Study Protocol
CSR
Clinical Study Report 
CV
Coefficient of variation
DAE
Adverse event leading to the discontinuation of IMP
DCF
Data clarification form
DMP
Data management plan
DNA
Deoxyribonucleic acid
DRESS
Drug rash with eosinophilia and systemic symptoms


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Abbreviation or 
special term
Explanation
DVS
Data validation specification
ECG
Electrocardiogram
eGRF
Estimated Glomerular Filtration Rate
EMA
European Medicines Agency
Emax, CB
Maximum percentage CB (time-matched, Day -1) in sUA concentrations up to and 
including 72 hours post-dose
ER
Extended-release
FDA
Food and Drug Administration
FDC
Fixed-dose combination
FSH
Follicle stimulating hormone
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
GGT
Gamma glutamyl transpeptidase (transferase)
GMP
Good Manufacturing Practice
gSD
Geometric standard deviation
Hb
Haemoglobin
HbsAg
Hepatitis B surface antigen
HCT
Haematocrit
HF
Heart Failure
HIV
Human immunodeficiency virus
HL
Hy’s Law
HPMC
Hydroxypropyl methylcellulose
IATA
International Airline Transportation Association
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonization
IEC
Independent Ethics Committee
IgG
Immunoglobin G
IMP
Investigational medicinal product
INR
International normalized ratio
IR
Immediate release
LLOQ
Lower limit of quantification
MCH
Mean corpuscular haemoglobin
MCHC
Mean corpuscular haemoglobin concentration
MCV
Mean corpuscular volume


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Abbreviation or 
special term
Explanation
MedDRA
Medical Dictionary for Regulatory Activities
MRTinf
Mean residence time of the unchanged drug in the systemic circulation from zero to 
infinity (parent drug only)
ms
milliseconds
N
Number of subjects
n
Number of data values
NA
Not applicable
NC
Not calculated
ND
Not determined
NQ
Not quantifiable
NR
No result
NS
No sample
OAE
Other significant adverse events
OTC
Over-the-counter
PDF
Portable Document Format
PHL
Potential Hy’s Law
PI
Principal Investigator
PK
Pharmacokinetics
QRS
ECG interval measured from the onset of the QRS complex to the J point
QT
ECG interval measured from the onset of the QRS complex to the end of the T 
wave
QTcF
QT interval corrected for heart rate using Fridericia’s formula
R&D
Research and Development
RBC
Red blood cell
Rsq_adj
Statistical measure of fit for the regression used for λz determination adjusted for 
the number of used data points (λzN)
RT-PCR
Reverse transcriptase polymerase chain reaction
SAE
Serious adverse event (see definition in Section 6.3.1.2).
SAP
Statistical Analysis Plan
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SD
Standard deviation
SJS
Stevens-Johnson syndrome
SoA
Schedule of assessments
SOC
System Organ Class
SOP
Standard operating procedure
SRC
Safety Review Committee


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Abbreviation or 
special term
Explanation
sUA
Serum uric acid
SUSAR
Suspected unexpected serious adverse reaction
t½λz
Half-life associated with terminal slope (λz) of a semi-logarithmic 
concentration-time curve
TBL
Total bilirubin
TCA
Tricyclic anti-depressant
TCS
Tata Consultancy Services – an AstraZeneca partner who conduct data entry onto 
Sapphire
TEAE
Treatment-emergent adverse event
tEmax, CB
Time of maximum percentage CB (time-matched, Day -1) in sUA concentrations
up to and including 72 hours post-dose
TEN
Toxic epidermal necrolysis
TFL
Table, Figure and Listing 
tlag
Time delay between drug administration and the first observed concentration in 
plasma
tlast
Time of last observed (quantifiable) concentration
tmax
Time to reach maximum observed plasma concentration following drug 
administration
TSH
Thyroid-stimulating hormone
uUA
Urine uric acid
UA
Uric acid
ULN
Upper limit of normal
URAT1
Human urate transporter 1
US
United States
Vss/F
Volume of distribution (apparent) at steady state following extravascular 
administration (parent drug only)
Vz/F
Apparent volume of distribution during the terminal phase after extravascular 
administration (parent drug only)
WAD
Windows Allowance Document
WBC
White blood cell
WHO
World Healthy Organisation
XO
Xanthine oxidase
XOI
Xanthine oxidase inhibitor
λz
Terminal elimination rate constant
λz lower
Lower (earlier) t used for λz determination
λz span ratio
Time period over which λz was determined as ratio of t½λz
λz upper
Upper (later) t used for λz determination


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Abbreviation or 
special term
Explanation
λzN
Number of data points used for λz determination


Cli nical St u d y Pr ot oc ol
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V eri n ura d a n d A ll o p uri n ol - D 5 4 9 5 C 0 0 0 1 4
2 2 Fe br uar y 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y
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I N V E S TI G A T O R S A N D S TU D Y A D MI NI S T R A TI V E S T R U C T U R E
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S p o ns or’s Lea d P h ysicia n:
Astra Ze neca Bi o P har mace uticals R & D
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U n ite d States of A merica
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Cli nical St u d y Pr ot oc ol
Astra Ze neca
V eri n ura d a n d A ll o p uri n ol - D 5 4 9 5 C 0 0 0 1 4
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C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 3 of 9 6
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Cli nical St u d y Pr ot oc ol
Astra Ze neca
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P P D
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1.
INTRODUCTION
1.1.
Background Information
Verinurad is a novel URAT1 inhibitor being developed by AstraZeneca to treat patients with 
CKD and/or HF. By inhibiting URAT1, verinurad prevents UA reabsorption, increases renal 
UA excretion, and thereby lowers sUA concentrations [1].
The initial development focus for verinurad was for the treatment of gout, which is caused by 
hyperuricaemia. Therefore, the initial clinical data accumulated on verinurad relate to gout. 
However, hyperuricaemia is also associated with an increased risk of CKD [2, 3, 4, 5] and 
HF [6, 7, 8] providing a rationale for developing verinurad in these indications. Despite the 
established association between hyperuricaemia and CKD and HF, a causal relationship 
between them remains to be proven.
Potent URAT1 inhibition has been associated with creatinine elevations in a fraction of 
patients, likely related to increased UA peak concentrations in the proximal tubuli of the 
kidney. Verinurad is to be developed exclusively in FDC with the XOI, allopurinol, thus also 
reducing the production of UA and thereby mitigating the risk of creatinine elevations.
The IB describes results from pre-clinical studies, clinical pharmacological studies, and 
clinical monotherapy and combination therapy with allopurinol [1].
1.1.1.
Description of Verinurad
Verinurad is a potent and specific URAT1 inhibitor. URAT1 is responsible for most of the 
reabsorption of filtered UA from the renal tubular lumen. By inhibiting URAT1, verinurad 
increases urine UA excretion and thereby lowers sUA.
1.1.1.1.
Clinical Pharmacokinetics
Following administration of verinurad as an extended-release capsule formulation (ER8), 
Cmax occurred 4 hours after dosing. Food did not affect verinurad exposure except for a 
2-hour increase in tmax. The degree of protein binding of verinurad in human plasma was 
97%. Glucuronidation is the major metabolic pathway of verinurad with oxidation as the 
minor pathway. The major metabolites observed in humans after oral verinurad dosing are the 
acyl glucuronides M1 and M8 which are renally cleared. The amount of verinurad in urine is 
small (< 2% of given dose). The terminal half-life (t½) of verinurad was 13 hours in subjects 
with normal renal function and 21 hours in those with moderate renal impairment. The 
exposure ([AUC] and Cmax) of verinurad increased in a dose proportional manner and the 
accumulation was minimal after once daily dosing. Subjects with an eGFR of 45 and 
60 mL/min/1.73 m2 are predicted to have a 1.4 and 1.2-fold higher verinurad exposure, 
respectively, compared to those with normal renal function (eGFR of 90 mL/min/1.73 m2). 


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Asian subjects are predicted to have about 44% higher exposure compared to non-Asians after 
accounting for differences in renal function and body weight.
Further information on PK findings (including PK parameters of the verinurad IR 
formulation) is available in the IB [1].
1.2.
Background to COVID-19
There is currently an outbreak of COVID-19 caused by the novel virus SARS-CoV-2 that was 
first detected in Wuhan City, Hubei Province, China in 2019. This new virus has rapidly 
spread across the globe, causing the WHO to declare a pandemic situation on 11 March 2020. 
The countermeasures initiated by national and local governments worldwide and the 
recommendations issued by the health authorities have impacted current and new clinical 
studies. As the threat of pandemic burden, including recent outbreaks, locally or globally, will 
impact the further conduct of clinical studies, appropriate risk assessments and mitigation 
measures will need to be taken into consideration in all clinical studies to protect subjects, site 
staff and society as a whole.
Both EMA [9] and FDA [10], as well as national health authorities in Europe, have issued 
new guidelines that aim to provide recommendations for actions for conduct of clinical studies 
of medical products during COVID-19 pandemic. The FDA have also issued guidance to 
provide recommendations on statistical considerations to address the impact of COVID-19 on 
meeting trial objectives for clinical trials conducted during the duration of the COVID-19 
public health emergency [11]. Since the pandemic situation is evolving, guidelines, 
recommendations, national laws and local restrictions may change at a high pace. Given the 
circumstances of potentially relapsing pandemic or epidemic situation with regard to the 
spread of COVID-19 in future, special attention will be paid to protect subjects participating 
in the study and site staff involved in the investigations against infection with SARS-CoV-2 as 
requested by the newly issued EMA guideline.
1.3.
Rationale for Conducting this Study
This study is intended to assess the relative bioavailability between the fixed-dose 
combination (FDC, ie, verinurad/allopurinol FDC capsule 12/300 mg) and free combination 
formulations of verinurad (ie, verinurad prolonged release HPMC capsule 12 mg) and 
allopurinol (ie, allopurinol table 300 mg) in fasted and fed conditions. The study will also 
assess the relative bioavailability between a formulation only containing verinurad (ie, 
verinurad prolonged release gelatin capsule 12 mg) and the FDC capsule. For verinurad, all
formulations have prolonged release profile. For allopurinol, both formulations containing 
alopurinol have an immediate release profile.


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2.
STUDY OBJECTIVES
2.1.
Primary Objective
Table 2-1
Primary Objective and Outcome Measures
Primary Objective
Outcome Measures
•
To evaluate the relative bioavailability of 
verinurad, allopurinol and oxypurinol after 
dosing with the verinurad/allopurinol FDC 
capsule 12/300 mg and free combination 
formulations of verinurad (verinurad prolonged 
release HPMC capsule 12 mg) and allopurinol 
(allopurinol tablet 300 mg), under fasted 
conditions.
•
Primary pharmacokinetic parameters:
AUCinf, AUClast and Cmax of verinurad, 
allopurinol and oxypurinol
2.2.
Secondary Objectives
Table 2-2
Secondary Objectives and Outcome Measures
Secondary Objectives
Outcome Measures
•
To evaluate the relative bioavailability of 
verinurad, allopurinol and oxypurinol after 
dosing with the verinurad/allopurinol FDC 
capsule 12/300 mg under fed and fasted 
conditions and with free combination 
formulations (verinurad prolonged release 
HPMC capsule 12 mg) and allopurinol 
(allopurinol tablet 300 mg), under fed and fasted 
conditions
•
Primary pharmacokinetic parameters:
AUCinf, AUClast and Cmax of verinurad, 
allopurinol and oxypurinol
•
To evaluate the relative bioavailability of 
verinurad after dosing with the verinurad 
prolonged release gelatin capsule 12 mg and 
verinurad/allopurinol FDC capsule 12/300 mg 
under fasted conditions
•
Primary pharmacokinetic parameters:
AUCinf, AUClast and Cmax of verinurad, 
allopurinol and oxypurinol
•
To assess the pharmacokinetic profiles of 
verinurad, allopurinol and oxypurinol when 
administered as the verinurad/allopurinol FDC 
capsule 12/300 mg and free combination 
formulations of verinurad (verinurad prolonged 
release HPMC capsule 12 mg) and allopurinol 
(allopurinol tablet 300 mg) under fed and fasted 
conditions and of verinurad when administered 
as a prolonged release gelatin capsule 12 mg 
under fasted conditions
•
Plasma concentration-time profiles of verinurad, 
allopurinol and oxypurinol.
•
Primary pharmacokinetic parameters:
AUCinf, AUClast and Cmax of verinurad, 
allopurinol and oxypurinol
•
Secondary pharmacokinetic parameters:
tmax, tlag, z, t½λz, CL/F, MRTinf, Vss/F, and 
Vz/F of verinurad, allopurinol and oxypurinol
•
To assess the safety of single doses of verinurad 
and allopurinol
•
Adverse events, vital signs (systolic and 
diastolic blood pressure, pulse, tympanic 
temperature), resting 12-lead 
electrocardiograms, physical examination, and 
laboratory assessments (haematology, clinical 
chemistry and urinalysis)


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Secondary Objectives
Outcome Measures
•
To assess the PD of verinurad, allopurinol and 
oxypurinol when administered as the 
verinurad/allopurinol FDC capsule 12/300 mg 
and free combination formulations of verinurad 
(verinurad prolonged release HPMC capsule 12 
mg) and allopurinol (allopurinol tablet 300 mg) 
under fed and fasted conditions and of verinurad 
when administered as a prolonged release 
gelatin capsule 12 mg under fasted conditions
•
Observed values and percentage CB
(time-matched, Day -1) in sUA concentrations
at each time point up to and including 72 hours 
following administration of verinurad and 
allopurinol (verinurad only for Treatment 5) in
each treatment period
•
Emax, CB: Maximum percentage CB
(time-matched, Day -1) in sUA concentrations
up to and including 72 hours post-dose
•
tEmax, CB: Time of maximum percentage CB
(time-matched, Day -1) in sUA concentration up 
to and including 72 hours post-dose
Refer to Section 6.4.1 for collection of PK samples and Section 6.3 for safety assessments.
3.
STUDY DESIGN
3.1.
Overall Study Design and Flow Chart
This study will be a single-centre, randomised, open-label, single-dose, 5-period, 5-treatment, 
crossover study in healthy male and female subjects.
The study will comprise:

A Screening Period of maximum 28 days.

Five treatment periods during which subjects will be resident from the morning of Day -2
until at least 72 hours after dosing in Treatment Period 5; discharged on the morning of 
Day 4 of Treatment Period 5.

A Follow-up Visit 7 to 14 days after the last dosing.
There will be a minimum washout period of 5 days between each dose administration.
A total of 25 healthy male and female subjects will be randomised into one of 5 treatment 
sequences to ensure at least 20 evaluable subjects at the end of the last treatment period. Each 
subject will receive 5 single-dose treatments of verinurad and allopurinol or verinurad alone:

Treatment 1: verinurad prolonged release HPMC capsule 12mg and allopurinol tablet 
300mg, as a free combination, fasted state.

Treatment 2: verinurad/allopurinol FDC capsule 12/300 mg, fasted state.

Treatment 3: verinurad/allopurinol FDC capsule 12/300 mg, fed state.

Treatment 4: verinurad prolonged release HPMC capsule 12mg and allopurinol tablet 
300mg, as a free combination, fed state.

Treatment 5: verinurad prolonged release gelatin capsule 12 mg, fasted state.


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All subjects will be instructed to drink approximately 2 L to 2.5 L of liquid a day, starting on
Day -2 and throughout the stay at the clinic.
Subjects will follow an overnight fast of at least 10 hours before the dosing procedures: for the 
fed dosing, a high-fat, high-calorie breakfast (see Section 0) will be served 30 minutes before 
the planned administration of IMP, and is to be consumed in full at least 5 minutes before 
dosing; for the fasted dosing, no breakfast will be served. A meal can be given 4 hours after 
administration of IMP for both dosing states.
Details on IMP administration and food and fluid restrictions in relation to IMP administration 
are provided in Section 5.4.3.
The study flow-chart is presented in Figure 3-1. The SoA displaying assessments/tasks and 
time-points is presented in Table 3-1.
The study design is deemed appropriate for conduct in healthy volunteers during the 
COVID-19 pandemic (Section 3.3.3).


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Figure 3-1
Study Flow Chart
Screening
< 28 days before randomisation
Admission Day -2 a
Randomisation 
Treatment Period 1
Dosing (Treatment 1/2/3/4/5) Day 1
At least 5 days washout between IMP 
administration 
Treatment Period 2
Dosing (Treatment 1/2/3/4/5) Day 1
At least 5 days washout between IMP 
administration
Treatment Period 3
Dosing (Treatment 1/2/3/4/5) Day 1
At least 5 days washout between IMP 
administration
Treatment Period 4
Dosing (Treatment 1/2/3/4/5) Day 1
At least 5 days washout between IMP 
administration
Treatment Period 5
Dosing (Treatment 1/2/3/4/5) Day 1
Discharge on Day 4
7 to 14 days after last IMP 
administration
Follow-up Visit
7 to 14 days post-final dose
Treatment 1: verinurad prolonged release HPMC capsule 12mg and allopurinol tablet 300mg, as a free 
combination, fasted state.
Treatment 2: verinurad/allopurinol FDC capsule 12/300 mg, fasted state.
Treatment 3: verinurad/allopurinol FDC capsule 12/300 mg, fed state.
Treatment 4: verinurad prolonged release HPMC capsule 12mg and allopurinol tablet 300mg, as a free 
combination, fed state.
Treatment 5: verinurad prolonged release gelatin capsule 12 mg, fasted state.
IMP: Investigational Medicinal Product.


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Table 3-1
Schedule of Assessments
Screening
Admission
Treatment Periods 1, 2, 3, 4, and 5
Follow-up 
Visit
Corresponding
Section in 
Protocol
Visit
1
2
3
Study Day
Day -28 
to -3
Day -2
Day -1
Day 1 to 4
7 to 14 
days post
final dose
Inclusion/exclusion criteria
X
X
X a
Sections 4.1.1
and 4.1.2
Demographic data
X
Section 11.2.3.1
Medical history
X
Section 11.2.3.1
Urinary drug/alcohol/cotinine screen
X
X
Section 6.3.2.8
Serology
X
Section 6.3.2.6
Informed consent
X
Section 8.5
HLA-B*58:01 allele genotyping
X
Section 6.3.2.3
Randomisation
X b
Section 5.1.1
Study Residency:
Check-in
X
(in the 
morning) c
Section 3.1
Check-out
Day 4 (after 72 h 
post-dose 
assessments) c
Section 3.1
Non-residential visit
X
X
Section 3.1
Verinurad and Allopurinol 
(verinurad only for Treatment 5)
Administration:
Day 1 (0 h)
Sections 3.1
and 5.4.3


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Screening
Admission
Treatment Periods 1, 2, 3, 4, and 5
Follow-up 
Visit
Corresponding
Section in 
Protocol
Visit
1
2
3
Study Day
Day -28 
to -3
Day -2
Day -1
Day 1 to 4
7 to 14 
days post
final dose
Safety and Tolerability:
Tympanic temperature d
X
X
X e
X
X
Section 6.3.5
Adverse event questioning and 
reporting f
X
X
X e
Spontaneous plus
Day 1: pre-dose, 3 
and 12 h post-dose
Day 2: 24 h post-dose
Day 3: 48 h post-dose
Day 4: 72 h post-dose
X
Section 6.3.1
Prior and concomitant medications 
questioning
X
X
X e
X
X
Section 11.2.4.1
Blood pressure and pulse (supine)
X
X
X e
Day 1: Pre-dose
Day 4: 72 h post-dose
X
Section 6.3.5
Safety 12-lead electrocardiograms
X
X
Section 6.3.4
Clinical laboratory evaluations g
X
X
X e
X
Section 6.3.2
Physical examination
X
X (brief)
X (brief) e
Day 4: 72 h post-dose 
(brief)
X
Section 6.3.3
Body weight and height, BMI
X
Pregnancy test h
X
X
X
Section 6.3.2.5
COVID-19 Assessments
Pre-visit phone call i
X
X
X
SARS-CoV-2 RT-PCR
X j
Section 6.3.2.7
SARS-CoV-2 antibody
X
Section 6.3.2.7


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Screening
Admission
Treatment Periods 1, 2, 3, 4, and 5
Follow-up 
Visit
Corresponding
Section in 
Protocol
Visit
1
2
3
Study Day
Day -28 
to -3
Day -2
Day -1
Day 1 to 4
7 to 14 
days post
final dose
Pharmacokinetics
Pharmacokinetic sampling for 
verinurad, allopurinol and oxypurinol
k
Day 1: Pre-dose, 0.5, 
1, 1.5, 2, 3, 4, 5, 6, 8, 
10 and 12 h post-dose
Day 2: 24 and 36 h 
post-dose
Day 3: 48 h post-dose
Day 4: 72 h post-dose
Section 6.4.1
Pharmacodynamics
Pharmacodynamic sampling for sUA
-24, -23, -22, -21, -20, -19, 
-18, -16, -14 and -12 h l
Day 1: Pre-dose, 1, 2, 
3, 4, 5, 6, 8, 10 and 
12 h post-dose
Day 2: 24 h, Day 3: 
48 h post-dose, Day 4: 
72 h post-dose h 
post-dose
Section 6.5.1
a
Eligibility criteria will be reconfirmed on Day -1 of Treatment Period 1, prior to randomisation.
b
Randomisation will take place on Day -1 of Treatment Period 1, after eligibility has been reconfirmed.
c
Subjects will be admitted to the Clinical Unit on Day -2 and will remain residential until they are discharged on Day 4 of Treatment Period 5.
d
Tympanic temperature will be measured at least once daily (in the morning) on the days of assessment.
e
Applicable to Day -1 of Treatment Periods 2 to 5 only.
f
Adverse events will be collected from the start of randomisation throughout the treatment periods up to and including the Follow-up Visit. Serious adverse 
events will be recorded from the time of informed consent.
g
Blood (clinical chemistry and haematology) and urine (urinalysis) sample collection. Samples will be collected following an overnight fast.
h
Serum pregnancy tests will be performed at Screening. Urine pregnancy test will be performed at admission (Day -2 of Treatment Period 1) and the 
Follow-up Visit.


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i
Phone calls will be made 1 day prior to each visit to record signs and symptoms of COVID-19 or any contact with persons having confirmed SARS-CoV-2 
infection. In case of signs or symptoms or contact, the visit will be cancelled and the reason for cancellation will be appropriately documented.
j
At the discretion of the investigator, an unscheduled SARS-CoV-2 RT-PCR can be performed in case of any signs or symptoms of COVID-19.
k
Samples for allopurinol and oxypurinol will not be collected for Treatment 5.
l
Applicable to Treatment Period 1 only.
AE: Adverse event; BMI: Body mass index; COVID-19: Coronavirus disease 2019; RT-PCR: Reverse transcriptase polymerase chain reaction;
SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; sUA: Serum uric acid.


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3.1.1.
Order of Assessments
It is important that PK sampling occurs as close as possible to scheduled time. In order to 
achieve this, other assessments scheduled at the same time may be initiated prior to the time 
point. The sequence at a particular time point is:
1
Electrocardiograms.
2
Vital signs (systolic and diastolic BP, pulse and tympanic temperature).
3
Pharmacokinetic blood sampling (will be drawn at the specified time point).
4
Pharmacodynamic and safety blood sampling.
Details of acceptable window allowance for the timing of safety and PK assessments will be 
included in a WAD which will be agreed upon and signed off before the start of the study.
3.1.2.
End of Study
The end of study is defined as the last subject’s last visit to the Clinical Unit.
3.1.3.
Expected Duration of the Study
Each subject will be involved in the study for 52 to 59 days.
3.2.
Rationales for Study Design and Dose Selection
3.2.1.
Rationale for Study Design
This study is intended to assess the relative bioavailability between the fixed-dose 
combination (FDC, ie, verinurad/allopurinol FDC capsule 12/300 mg) and free combination 
formulations of verinurad (ie, verinurad prolonged release HPMC capsule 12 mg) and 
allopurinol (ie, allopurinol table 300 mg) in fasted and fed conditions. The study will also 
assess the relative bioavailability between a formulation only containing verinurad (ie, 
verinurad prolonged release gelatin capsule 12 mg) and the FDC capsule. For verinurad, all
formulations have prolonged release profile. For allopurinol, both formulations containing 
alopurinol have an immediate release profile.
Assessment of PD parameters will be done in a time-matched manner, to account for the 
diurnal effect of sUA.
3.2.2.
Dose Rationale
Currently, the highest strength (12 mg) of the formulation being used in ongoing Phase 2 
studies development of verinurad will be tested in this study. In Phase 2b, 300 mg allopurinol 
is given together with verinurad and is the planned dose of allopurinol in the 
verinurad/allopurinol FDC product. 


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3.3.
Risk-benefit Assessment
There are no direct benefits for the subjects participating in this study. However, study-related 
health assessments are provided without costs for the subjects. The major risks for subjects 
who participate in the study will come from IMP administration. In addition, there might be a 
slight risk of infection or bruising that might occur after insertion of an intravenous cannula 
for frequent blood sampling. Subjects may experience slight skin irritation from the adhesive 
on the ECG electrodes. These procedural effects are generally mild and clear up completely 
within a few days.
The main toxicity concern noted with verinurad monotherapy in healthy subjects is serum 
creatinine elevations >1.5 × baseline, which occurred in 1.7% of healthy subjects. A change 
from baseline of ≥0.3 mg/dL was reported for 6.8% of all subjects. There was no apparent 
relationship between serum creatinine elevations and dose of verinurad. The creatinine 
elevations were primarily transient, and often resolved despite continued dosing with 
verinurad. In order to mitigate the risk in this study verinurad is administered with an XOI, 
except for Treatment 5, and appropriate hydration is mandated. Further information is 
provided in the IB [1].
In previous studies, verinurad combined with allopurinol was well tolerated and associated 
with acceptable side effects. Most AEs were minor and not related to treatment.
Allopurinol is an approved XOI. Most common AEs noted in the prescribing information are 
rash and blood thyroid-stimulating hormone increased. Allopurinol hypersensitivity reactions 
can manifest in many different ways, including maculopapular exanthema, hypersensitivity 
syndrome (also known as DRESS) and SJS/TEN. The HLA-B*58:01 allele has been shown to 
be associated with increased risk of developing allopurinol-related hypersensitivity syndrome 
and SJS/TEN. The frequency of the HLA-B*58:01 allele varies widely between ethnic 
populations: up to 20% in the Han Chinese population, 8 to 15% in the Thai population, about 
12% in the Korean population and 1 to 2% in individuals of Japanese or European origin. At 
the Screening Visit, the subject’s HLA-B*58:01 status will be tested and carriers of 
HLA-B*58:01 will be excluded [1].
Overall, the study has been designed to minimise the risks to participating subjects by 
excluding subjects at high risk of AEs and by applying appropriate safety monitoring of 
recruited study subjects. The dose selected has been carefully considered in light of the target 
subject population. The potential benefits of developing a new treatment for CKD with 
hyperuricemia, therefore, outweigh the limited risks to the subjects exposed to verinurad and 
allopurinol single doses in this study.


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3.3.1.
Verinurad
3.3.1.1.
Non-clinical Findings
A series of non-clinical studies were performed with results supporting clinical development 
of verinurad. Overall, verinurad was well tolerated in the chronic rat and dog studies at high 
multiples of the exposures achieved at the highest doses tested in man. No additive or new 
toxicity was observed in 13-week combination studies of verinurad and febuxostat or 
allopurinol in rats.
Verinurad was not genotoxic or carcinogenic based on results from the in vitro and in vivo 
batteries of genotoxicity tests and carcinogenicity studies in mice and rats. Verinurad is not 
considered a reproductive hazard based on the results of reproductive toxicology studies and 
the lack of effects on reproductive organs in the 6 and 9 month studies in rats and dogs, 
respectively.
Further information on non-clinical findings is available in the IB [1].
3.3.1.2.
Clinical Studies
As of 01 May 2020, 19 clinical studies have been completed with verinurad, 12 Phase 1 
studies and 7 Phase 2 studies. In these studies, verinurad was administered either as 
monotherapy or in combination with an XOI (allopurinol or febuxostat), and the studies were 
conducted in healthy subjects, in subjects with renal impairment, in patients with gout or 
asymptomatic hyperuricaemia, and in patients with diabetes and albuminuria [1].
Verinurad was initially developed as a treatment for gout. Therefore, the first Phase 2 studies 
recruited patients with gout or asymptomatic hyperuricemia and did not include renal 
endpoints such as albuminuria and eGFR. Nevertheless, they provide a body of data on the PD
effects of verinurad (with and without concomitant XOI therapy) on sUA concentrations. 
Subsequent clinical studies incorporated renal endpoints [1].
3.3.2.
Allopurinol
Allopurinol is a commercially available oral XO inhibitor for conditions where urate/UA 
deposition has already occurred or is a predictable clinical risk. Allopurinol and its main 
metabolite oxypurinol inhibit production of and thus lower the level of sUA.
Please refer to the product information sheet of allopurinol tablets [12] for information on PK, 
PD, and safety.
3.3.3.
Risk Assessment for COVID-19 Pandemic
Verinurad is a potent and specific URAT1 inhibitor. Allopurinol is a well-known drug to treat 
hyperuricemia. The COVID-19 pandemic is not expected to impact the risk in this healthy 
volunteer study.


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Therefore, the risk of the subjects being exposed to SARS-CoV-2 or suffering from 
COVID-19 will be similar to the general population. However, the risk of exposure to infected 
people cannot be completely excluded as the subjects may need to expose themselves to 
public areas (eg, commute to the site) and have additional human contact (eg, with site staff 
and other participants of the clinical study).
Measures to mitigate the additional risks caused by COVID-19 are:

This study is going to start enrolling only when the Sponsor and CRO in collaboration 
deem it is safe to start the study. In addition, the study will not start until the local 
confinement measures or other safety restrictions linked to the COVID-19 pandemic are 
lifted by the local authorities.

Current national laws and local recommendations for prevention of pandemic will be 
strictly adhered to.

Subjects will be closely monitored for any signs and symptoms of COVID-19, including 
fever, dry cough, dyspnoea, sore throat and fatigue throughout the study. Once clinical 
signs of infection are reported by subjects, the Investigator needs to determine whether 
samples can be collected, and safety data can be recorded on site. If not, AEs and 
concomitant medications will be obtained via phone calls. Daily tympanic temperature 
measurements during in-house stay and outpatient visits will be implemented.

The Investigator will not dose subjects upon identification of any signs of COVID-19 
infection.

Confirmation of COVID-19 infection by laboratory assessment will be conducted based 
on availability (test capacity and turnaround time) of approved tests and on Investigator’s 
discretion. This would include serology testing at screening and virus testing prior to any 
admission.

The probability of virus transmission will be controlled as much as possible by:

Advice for subject to adhere to local requirements for reduction of the public 
exposure while ambulatory.

All subjects are contacted by phone 1 day prior to every visit for assessing 
COVID-19 symptoms and signs and are asked not to attend the site in case of 
suspected reports. In addition, subjects are asked for any contact with a person who 
has tested positive for SARS-CoV-2. If applicable, subjects will be referred to the 
local health care system for further follow-up and treatment.

Physical distancing and person-to-person contact restrictions will be applied during 
site visits and in-house stay.

Where physical distancing is not possible, personal protective equipment will be used 
by subject (surgical face mask, gloves) and staff (for example but not limited to face 
masks, gloves, protectors, medical suits) if deemed appropriate by the investigators 
and site staff and guided by local requirements.


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
Logistical improvements of the site and structural measures of the study site building 
will be implemented to further improve physical distancing.


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4.
STUDY POPULATION
4.1.
Selection of Study Population
The PI should keep a subject screening log of all potential subjects who consented and were 
subjected to screening procedures.
Subjects who fail to meet the inclusion criteria or meet any exclusion criterion should not, 
under any circumstances, be randomised into the study. There can be no exceptions to this 
rule.
This study will be conducted in healthy male and female subjects. The study may not 
necessarily be balanced regarding gender. The study was not formally powered to detect 
differences between genders for the primary endpoint. It is not planned to perform 
sub-analyses on gender.
4.1.1.
Inclusion Criteria
For inclusion in the study subjects should fulfil the following criteria:
1
Provision of signed and dated, written informed consent prior to any study specific 
procedures.
2
Healthy male and female subjects aged 18 to 50 years (inclusive) with suitable veins for 
cannulation or repeated venepuncture.
3
Have a body mass index between 18 and 30 kg/m2 (inclusive) and weigh at least 50 kg 
and no more than 100 kg (inclusive).
4
Females must have a negative pregnancy test at screening and on admission to the unit
and must be:
(1) not pregnant or currently lactating or breastfeeding.
(2) of non-childbearing potential (as defined in Section 4.2.1.1), confirmed at screening 
by fulfilling one of the following criteria:
(i)
postmenopausal defined as amenorrhoea for at least 12 months or more 
following cessation of all exogenous hormonal treatments and FSH levels in the 
postmenopausal range (FSH levels > 40 IU/mL).
(ii) documentation of irreversible surgical sterilisation by hysterectomy, bilateral 
oophorectomy or bilateral salpingectomy but not tubal ligation.
(3) OR if of childbearing potential (as defined in Section 4.2.1.2) must be willing to use 
an acceptable method of contraception (as described in Section 4.2.1.2) to avoid 
pregnancy for the entire study period.
5
Must be able to swallow multiple capsules and tablets.


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4.1.2.
Exclusion Criteria
Subjects will not enter the study if any of the following exclusion criteria are fulfilled:
1
History of gout or any clinically significant disease or disorder which, in the opinion of 
the PI, may either put the volunteer at risk because of participation in the study, or 
influence the results or the volunteer’s ability to participate in the study.
2
Any clinically important illness, medical/surgical procedure or trauma within 4 weeks of 
the first administration of verinurad.
3
History or presence of gastrointestinal, hepatic or renal disease, or any other condition 
known to interfere with absorption, distribution, metabolism, or excretion of drugs.
4
Any clinically important abnormalities in clinical chemistry, haematology or urinalysis 
results as judged by the Investigator at screening and first admission, including:
(1) Alanine aminotransferase > 1.5 × ULN,
(2) Aspartate aminotransferase > 1.5 × ULN,
(3) Bilirubin (total) > 1.5 × ULN,
(4) Gamma glutamyl transpeptidase > 1.5 × ULN.
If any of these tests are out-of-range, the tests can be repeated once.
5
Any clinically significant abnormal findings in vital signs at the Screening Visit and/or 
admission to the Clinical Unit, including, but not limited to, any of the following:
(1) Pulse (resting, supine) < 50 bpm or > 90 bpm,
(2) Systolic BP < 90 mmHg or > 140 mmHg and/or diastolic BP < 50 mmHg or 
> 90 mmHg sustained for > 10 minutes while resting in a supine position.
6
Any clinically significant abnormalities on 12-lead ECG at the Screening Visit, including, 
but not limited to any of the following:
(1) QTcF > 450 ms or < 340 ms or family history of long QT syndrome,
(2) Any significant arrhythmia,
(3) Conduction abnormalities:
(4) Clinically significant PR (PQ) interval prolongation (> 240 ms); intermittent second 
or third degree AV block, or AV dissociation,
(5) Complete bundle branch block and/or QRS duration > 120 ms.
7
Any positive result at the Screening Visit for serum HbsAg or anti-HBc antibody, 
hepatitis virus C antibody, and HIV antibody.
8
Suspicion or known Gilbert’s and/or Lesch-Nyhan syndrome.
9
Known or suspected history of alcohol or drug abuse or excessive intake of alcohol as 
judged by the PI. Excessive intake of alcohol defined as the regular consumption of more 
than 24 g of alcohol per day for men or 12 g of alcohol per day for women. 


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10 Has received another new chemical or biological entity (defined as a compound which 
has not been approved for marketing in the US) within 30 days or at least 5 half-lives 
(whichever is longer) of the first administration of verinurad in this study.
Note: subjects consented and screened, but not randomised in this study or a previous 
Phase 1 study, are not excluded.
11 Subjects who have previously received verinurad.
12 Plasma donation within 1 month of screening or any blood donation/loss of more than 
500 mL during the 3 months prior to the Screening Visit.
13 Subjects who are pregnant, lactating or planning to become pregnant.
14 Hypersensitivity to verinurad, allopurinol or any drug with a similar chemical 
structure/class to verinurad and/or allopurinol.
15 Current smokers or those who have smoked or used nicotine products (including 
e-cigarettes) within the 3 months prior to screening.
16 Excessive intake of caffeine-containing drinks or food (eg, coffee, tea, chocolate) as 
judged by the PI. Excessive intake of caffeine defined as regular consumption of more 
than 600 mg of caffeine per day (eg, > 5 cups of coffee) or would likely be unable to 
refrain from the use of caffeine-containing beverages during confinement at the 
investigational site.
17 Positive screen for drugs of abuse or cotinine (nicotine) at the Screening Visit or positive 
screen for alcohol, drugs of abuse and cotinine on each admission to the study centre.
18 Use of drugs with enzyme-inducing properties such as St John’s Wort within 3 weeks 
prior to the first administration of verinurad.
19 Use of any prescribed or non-prescribed medication including antacids, analgesics (other 
than paracetamol/acetaminophen), herbal remedies, megadose vitamins (intake of 20 to 
600 times the recommended daily dose) and minerals during the 2 weeks prior to the first 
administration of verinurad or longer if the medication has a long half-life.
The use of hormonal contraception therapy and hormonal replacement therapy for 
females are permitted.
20 Any AstraZeneca, Parexel or study site employee or their close relatives.
21 Subjects who cannot communicate reliably with the PI and/or is not able to read, speak 
and understand the German language.
22 Judgment by the PI that the subject should not participate in the study if they have any 
ongoing or recent (ie, during the screening period) minor medical complaints that may 
interfere with the interpretation of study data or are considered unlikely to comply with 
study procedures, restrictions, and requirements.
23 Vulnerable subjects, eg, kept in detention, protected adults under guardianship, 
trusteeship, or committed to an institution by governmental or juridical order.


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24 Subjects with any special dietary restrictions such as subjects that are lactose intolerant or 
are vegetarians/vegans.
25 Subject is a carrier of the HLA-B*58:01 allele.
26 Subject has a positive test result for SARS-CoV-2 RT-PCR before randomisation.
27 Subject has clinical signs and symptoms consistent with COVID-19, eg, fever, dry cough, 
dyspnoea, sore throat, fatigue or confirmed infection by appropriate laboratory test within 
the last 4 weeks prior to screening or on admission.
28 History of severe COVID-19 (hospitalisation, extracorporeal membrane oxygenation, 
mechanically ventilated).
29 Subjects who are regularly exposed to COVID-19 (eg, health care professionals working 
in COVID-19 wards or at emergency departments) as part of their daily life.
30 Subjects who have had or are planning to have the COVID-19 vaccination within 4 weeks
prior to screening or at any time during the study.
4.2.
Restrictions During the Study
The following restrictions apply for the specified times during the study period:
1
Subjects should not engage in any strenuous activity from 72 hours prior to check-in 
(Day -2) until after their Follow-up Visit.
2
Subjects should abstain from alcohol for the duration of the study from check-in (Day -2) 
until after their last PK sampling visit. Subjects should also abstain from alcohol for 
72 hours before the Screening Visit and their Follow-up Visit.
3
Subjects should abstain from caffeine-containing foods and beverages for 24 hours prior 
to check-in (Day -2) until the Follow-up Visit.
4
Subjects should abstain from grapefruit or grapefruit juice, Seville oranges, quinine (eg, 
tonic water) from 7 days prior to check-in (Day -2) until after their Follow-up Visit.
5
During admission periods, subjects will receive a standard diet, which excludes all 
alcohol and grapefruit-containing products. No additional food or beverages (except for 
water) must be consumed while in the Clinical Unit.
6
During the subjects’ outpatient periods, subjects should abstain from consuming, 
high-energy drinks (eg, red bull), and food containing poppy seeds and any OTC 
medication or herbal preparations until after their Follow-up Visit has been completed.
7
Subjects will be required to abstain from blood or plasma donation until 3 months after 
the final medical examination at the Follow-up Visit.
8
Subjects are advised to adhere to local requirements for reduction of the public 
SARS-CoV-2 exposure while ambulatory. All subjects are called 1 day prior to every 
visit for assessing COVID-19 symptoms and signs and are asked not to attend the site in 
case of suspected infection. In addition, subjects are asked for any contact with a person 
who has confirmed infection. If applicable, subjects will be referred to the local health 


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care system. Physical distancing and person to person contact restrictions will be applied 
and explained to subjects while staying at the study site. Where physical distancing is not 
possible, subjects will be asked to use surgical face masks and/or gloves if deemed 
appropriate by the Investigator and site staff and guided by local requirements.
For food and fluid intake restrictions in relation to dosing please refer to Section 5.4.2.
For medication restrictions, please refer to Section 5.6.
4.2.1.
Reproductive Restrictions
4.2.1.1.
Women of Non-childbearing Potential
Women of non-childbearing potential are defined as female subjects who are permanently 
surgically sterilised or postmenopausal.
Acceptable methods of sterilisation include:

Surgical bilateral oophorectomy (with or without hysterectomy) at least 6 weeks before 
Screening. In the case of oophorectomy alone, only when the reproductive status of the 
woman has been confirmed by follow-up hormone level assessment.

Hysterectomy at least 6 weeks before Screening.

Bilateral salpingectomy.
Females are considered postmenopausal if they have had amenorrhea for at least 12 months or 
more following cessation of all exogenous hormonal treatments and FSH levels are in the 
postmenopausal range (eg, age-appropriate, history of vasomotor symptoms) or for women 
< 60 years the FSH levels is > 40 mIU/mL.)
4.2.1.2.
Women of Childbearing Potential
Women of childbearing potential who are sexually active must agree to use, with their partner, 
an approved method of highly effective contraception from the time of verinurad 
administration until 3 months after the study Follow-up Visit.

A barrier method must be used in combination with one of the following methods, 
considered to be highly effective (failure rate < 1% per year when used consistently and 
correctly):

Hormonal contraception, ie, combined oral contraceptives, injectable * or 
implantable * hormonal contraceptives.

Hormonal or non-hormonal intrauterine device * (IUD, loop), established IUD * or 
intrauterine system (Note: The IUD must have a failure rate < 1%).
                                               
*
These methods are considered to have low user dependency


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
Surgical sterilisation * (ie, bilateral tubal ligation for females; vasectomy for male 
partners [must have been vasectomised before the female subject entered the clinical 
trial and he is the sole sexual partner of the female subject during the clinical trial]).

Barrier methods of contraception include:

Condom (without spermicidal foam/gel/film/cream/suppository or fat- or 
oil-containing lubricants),

Occlusive cap (diaphragm or cervical/vault caps) with spermicidal 
gel/film/cream/suppository.
Note: Double-barrier is not considered a highly effective method. 
Female subjects must agree not to attempt to become pregnant, must not donate ova and must 
not breastfeed starting at screening and throughout the clinical study and for 90 days 
(3 months) after the Follow-up Visit.
Women should be informed of the potential risks associated with becoming pregnant while 
enrolled.
Alternatively, † true abstinence is acceptable when it is in line with the subject’s preferred and 
usual lifestyle. 
Pregnancy Testing
Women of childbearing potential can be included only after a negative highly sensitive serum 
pregnancy test. Additionally, urine pregnancy testing will be done as per the SoA (Table 3-1).
Pregnancy
If the subject becomes pregnant during the study this should be reported to the Investigator. 
The Investigator should also be notified of pregnancy occurring during the study but 
confirmed after completion of the study. The pregnancy will be followed, and the status of 
mother and/or child will be reported to the Sponsor after delivery.
A pregnancy notification form and follow-up will be completed.
                                               
†
True abstinence: When this is in line with the preferred and usual lifestyle of the subject. Periodic 
abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the 
duration of a trial and withdrawal are not acceptable methods of contraception.


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4.2.1.3.
Male Subjects
Restrictions for Male Subjects
Verinurad had no effects on fertility or embryo-foetal development in rats at doses up to 
300 mg/kg/day and did not affect embryo-foetal development in rabbits at doses up to 
30 mg/kg/day.
Male subjects participating in this study are not required to apply contraception. However, it is 
recommended that male subjects should not donate sperm until at least 3 months after the 
Follow-up Visit. In addition, as a precaution, all male subjects should avoid fathering a child 
AND exposing a foetus to verinurad by either true abstinence or use together, with their 
female partner/spouse, of a highly effective method of contraception (see definition above), 
starting from the time of verinurad administration until at least 3 months after the Follow-up 
Visit.
Sperm Donation
Male subjects should not donate sperm for the duration of the study and for at least 3 months 
after the study Follow-up Visit.
Pregnancy
Subjects will be instructed that if their partner becomes pregnant during the study this should 
be reported to the Investigator. The Investigator should also be notified of pregnancy 
occurring during the study but confirmed after completion of the study. In the event that a 
subject’s partner is subsequently found to be pregnant after the volunteer is included in the 
study, then consent will be sought from the partner and if granted any pregnancy will be 
followed and the status of mother and/or child will be reported to the Sponsor after delivery.
A pregnancy notification form and follow-up will be completed.
4.3.
Replacement of Subjects
Subjects who are withdrawn from the study due to AEs or changes in safety variables will not 
be replaced unless a specific sample size is to be met for statistical purposes and if the
Sponsor’s responsible physician and the PI agree it is safe to do so. Subjects who withdraw or 
are withdrawn from the study for suspected or confirmed COVID-19 infection or other 
reasons may be replaced following discussion with the Sponsor.


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5.
STUDY CONDUCT
5.1.
Subject Enrolment and Randomisation
The PI will ensure:

Signed informed consent is obtained from each potential subject before any study specific 
procedures are performed.

Each potential subject is assigned a unique enrolment number at screening upon signing 
the informed consent.

The eligibility of each subject is in accordance with the inclusion and exclusion criteria.

Each eligible subject is assigned a unique randomisation code.
Randomisation will be done on Day -1 of Treatment Period 1.
Randomisation codes will be assigned strictly sequentially as subjects become eligible for 
randomisation (codes to be used without leading zero(s)).
When using unique enrolment number, the specific format must be followed (ie, reduced 
enrolment number “1001” in ClinBase™ and on labels, full enrolment number “E0001001” 
for outputs).
If a subject withdraws his/her participation in the study, then his/her enrolment/randomisation 
code cannot be reused. If a replacement is mandated replacement subjects will receive a new 
randomisation number and will be allocated to the same treatment sequence as the replaced 
subject.
5.1.1.
Procedures for Randomisation
Upon completion of the randomisation requirements specifications form, the randomisation 
will be produced by Parexel according to the AstraZeneca randomisation system.
Subjects will be randomised to treatment sequences in a ratio of 1:1:1:1:1 so that all subjects 
will receive all formulations. The reference product (capsule and tablet as free combination)
(Treatments 1 and 4) and the test product (FDC or monotherapy capsule) (Treatments 2 and 3)
and a prolonged release gelatin capsule (Treatment 5) will be given under fasted and/or fed 
conditions as per study design (see Section 3.1).
The randomisation will be completed using consecutive randomisation codes.
The number of subject identifiers generated for the study will account for the number of 
randomised subjects per the sample size calculation (N = 25) (see Section 11.4) as well as 
providing sufficient randomisation numbers for replacements. For this study, a total of 


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25 × 2 subject identifiers will be randomly assigned to the treatment sequences: 12345, 23451,
34512, 45123, and 51234.
5.2.
Procedures for Handling Incorrectly Randomised Subjects
Subjects who fail to meet the inclusion criteria or meet any exclusion criterion should not, 
under any circumstances, be randomised into the study. There can be no exceptions to this 
rule.
Where a subject, who does not meet the selection criteria, is randomised in error and this is 
identified before dosing, the subject should be withdrawn from the study. If a subject is 
withdrawn prior to dosing they will be replaced.
If a subject, who does not meet the selection criteria and has been dosed before the error is 
identified, the subject should be withdrawn and advised to continue safety assessments to 
ensure their safety. The PI will inform the AstraZeneca Lead Physician of the error and a joint 
decision made as to whether the subject should be replaced.
5.3.
Blinding
This is an open-label study and blinding is not applicable.
5.4.
TREATMENTS
5.4.1.
Identity of the Investigational Medicinal Product
Details on the identity of the IMP are presented in Table 5-1.
Table 5-1
Identity of the Investigational Medicinal Product
Supplier:
AstraZeneca
Formulations:
Verinurad prolonged release HPMC capsule 12 mg
Verinurad prolonged release gelatin capsule 12 mg
Verinurad/allopurinol FDC capsule 12/300 mg
Allopurinol tablet 300 mg
Strength/concentration:
Verinurad: 12 mg
Allopurinol: 300 mg
Dose:
Verinurad: 12 mg
Allopurinol: 300 mg
Route of administration:
Oral
Specific device for drug 
administration, if applicable:
Not applicable


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Supplier:
AstraZeneca
Regimen:
Treatment 1: verinurad prolonged release HPMC capsule 12mg and 
allopurinol tablet 300mg, as a free combination, fasted state
Treatment 2: verinurad/allopurinol FDC capsule 12/300 mg, fasted state
Treatment 3: verinurad/allopurinol FDC capsule 12/300 mg, fed state
Treatment 4: verinurad prolonged release HPMC capsule 12mg and 
allopurinol tablet 300mg, as a free combination, fed state
Treatment 5: verinurad prolonged release gelatin capsule 12 mg, fasted 
state
Details of the batch numbers will be included in the Trial Master File and the final CSR.
5.4.2.
Supply of Investigational Medicinal Product
The IMP will be supplied by AstraZeneca and provided bulk bottles with study specific open 
labels.
If applicable, technical agreement between the Investigator and AstraZeneca will be in place 
to cover all pharmacy related activities, detailing roles and responsibilities prior to receipt of 
the IMPs at the Clinical Unit.
A release document signed by a legally authorised Qualified Person at the Clinical Unit will 
be placed in the appropriate section of the Trial Master File to document labelling and 
dispensing of the study drug to the subject.
5.4.3.
Dose and Treatment Regimens
Subjects will receive single doses of 4 different formulations of IMP under fasted and fed 
conditions during the 5 treatment periods.
Subjects will be fasted for 10 hours prior to dosing (or prior to receiving the FDA high-fat, 
high-calorie breakfast in fed dosing) until 4 hours after dosing on Day 1 of each treatment 
period. No fluids will be allowed apart from water which can be given until 1 hour prior to 
dosing and then from 1 hour after dosing, beverages provided with the high-fat, high-calorie 
breakfast with dosing under fed conditions and water given during administration. The IMP 
will be administered with 240 mL of water on Day 1 of each treatment period. All subjects 
will be instructed to drink approximately 2 L to 2.5 L of liquid a day, starting on Day -2 and
throughout the stay at the clinic.
During fed dosing, subjects will be provided with an FDA high-fat, high-calorie breakfast 
30 minutes before the scheduled dosing time (following the overnight fast as above), subjects 
should consume the breakfast within 25 minutes and finish the breakfast approximately 
5 minutes before the scheduled dosing. During the fasted dosing, subjects will remain fasted 
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Following the restrictions above, each subject will receive a single-dose of 4 different 
formulations of IMP under fasted and/or fed conditions on 5 occasions:
Treatment 1
verinurad prolonged release HPMC capsule 12mg and 
allopurinol tablet 300mg, as a free combination, fasted state
Treatment 2
verinurad/allopurinol FDC capsule 12/300 mg, fasted state.
Treatment 3
verinurad/allopurinol FDC capsule 12/300 mg, fed state
Treatment 4
verinurad prolonged release HPMC capsule 12mg and 
allopurinol tablet 300mg, as a free combination, fed state
Treatment 5
verinurad prolonged release gelatin capsule 12 mg, fasted state
Other restrictions, including posture control are described in Section 4.2. Data of subjects may 
be excluded from the PK analysis set as described in Section 11.1.2.
5.4.4.
FDA Breakfast Menu
The breakfast will constitute the following:

Two eggs fried in butter

Two slices of bacon

One buttered English muffin

120 g of hash-browned potatoes

240 mL of whole milk
5.4.5.
Labelling
Labels will be prepared in accordance with Good Manufacturing Practice and local regulatory 
guidelines.
The labels will fulfil GMP Annex 13 requirements and medical device directive for labelling.
5.4.6.
Storage and Handling Procedures
All IMPs will be stored in a secure facility; details of storage conditions will be provided on 
the label of the IMP.
AstraZeneca will be permitted upon request to audit the supplies, storage, dispensing 
procedures and records.
5.5.
Concomitant and Post-study Treatment(s)
Apart from paracetamol/acetaminophen, hormone replacement therapy and systemic 
contraceptives no concomitant medication or therapy will be allowed.


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The subjects should be instructed that no other medication is allowed, including herbal 
remedies, vitamin supplements and over-the-counter products, without the consent of the PI.
Medication, which is considered necessary for the subject’s safety and well-being, may be 
given at the discretion of the PI during the residential period.
When any medication is required, it should be prescribed by the PI. Following consultation 
with AstraZeneca Lead Physician, the PI should determine whether or not the subject should 
continue in the study. Administration of concomitant medications that may influence the 
measurement of the PK endpoints may be documented as a protocol deviation after 
consultation of the PI with AstraZeneca Lead Physician.
5.6.
Treatment Compliance
Dosing will take place at the Parexel Early Phase Clinical Unit.
The administration of all IMPs will be recorded in ClinBase™.
Compliance will be assured by direct supervision and witnessing of IMP administration. After 
IMP administration, a check of the subject’s mouth and hands will be performed.
Drug Accountability, Dispensing and Destruction
The IMP provided for this clinical study will be used only as directed in the CSP.
In accordance with GCP, the investigational site will account for all supplies of IMP. Details 
of receipt, storage, assembly/dispensing and return will be recorded.
All unused supplies of the IMP will either be destroyed by Parexel or returned at the end of 
the study in accordance with instruction by the Sponsor.
5.7.
Discontinuation of Investigational Product and Withdrawal from 
Study
Dosing for any individual subject must be stopped if the subject experiences a possibly 
IMP-related SAE or a possibly IMP-related significant non-serious AE, which in the opinion 
of the Principal Investigator warrants discontinuation of the subject from the active protocol 
for his or her well-being.
Subjects must be discontinued from IMP in the following situations:

Healthy subject decision. The healthy subject is at any time free to discontinue treatment, 
without prejudice to further treatment.

Severe non-compliance to study protocol.


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
Any significant and clinically relevant changes in the safety variables (eg, ECG, BP, 
pulse, tympanic temperature, laboratory assessments and AEs) making the continuation of 
IMP administration unjustified.

Any case of PHL according to Appendix C.

Study specific withdrawal criteria: If the subject reports symptoms which are considered 
unacceptable by the subject or the PI, he/she must be withdrawn from the study. In 
particular:

Any other severe or SAE that is judged as possibly related to verinurad by the 
Investigator.

Study treatment must be stopped if a subject has elevated serum creatinine levels 
greater than 1.5 times the pre-treatment value and retest of the creatinine should be 
performed as soon as possible (see Appendix D).

In subjects who report symptoms that indicate acute UA nephropathy including flank 
pain, nausea, or vomiting, treatment must be permanently discontinued. Appendix D
contains guidelines on management of such subjects. 

See Appendix D for details on the handling of renal-related or urolithiasis 
treatment-emergent AEs, and the handling of serum creatinine elevation, which 
includes criteria for stopping treatment.

Pregnancy.

Any confirmed COVID-19 case that warrants discontinuation in the judgment of the 
Investigator or Sponsor to protect the safety of the subject, other study participants or 
study site staff.
The appropriate AE form in the CRF must be completed.
5.7.1.
Procedures for Withdrawal of a Subject from the Study
If a subject withdraws or is withdrawn from the study, the subject will be encouraged to return 
to the Clinical Unit for an Early Termination Visit to ensure the subject’s safety.
5.8.
Premature Termination of the Study
The study must be terminated prematurely if:

The PI and the Sponsor assess that the number and/or severity of AEs justify 
discontinuation of the study. 
For instance, when there is 1 case of SAE considered at least possibly related to the IMP 
by the PI and the Sponsor.
The Sponsor considers the applied doses of the study drug to be no longer relevant.

The Sponsor decides to discontinue the study.

Data, that were not known before, become available and raise concern about the safety of 
IMP so that continuation would pose potential risks to the subjects.


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
New data become available regarding COVID-19, which raises concern for the safe study 
conduct so that continuation would pose potential risks to the subjects or the study site 
staff.
Premature termination of the study must be mutually agreed upon by the PI and the Sponsor
and must be documented. However, study results will be reported according to the 
requirements outlined in this CSP as far as applicable.


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6.
COLLECTION OF STUDY VARIABLES
6.1.
Recording of Data
Standard measures to assess PK, safety and tolerability apply during the study. For the single 
doses of IMP planned to be given during this study, no safety issues are expected.
For timing of assessments refer to Table 3-1.
6.2.
Enrolment and Screening Procedures
Viral serology and drugs of abuse, alcohol and cotinine will be assessed for eligibility. Follicle 
stimulating hormone (females only), pregnancy testing (females only) and use of concomitant 
medication will also be assessed and reported.
6.3.
Safety and Eligibility Measurements
Safety and tolerability variables will include:

Adverse events

Laboratory assessments (haematology, clinical chemistry and urinalysis).

Physical examination

Electrocardiogram

Vital signs (systolic and diastolic BP, pulse, tympanic temperature)
6.3.1.
Adverse Events
6.3.1.1.
Definition of Adverse Events
An AE 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 (eg 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.


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6.3.1.2.
Definitions of Serious Adverse Event
A SAE is an AE occurring during any study period (ie, run-in, treatment, washout, follow-up), 
that fulfils one or more of the following criteria:

Results in death

Is immediately life-threatening

Requires in-patient hospitalisation or prolongation of existing hospitalisation

Results in persistent or significant disability or incapacity or substantial disruption of the 
ability to conduct normal life functions

Is a congenital abnormality or birth defect

Is an important medical event that may jeopardise the subject or may require medical 
intervention to prevent one of the outcomes listed above.
For further guidance on the definition of a SAE, see Appendix A of this CSP.
Adverse events for malignant tumours reported during a study should generally be assessed as 
SAEs. If no other seriousness criteria apply, the “Important Medical Event” criterion should 
be used. In certain situations, however, medical judgment on an individual event basis should 
be applied to clarify that the malignant tumour event should be assessed and reported as a 
non-serious AE. For example, if the tumour is included as medical history and progression 
occurs during the study, but the progression does not change treatment and/or prognosis of the 
malignant tumour, the AE may not fulfil the attributes for being assessed as serious, although 
reporting of the progression of the malignant tumour as an AE is valid and should occur. Also, 
some types of malignant tumours, which do not spread remotely after a routine treatment that 
does not require hospitalisation, may be assessed as Non-Serious; examples include Stage 1 
basal cell carcinoma and Stage 1A1 cervical cancer removed via cone biopsy. 
6.3.1.3.
Other Significant Adverse Events
During the evaluation of the AE data, an AstraZeneca medically qualified expert will review 
the list of AEs that were not reported as SAEs or where relevant DAEs and withdrawal from 
the study. Based on the expert’s judgment, significant adverse events of particular clinical 
importance may, after consultation with the Global Safety Physician, be considered OAEs and 
reported as such in the CSR. A similar review of other data from laboratory tests, vital signs, 
ECGs and other safety assessments will be performed for identification of OAEs.
Examples of these are marked haematological and other laboratory abnormalities, and certain 
events that lead to intervention (other than those already classified as serious), dose reduction 
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6.3.1.4.
Recording of Adverse Events
Time Period for Collection of Adverse Events
Adverse events will be collected from the first administration of the IMP throughout the 
treatment periods up to and including the Follow-up Visit.
Serious adverse events will be recorded from the time of informed consent.
Follow-up of Unresolved Adverse Events
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 ClinBase™.
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.
Variables
The following variables will be collected for each AE:

AE diagnosis/description

The date and time when the AE started and stopped

Intensity

Whether the AE is serious or not

Investigator causality rating against the investigational product (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

Probable cause of death

Date of death

Autopsy performed

Causality assessment in relation to Study procedure(s)

Causality assessment to other medication


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The following intensity ratings will be used:
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 A.

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. On 
the other hand, a stroke that results in only a limited degree of disability may be 
considered a mild stroke but would be an SAE.
Causality Collection
The Investigator will assess causal relationship between investigational product and each AE, 
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, any additional drug 
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 A of this CSP.
Adverse Events Based on Sign and Symptoms
All AEs spontaneously reported by the subject or reported in response to the open question 
from the study personnel: “Have you had any health problems since you were last asked?”, or 
revealed by observation will be collected and recorded in ClinBase™.
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.
Adverse Events Based on Examinations and Tests
The results from protocol-mandated laboratory tests, vital signs, ECGs and other safety 
assessments will be summarised in the CSR.


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Deterioration as compared to baseline in protocol-mandated laboratory values, vital signs, 
ECGs and other safety assessments should therefore only be reported as AE if it fulfils any of 
the SAE criteria, is clinically significant according to Investigator judgment, or is the reason 
for discontinuation of treatment with the IMP.
If deterioration in a laboratory value or vital sign is associated with clinical signs and 
symptoms, the sign or symptom will be reported as an AE and the associated laboratory result 
or vital sign will be considered as additional information.
Wherever possible the reporting Investigator should use the clinical, rather than the laboratory 
term (eg, anaemia versus low haemoglobin value).
In the absence of clinical signs or symptoms, clinically relevant deteriorations in 
non-protocol-mandated parameters should be reported as AE(s).
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.
Hy's Law
Cases where a subject shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥ 3 × ULN together with total bilirubin ≥ 2 × ULN may need 
to be reported as SAEs. Please refer to Appendix C for further instruction on cases of 
increases in liver biochemistry and evaluation of Hy’s Law.
COVID-19
Confirmed and suspected SARS-CoV-2 infection and COVID-19 will be recorded as AEs.
6.3.1.5.
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 ClinBase™.
If any SAE occurs in the course of the study, then investigators or other site personnel will 
inform appropriate AstraZeneca representatives immediately, or no later than 24 hours of 
when he or she becomes aware of it.
The designated AstraZeneca representative will work 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.


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For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up will be undertaken immediately.
Investigators or other site personnel will inform AstraZeneca representatives of any follow-up 
information on a previously reported SAE immediately, or no later than 24 hours of when he 
or she becomes aware of it.
The reference document for definition of expectedness/listedness is the IB for the AstraZeneca 
drug.
6.3.1.6.
Regulatory Reporting Requirements for Serious Adverse Events
Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting 
to the regulatory authority, IEC, and investigators.
For all studies except those utilising medical devices investigator safety reports must be 
prepared for SUSARs according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary.
An Investigator who receives an investigator safety report describing a SAE or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will review and then 
file it along with the IB or and will notify the IEC, if appropriate according to local 
requirements.
6.3.2.
Laboratory Assessments
6.3.2.1.
Haematology
Haematology
White blood cell (WBC) count
Neutrophils absolute count 
Red blood cell (RBC) count
Lymphocytes absolute count 
Haemoglobin (Hb)
Monocytes absolute count 
Haematocrit (HCT)
Eosinophils absolute count 
Mean corpuscular volume (MCV)
Basophils absolute count 
Mean corpuscular haemoglobin (MCH)
Platelets
Mean corpuscular haemoglobin concentration (MCHC)
Reticulocytes absolute count 


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6.3.2.2.
Serum Clinical Chemistry
Serum Clinical Chemistry
Sodium
Alkaline phosphatase (ALP)
Potassium
Alanine aminotransferase (ALT)
Urea
Aspartate aminotransferase (AST)
Creatinine
Gamma glutamyl transpeptidase (GGT)
Albumin
Total Bilirubin
Calcium
Unconjugated bilirubin
Phosphate
Creatine kinase
Glucose(fasting)
Uric acid
C-reactive protein (CRP)
T4 a
FSH a,b
TSH a
a
Screening only
b
To confirm postmenopausal status of female subject
6.3.2.3.
Genotyping
Genotyping
HLA-B*58:01B
6.3.2.4.
Urinalysis
Urinalysis
Glucose
pH
Protein
Blood
Upon a positive urine test from leucocytes, blood, nitrite or protein, the Investigator may require further urine 
analysis, such as flow cytometry. Results of additional urine analyses will be included in the database. If the flow 
cytometry examination shows a different result than the urine sticks, the urine will be investigated by fully 
automated digital imaging where leukocytes, erythrocytes, casts in urine will be analysed.
6.3.2.5.
Pregnancy Testing
Pregnancy test (females only)
Beta human chorionic gonadotrophin (Serum)
Urine Assessment


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6.3.2.6.
Viral Serology
Viral Serology
Human immunodeficiency virus (HIV) I and II
anti-HBc antibody
Hepatitis B surface antigen (HBsAg)
SARS-CoV-2 antibody
Hepatitis C Virus antibody
6.3.2.7.
SARS-CoV-2 Virology
SARS-CoV-2 Virology
SARS-CoV-2 RT-PCR
6.3.2.8.
Drugs of Abuse, Alcohol, and Cotinine
Drugs of Abuse and Alcohol Testing, Cotinine
Amphetamine / Ecstasy
Benzodiazepines
Ethanol
Methadone Metabolites
Cannabinoids
Barbiturates
Cocaine
Phencyclidine
Opiates 
Urine Creatinine
Cotinine
Tricyclic anti-depressants (TCA)
6.3.3.
Physical Examination
Full (Complete)
The complete physical examinations will include an assessment of the general appearance, 
respiratory, cardiovascular, abdomen, skin, head, and neck (including ears, eyes, nose, and 
throat), lymph nodes, thyroid, musculoskeletal and neurological systems.
Brief (Abbreviated)
The brief physical examinations will include an assessment of the general appearance, skin, 
abdomen, cardiovascular system and respiratory. 
6.3.4.
Electrocardiograms
6.3.4.1.
Resting 12-lead Electrocardiogram
At the time-points specified in the SoA (Table 3-1), a 10-second 12-lead safety ECG will be 
obtained after 10 minutes supine rest, using the site’s own ECG machines.
The PI will judge the overall interpretation as normal or abnormal and this evaluation will be 
reported in ClinBase™. If abnormal, it will be further documented as to whether or not the 


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abnormality is clinically significant by the PI. For all abnormalities (regardless of clinical 
significance) the specific type and nature of the abnormality will be documented in 
ClinBase™. Clinically significant findings should also be documented on the AE page of the 
CRF if applicable.
The PI may add extra 12-lead resting ECG safety assessments if there are any abnormal 
findings or if the PI considers it is required for any other safety reason. These assessments 
should be entered as an unscheduled assessment.
All ECG readings will be digitally stored as source documents.
6.3.5.
Vital Signs
The following variables will be collected after the subject has rested in the supine position for 
at least 5 minutes:

Systolic BP (mmHg)

Diastolic BP (mmHg)

Pulse (bpm)

Tympanic body temperature (°C)
The measurement of vital signs will be carried out according to the relevant Parexel SOPs.
Tympanic temperature will be measured at least once daily (in the morning) at every visit or 
during in-house stay.
6.4.
Pharmacokinetics
6.4.1.
Collection of Pharmacokinetic Samples
6.4.1.1.
Plasma Samples
Blood samples for the determination of plasma concentrations of verinurad, allopurinol and 
oxypurinol will be collected for each treatment period as specified in the SoA (Table 3-1).
Samples will be collected, handled, labelled, stored and shipped as detailed in the Laboratory 
Manual.
6.4.2.
Pharmacokinetic Drug Assays
Blood samples for determination of verinurad, allopurinol and oxypurinol concentrations in 
plasma will be analysed by Covance Bioanalytical Service on behalf of AstraZeneca, using 
validated assays.
Full details of the analytical methods and analyses performed will be described in a separate 
bioanalytical report.


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6.5.
Pharmacodynamics
6.5.1.
Collection of Pharmacodynamic Samples
Blood samples for the determination of sUA concentrations will be collected on Day -1 
(Treatment Period 1) and for each treatment period as specified in the SoA (Table 3-1).
Samples will be collected, handled, labelled, stored and shipped as detailed in the Laboratory 
Manual.
7.
BIOLOGICAL SAMPLES PROCEDURES
All biological sample collections will be performed by trained staff and in accordance with the 
Clinical Unit’s SOPs. 
7.1.
Total Blood Volume
The approximate total amount of blood to be collected from each subject in this study, 
excluding repeat samples, is summarised in Table 7-1.
Table 7-1
Total Blood Volume
Volume per Sample
Number of Samples
Total
Clinical Laboratory:
Haematology
2.7 mL
7
18.9 mL
Clinical chemistry a
7.5 mL
7
52.5 mL
HLA-B*58:01 allele genotyping
3.0 mL
1
3.0 mL
SARS-CoV-2 antibody ELISA
2.6 mL
1
2.6 mL
Pharmacokinetics:
Verinurad sampling
2 mL
80
160 mL
Allopurinol, and oxypurinol 
sampling
2 mL
64
128 mL
Pharmacodynamics:
sUA
1.1 mL
75
82.5 mL
Total
447.7 mL
a
When applicable, serology, serum pregnancy (females only) and follicle stimulating hormone analyses will 
be performed on the sample collected for clinical chemistry analyses.
ELISA: enzyme-linked immunosorbent assay; HLA: human leukocyte antigen; SARS-CoV-2: severe acute 
respiratory syndrome coronavirus 2; sUA: Serum uric acid.
Repeat blood samples may be collected for safety reasons. The maximum volume to be drawn 
from each subject must not exceed 500 mL.


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7.2.
Handling, Storage and Destruction of Biological Samples
7.2.1.
Safety Samples
Samples will be disposed of, on instruction from AstraZeneca, after the CSR has been 
finalised, unless samples are retained for additional or future analyses.
7.2.2.
Pharmacokinetic Samples
Pharmacokinetic samples will be disposed of after the bioanalytical report finalisation or 
6 months after issuance of the draft bioanalytical report (whichever is earlier), unless 
requested for future analyses.
Pharmacokinetic samples may be disposed of or anonymised by pooling. Additional analyses 
may be conducted on the anonymised, pooled PK samples to further evaluate and validate the 
analytical method. Any results from such analyses may be reported separately from the CSR.
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples. The results from the evaluation will not be reported in the CSR but 
separately in a bioanalytical report.
7.2.3.
Pharmacodynamic Samples
All PD samples collected during the study will be analysed locally. Samples will be collected 
and analysed per the processes of the local laboratory. Samples will be disposed of, on 
instruction from AstraZeneca, after the CSR has been finalised, unless samples are retained 
for additional or future analyses.
7.3.
Labelling and Shipment of Biohazard Samples
Samples will be labelled and shipped in accordance with the Laboratory Manual and the 
Biological Substance, Category B regulations (materials containing or suspected to contain 
infectious substances that do not meet Category A criteria), see Appendix B of this CSP
“International Airline Transportation Association 6.2 Guidance Document”.
Any samples identified as Infectious Category A materials will not be shipped and no further 
samples will be taken from the subject unless agreed with AstraZeneca and appropriate 
labelling, shipment and containment provisions are approved.
7.4.
Chain of Custody of Biological Samples
A full chain of custody will be maintained for all samples throughout their lifecycle.
The Principal Investigator will ensure full traceability of collected biological samples from the 
subjects while in storage at the centre until shipment and will keep documentation of receipt 
of arrival.


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The sample receiver will keep full traceability of samples while in storage and during use, 
until used, disposed of, or until further shipment or disposal (where appropriate) and will keep 
documentation of receipt of arrival.
7.5.
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 if not already analysed and the action documented.
AstraZeneca ensures the central laboratory(ies) 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 Clinical Unit.


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8.
ETHICAL AND REGULATORY REQUIREMENTS
8.1.
Ethical Conduct of the Study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH GCP and the AstraZeneca policy on 
Bioethics and Human Biological Samples.
8.2.
Subject Data Protection
The ICF will incorporate (or, in some cases, be accompanied by a separate document 
incorporating) wording that complies with relevant data protection and privacy legislation.
All clinical study findings and documents will be regarded as confidential. The PI and 
members of his/her research team must not disclose such information without prior written 
approval from the Sponsor.
The anonymity of participating subjects must be maintained. Subjects will be specified in 
outputs and other documents containing subject data by their subject number, not by name. 
Documents that identify the subject (eg, signed ICF) will be maintained in confidence by the 
PI.
Study data will be stored in accordance with local and global data protection laws.
8.3.
Ethics and Regulatory Review
The study will be submitted to the national regulatory agency, BfArM, for review and 
approval, by Parexel in accordance with local regulatory procedures.
The study will be submitted to the IEC for ethical review and approval by the PI in accordance 
with local procedures.
Parexel will provide the IEC and PI with safety updates/reports according to local 
requirements, including SUSARs, where relevant.
AstraZeneca will provide the regulatory authority with safety updates/reports according to 
local requirements, including SUSARs, where relevant.
Compensation will be reasonable and related to the nature and degree of inconvenience and 
discomfort as a result of participation in the study. Information on how participants will be 
compensated is contained in the ICF.
8.4.
Insurance
The Sponsor has covered this clinical study by means of an insurance of the clinical study 
according to national requirements. The name and address of the relevant insurance company, 


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the certificate of insurance, the policy number and the sum insured are provided in the 
Investigator's Site File.
8.5.
Informed Consent
The subjects shall be informed of the nature, significance, implications and risks of the trial, 
and informed consent will be freely given and evidenced in writing, dated and signed, or 
otherwise marked, by the subject as evidence to indicate his/her free informed consent, prior 
to the start of the study.
The nature of the informed consent will comply with the Declaration of Helsinki, the current 
requirements of GCP (EMA/CHMP/135/1995) and local regulation which ever offers the 
greater subject protection.
8.6.
Changes to the Protocol and Informed Consent Form
Study procedures will not be changed without the mutual agreement of the PI and 
AstraZeneca.
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol.
If a protocol amendment requires a change to the ICF the IEC should approve the revised ICF 
before the revised form is used.
If local regulations require, any administrative change will be communicated to or approved 
by the IEC.


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9.
DATA QUALITY ASSURANCE AND DATA MANAGEMENT
9.1.
Quality Control and Source Data Verification
Source data verification will be conducted with due regard to subject confidentiality.
The Clinical Unit will allow the study monitor and Sponsor representative direct access to all 
study documents, medical files and source documents to enable verification of the study data, 
while maintaining the anonymity of the subject and confidentiality of the data.
Internal quality control will be performed at all stages of the study by the Clinical Unit.
9.2.
Audit/Inspections
The Clinical Unit facilities and all study data/documentation may be audited/inspected by 
independent auditor/inspector/any representatives of regulatory authorities. The PI must allow 
the applicable persons access to all relevant facilities and data/documents. The PI must be 
available to discuss any findings/issues.
If an audit was performed, the audit certificate will be included in the CSR.
9.3.
Study Monitoring
The conduct of the study will be monitored by an independent Parexel monitor to ensure 
compliance with applicable regulatory requirements and GCP. The summary of the 
documentation of the monitoring visits will form part of the study documentation and will be 
archived as such.
Monitoring visits at site will be limited to a minimum, required as deemed appropriate during 
COVID-19 pandemic.
9.4.
Data Collection
The ClinBase™ system is an electronic source data capturing and information management 
system. The system combines all aspects of source data capturing with process control and 
clinical study management. All clinical and laboratory data, except those which are 
paper-based or provided by an external vendor, will be collected in ClinBase™. Only 
paper-based data will be subject to data entry. For electronic source data, no data entry will be 
performed.
The responsible study monitor will check data at the monitoring visits to the Clinical Unit. 
The PI will ensure that the data collected are accurate, complete and legible. Data will be 
monitored within ClinBase™ by the study monitor before being exported. Any changes made 
during monitoring will be documented with a full audit trail within ClinBase™.


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9.4.1.
Case Report Forms and Source Documents
All data obtained using paper collection methods during the clinical study will be recorded in 
ClinBase™. All source documents from which ClinBase™ entries are derived should be 
placed in the subject’s personal records.
The original ClinBase™ entries for each subject will be checked against source documents by 
the study monitor. Instances of missing or uninterpretable data will be discussed with the PI 
for resolution.
9.4.2.
Access to Source Documents
During the course of the clinical study, a study monitor will make Clinical Unit visits to 
review protocol compliance, compare ClinBase™ entries and individual subject’s personal 
records, assess IMP accountability and ensure that the clinical study is being conducted 
according to pertinent regulatory requirements. ClinBase™ entries will be verified against 
source documents. The review of medical records will be handled confidentially to ensure 
subject anonymity.
Checking of the ClinBase™ entries for completeness and clarity and verifying with source 
documents, will be required to monitor the clinical study for compliance with GCP and other 
regulations. Moreover, regulatory authorities of certain countries, IECs may wish to carry out 
source data inspections on-site, and the Sponsor’s clinical quality assurance group may wish 
to carry out audits. Direct access to source data will be required for these inspections and 
audits; they will be carried out giving due consideration to data protection and subject 
confidentiality. The PI assures the Sponsor of the necessary support at all times.
9.5.
Data Management
Parexel will utilise standardised and validated procedures and systems to collect, process and 
file the clinical data of this study. Any system used will be compliant with FDA 21 CFR 
Part 11 requirements.
A DMP will be prepared to describe the processes and data-flow within the clinical study. 
Timelines, versions for the computer systems and the coding will be defined in the DMP, and 
if applicable, sponsor specific requests will also be documented within. The DMP will be 
finalised before first dose where possible but before database lock.
A DVS will be created to outline the validation checks to be performed during the study. The 
DVS must be finalised before data validation.
After the data has been monitored by the responsible study monitor all data received will be 
reviewed, logged and filed.


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The raw data intended for further processing will be checked by standard routines or 
according to the DVS and queries will be generated and sent to the PI for review and 
resolution. Corrections resulting from these queries will be confirmed on the DCFs. This 
process will be repeated until no further discrepancies are found. The data will then be 
declared as clean. Applicable documentation will be stored in the study files.
Only trained study staff will have access to the clinical database and every change in data will 
have a full audit trail.


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10.
EVALUATION AND CALCULATION OF VARIABLES
10.1.1.
Adverse Events
All AEs will be coded using MedDRA vocabulary and will be listed for each subject. 
Adverse events will be assigned to a treatment based on the start date/time of the AE in 
relation to dosing in that period; for tabulation purposes the AE will then be assigned to the 
treatment received in the respective treatment period as follows:

Treatment Period 1: AEs with start date/time at the time of or after dosing in Treatment 
Period 1 until the time of dosing in Treatment Period 2.

Treatment Period 2: AEs with start date/time at the time of or after dosing in Treatment 
Period 2 until the time of dosing in Treatment Period 3.

Treatment Period 3: AEs with start date/time at the time of or after dosing in Treatment 
Period 3 until the time of dosing in Treatment Period 4.

Treatment Period 4: AEs with start date/time at the time of or after dosing in Treatment 
Period 4 until the time of dosing in Treatment Period 5.

Treatment Period 5: AEs with start date/time at the time of or after dosing in Treatment 
Period 5 until the final Follow up Visit.
Adverse events with missing start dates/times will be handled as follows:

If the start date is completely missing but the end date is known and shows that the AE 
ended on or after the first dose date, then the start date will be imputed as the first day of 
dosing; if the end date is known and shows that the AE ended before the first dose date, 
then the screening date will be used for the start date. If the end date is non-informative 
(ie, is missing or does not contain enough information), the start date will be imputed as 
the first date of dosing.

If only the start day is missing the day will be imputed as the first day on which a dose 
was given in that month unless the end date is known and shows that the AE ended before 
a dose was given in that month; in which case the date will be imputed as 01. If the end 
date is non-informative (ie, is missing or does not contain enough information), the start 
date will be imputed as the first date of dosing in the known month. If the month is not a 
dosing month the date will be imputed as 01.

If the start day and month are missing the date will be imputed as the first day of dosing 
in the known year unless the end date is known and shows that the AE ended before a 
dose was given in that year; in which case the start day and month will be imputed as 
01Jan or with the date of screening if this is later. If the end date is non-informative (ie, is 
missing or does not contain enough information), the start date will be imputed as the first 
date of dosing in the known year. If the year is not a year of dosing then the date will be 
imputed as 01Jan or with the date of screening if this is later.

Missing times will be imputed as 00:00 h or with the time of dosing for events starting on 
a dosing day.


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For purposes of the AE summaries, the following will apply:

AEs with unknown intensity will be treated as “severe” for the tabulations.

AEs with unknown relationship will be treated as “related” for the tabulations.

AEs with unknown seriousness will be treated as “serious” for the tabulations
There will be no imputation of AE data for the data listings. All data will be listed as recorded 
in the CRF.
Adverse events with onset (start date/time) after dosing in Treatment Period 1 will be 
summarised by treatment (where treatments will be pooled across treatment periods) and 
overall for all subjects, including tabulations by causality and severity (mild, moderate and 
severe). All tabulations will be presented by SOC and Preferred Term with the exception of 
the causality and severity tables, which will be presented by Preferred Term only. 
Furthermore, separate listings of SAEs, DAEs and AEs that led to death will be presented.
Adverse events will be listed and the following information will be included in the listings: 
verbatim term, SOC, PT and lowest level term, start date/time, end date/time, time from last 
dose, causality, action taken, whether the AE was classified as serious and the outcome.
All tabulations will include the number and percentage of subjects. In addition, a separate 
tabulation will be presented showing the number of events by treatment and PT.
Finally, an overview of all AEs will be presented, separately for the number and percentage of 
subjects and the number of events. This will include categories for any AE, AEs with outcome 
of death and SAEs.
10.1.2.
Laboratory Assessments
Haematology and clinical chemistry values will be listed by subject and time point including 
changes from baseline and repeat/unscheduled measurements. Summary tabulations including 
absolute values and changes from baseline will be presented by time point for the safety 
analysis set. The baseline for the measurements in Treatment Period 1 will be the Day -2 
assessment and for the measurements in Treatment Period 2, 3, 4, and 5, it will be the Day -1 
assessment performed prior to dosing in each of the respective treatment periods. Shift tables 
will also be presented.
Any laboratory variables with results from the laboratory given as “< xx” or “>xx” in the 
database will be imputed with the absolute value of the number without the sign (eg, < 2.2 will 
be imputed as 2.2) for the descriptive statistics and changes from baseline.


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The listings will include the following information: test name, date of measurement, reference 
range, result and flags for any measurements that are outside the reference range (eg, 
AstraZeneca, program, or laboratory ranges). Clinical laboratory data will be reported in 
System International units in the CSR.
Additional listings will be presented for the following:

Urinalysis (macroscopic and microscopic, if applicable)

Pregnancy testing (including FSH)

The results of viral serology, SARS-CoV-2 virology, and the drugs of abuse, alcohol, and 
cotinine screen will not be listed in the CSR.
10.1.3.
Physical Examination
The baseline/screening results of the physical examination will be documented in medical 
history for each subject.
Any new or aggravated clinically relevant abnormal medical physical examination finding 
compared to the baseline assessment will be reported as an AE.
10.1.4.
Resting 12-lead Electrocardiogram
12-Lead ECG results will be listed for each subject.
10.1.5.
Vital Signs
The results of the vital signs measurements will be listed by subject and time point including 
the date/time of the assessment, changes from baseline and repeat/unscheduled measurements. 
The baseline for vital signs measurements will be the pre-dose assessment on Day 1 in each 
treatment period. Descriptive statistics will be presented by treatment and time point for both 
observed values and changes from baseline.
10.2.
Pharmacokinetic Parameters
The PK parameters will be estimated for verinurad, allopurinol and oxypurinol using plasma 
concentrations.
10.2.1.
Plasma Parameters
The following PK parameters will be determined where data allow for verinurad, allopurinol 
and its metabolite oxypurinol for each treatment.
Primary PK parameters
AUCinf
Area under plasma concentration-time curve from time zero to infinity


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AUClast
Area under the plasma concentration-time curve from time zero to time of last 
quantifiable concentration
Cmax
Maximum observed plasma (peak) drug concentration
Secondary PK parameters
tmax
Time to reach maximum observed plasma concentration following drug 
administration
tlag
Time delay between drug administration and the first observed concentration in 
plasma
t½λz
Half-life associated with terminal slope (λz) of a semi-logarithmic 
concentration-time curve
MRTinf
Mean residence time of the unchanged drug in the systemic circulation from zero 
to infinity (parent drug only)
λz
Terminal elimination rate constant
CL/F
Apparent total body clearance of drug from plasms after extravascular 
administration (parent drug only)
Vz/F
Apparent volume of distribution during the terminal phase after extravascular 
administration (parent drug only)
Vss/F
Volume of distribution (apparent) at steady state following extravascular 
administration (parent drug only)
The following diagnostic parameters will also be provided:
λz upper
Upper (later) t used for λz determination
λz lower
Lower (earlier) t used for λz determination
tlast
Time of last observed (quantifiable) concentration
λzN
Number of data points used for λz determination
λz span ratio
Time period over which λz was determined as ratio of t½λz
Rsq_adj
Statistical measure of fit for the regression used for λz determination adjusted for 
the number of used data points (λzN)
AUCextr
Extrapolated area under the curve from tlast to infinity, expressed as percentage of 
AUCinf
Additional PK parameters may be determined where appropriate.
10.2.2.
Calculation or Derivation of Pharmacokinetic Parameters
The PK analyses of the plasma concentration data for verinurad, allopurinol and oxypurinol 
will be performed by Covance, on behalf of Clinical Pharmacokinetic Alliance, AstraZeneca 
R&D and will be calculated according to the AstraZeneca standards (Guideline for PK 
Evaluations in Clinical Studies, v3, Feb 2020).


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Pharmacokinetic parameters will be derived using non-compartmental methods with Phoenix®
WinNonLin® Version 8.1 or higher. All descriptive and inferential statistical computations 
will be performed using SAS® Version 9.4, or higher.
Pharmacokinetic analysis will, where possible, be carried out using actual times recorded in 
the raw data. If actual times are missing, nominal times may be used.
10.3.
Pharmacodynamic parameters
The PD parameters will be assessed using sUA concentrations, calculating the percentage 
change from baseline (time-matched, Day -1) in sUA concentrations up to 72 hours post-dose 
at each timepoint following administration of IMP.
The following PD parameters will be derived from the calculated profiles using non-
compartmental analysis with WinNonLin (Version 8.1 or higher):
Serum uric acid derived PD parameters
Emax, CB 
Maximum observed percentage change from 
baseline (Time-Matched, Day -1 and pre-
dose on each day) in serum uric acid 
concentrations
tEmax, CB 
Time of maximum percentage change from 
baseline (Time-Matched, Day -1 and pre-
dose on each day) in serum uric acid 
concentrations
11.
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION
11.1.
Description of the Analysis Sets
11.1.1.
Safety Analysis Set
The safety analysis set will include all subjects who received at least 1 dose of IMP and for 
whom any safety post-dose data are available.
Unless otherwise stated, the safety analysis set will be used for the presentation of all 
demographic and disposition data, as well as all safety analyses. Exposure to IMP will also be 
presented using the safety analysis set.
11.1.2.
Pharmacokinetic Analysis Set
The PK analysis set will include all subjects in the safety analysis set who received a 
verinurad + allopurinol (or verinurad alone for Treatment 5) dose and who have at least 1 
quantifiable post-dose plasma concentration. In case of an important protocol deviation or 
event, affected PK data will be excluded from the descriptive and inferential statistical 


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analyses, but will still be included in the study result listings. For the formal relative 
bioavailability evaluations, only subjects who provide eligible PK data for both Test and 
Reference treatments can be included for each comparison.
Data for a subject may be excluded from the descriptive and inferential statistical analyses as a 
result of the following:

Where a subject experienced vomiting at or before median tmax.

Where the pre-dose concentration for an analyte is > 5% of Cmax in a specific PK 
sampling period
The exclusion of any subjects or any PK concentrations or parameters from the descriptive or 
inferential statistical analyses, or of any time-points from the PK parameter 
non-compartmental analysis, will be discussed and agreed with the AstraZeneca CPS prior to 
handover of the final PK parameters to programming.
11.1.3.
Pharmacodynamic Analysis Set
The PD analysis set will consist of all subjects in the safety analysis set who received at least 
1 of the verinurad and allopurinol (or verinurad alone for Treatment 5) doses and who have at 
least 1 quantifiable time-matched sUA concentration.
11.1.4.
Randomised Set
The Randomised Set will consist of all subjects randomised into the study.
11.2.
Methods of Statistical Analyses
11.2.1.
General Principles
The statistical methodology below describes the statistical analysis as it is foreseen when the 
study is being planned.
If circumstances should arise during the study rendering the analysis inappropriate, or if in the 
meantime improved methods of analysis should come to light, different analyses may be 
performed. A separate SAP will not be written for the study. Any deviations from the 
statistical methodology defined in this protocol, reasons for such deviations and all 
alternative/additional statistical analyses that may be performed will be described in the CSR. 
Such changes to analyses may be written into an abbreviated SAP, if appropriate. The 
verification and review of all statistical modelling assumptions will be documented 
appropriately.
All original and derived variables as well as demographic and disposition data will be listed 
and described using summary statistics. All safety data (scheduled and unscheduled) will be 
presented in the data listings.


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Demographic and baseline data will be summarised for all randomised subjects. 
Pharmacokinetic data will be summarised by treatment. Safety and tolerability data will be 
summarised by treatment, if applicable.
Frequency counts (number of subjects [n] and percentages) will be made for each qualitative 
variable. Descriptive statistics (n, mean, SD, median, minimum and maximum) will be 
calculated for each quantitative variable (unless otherwise stated). Descriptive statistics will 
only be presented if n ≥ 3. If no subjects have data at a given time point, then only n = 0 will 
be presented. If n < 3, only the n, minimum and maximum will be presented. If n = 3, only the 
n, median, minimum and maximum will be presented. The other descriptive statistics will be 
left blank. Due to the explorative nature of this study, no adjustment for multiple testing of 
variables will be done.
The following rules will apply to any repeated safety assessments occurring within each 
treatment period:

If the repeated measurement of a specific variable occurs prior to IMP administration 
(Day 1), then the last obtained value prior to dosing will be used in the descriptive 
statistics and in the calculation of changes from baseline.

If the repeated measurement of a specific parameter occurs after IMP administration 
(Day 1), then the first (non-missing) value after dosing will be used in descriptive 
statistics and in the calculation of changes from baseline.
The planned sequence for measurement of multiple assessments at the same time point is 
described in Section 3.1.1.
For safety assessments performed at screening and the follow-up, the following rules will 
apply for any repeated assessments:

If the repeated assessment occurs at screening the last available value will be used in the 
summary statistics.

If the repeated assessment occurs at the Follow-up Visit the first non-missing assessment 
will be used in the summary statistics.
All statistical analyses and production of tables, figures and listings will be performed using 
SAS® version 9.4 or higher.
11.2.2.
Missing Data
Missing dates and times in the AE data will be handled as described in Section 10.1.1. 
Concentrations that are marked non-quantifiable in the PK data will be handled as described 
in the most recent version of the AstraZeneca CPE TFL Standards.


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There will be no imputations of other missing data. All subjects will be included in the safety 
analyses as far as the data permit.
11.2.3.
Subject Characteristics
A randomisation listing will be presented and include the following: each subject’s 
randomisation number, the subject’s full enrolment number and the treatment to which the 
subject has been randomised and the country where the study centre is located.
Subjects and/or data excluded from the PK analysis set will be listed including the reason for 
exclusion. Subject disposition will be summarised and will include the following information: 
number of subjects randomised and dosed, number and percentage of subjects completing the 
study and the number and percentage of subjects who were withdrawn (including reasons for 
withdrawal). Disposition data will be presented based on all subjects randomised.
Subject discontinuations will be listed including the date of study exit, duration of treatment 
and reason for discontinuation. A listing of informed consent response will also be presented.
11.2.3.1.
Demographic and Baseline Data
Demographic variables (age, gender, race, ethnicity, height, weight and BMI) will be listed by 
subject. Demographic characteristics (age, gender, race and ethnicity) and subject 
characteristics (height, weight and BMI) will be summarised separately for all randomised 
subjects. The denominator for percentages will be the number of randomised subjects.
Medical history data will be listed by subject including visit, description of the 
disease/procedure, MedDRA SOC, MedDRA Preferred Term, start date and stop date (or 
ongoing if applicable).
11.2.4.
Prior and Concomitant Medication and Drug Administration
11.2.4.1.
Prior and Concomitant Medication
Prior medications are those that started and stopped prior to the first dose of IMP; all 
medications taken after first dosing are considered as concomitant (including medications that 
started prior to dosing and continued after). Prior medication started within 3 months prior to 
the first dose of IMP will be recorded also in the concomitant medication module of 
ClinBase™. 
Prior and concomitant medication will be listed by subject and will include the following 
information: reported name, Preferred Term, the route of administration, dose, frequency, start 
date/time, duration and indication. Prior and concomitant medication will be coded according 
to the Sponsor’s drug dictionary.
The duration will be calculated as:


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Duration = end date/time – start date/time + 1
The duration may be presented in hours or days in the listing depending on the applicability to 
the emerging data. For medications with partial or completely missing start date/times and/or 
end date/times, the duration will not be calculated.
Medications with missing or partial start date/time and/or end date/time such that it is not 
possible to classify as prior or concomitant will be considered as concomitant in the listings.
11.2.4.2.
Drug Administration
Drug administration dates and times will be listed for each subject and treatment period. 
Details of high-fat, high-calorie breakfast will be listed.
11.2.5.
Safety and Tolerability
All safety data (scheduled and unscheduled) will be presented in the data listings. Continuous 
variables will be summarised using descriptive statistics (n, mean, SD, minimum, median, 
maximum) by treatment. Categorical variables will be summarised in frequency tables 
(frequency and proportion) by treatment. The analysis of the safety variables will be based on 
the safety analysis set.
Adverse events will be summarised by Preferred Term and SOC using MedDRA vocabulary. 
Furthermore, listings of SAEs and adverse events that led to withdrawal will be made and the 
number of subjects who had any AE, SAEs, AEs that led to withdrawal, and AEs with severe 
intensity will be summarised. Adverse events that occurred from time of informed consent 
until first administration of IMP will be reported separately.
Tabulations and listings of data for vital signs, clinical laboratory tests and ECGs (listings 
only) will be presented. Any new or aggravated clinically relevant abnormal medical physical 
examination finding compared to the baseline assessment will be reported as an AE. Data will 
be summarised for the observed values at each scheduled assessment, together with the 
corresponding changes (and/or percentage change) from the baseline when baseline is defined. 
Clinical laboratory data will be reported in the units provided by the clinical laboratory for the 
SRC meeting, and in Système International units in the CSR.
Out-of-range values for safety laboratory, vital signs and ECG will be flagged in individual 
listings as well as summarised descriptively using agreed standard reference ranges and/or 
extended reference ranges (eg, AZ, program, or laboratory ranges).
11.2.6.
Presentation of Pharmacokinetic Parameter Data
A listing of PK blood sample collection times, as well as derived sampling time deviations 
and all reportable concentrations will be presented for verinurad and for allopurinol and 


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oxypurinol for all dosed subjects. An additional listing of PK concentrations versus time will 
be presented for those analytes based on the PK analysis set.
Plasma concentrations will be summarised for the PK analysis set for each time point by 
treatment for each analyte separately using CSP scheduled times and appropriate descriptive 
statistics.
All reportable PK parameters from the NCA will be listed for verinurad, allopurinol, and 
oxypurinol for subjects dosed.
Plasma PK parameters will be summarised for the PK analysis set by treatment for each 
analyte separately.
Further details on presentation of PK concentration and parameter data will be presented 
according to the most recent version of the AstraZeneca Corporate CSRHLD reporting 
standards, that includes applicable descriptive statistics, handling of individual concentrations 
below the LLOQ for listings, descriptive statistics and figures, and precision and rounding 
rules for concentrations and PK parameter data.
Individual plasma concentrations versus actual elapsed time after dose will be plotted on both 
the linear and semi-logarithmic scale with the all dosed treatments overlaid on the same plot 
and separate plots for each subject and analyte. Plots will be based on all dosed subjects.
Combined individual plasma concentration versus actual times will be plotted based on the PK 
analysis set on both the linear and semi-logarithmic scale, with all subjects for the same 
treatment overlaid on the same plot and separate plots for each treatment and analyte.
Geometric mean (+/- geometric standard deviation [gSD]) plasma concentration versus 
nominal sampling time will be plotted on both the linear scale and semi-logarithmic (no gSD 
presented) with all treatments overlaid on the same plot and separate plots for each analyte. 
Plots will be based on the PK analysis set. Focus plots may be provided if there will be no 
clear distinction among profiles.
11.2.7.
Inferential Statistical Analysis of Pharmacokinetic Data
For each individual relative bioavailability comparison, the ratios of Cmax, AUClast and 
AUCinf will be calculated for each treatment comparison (Test treatment versus Reference 
treatment) using log-transformed data.
The following comparisons of relative bioavailability (Cmax, AUCinf and AUClast) for each 
analyte (verinurad, allopurinol and oxypurinol) will be performed: 

Treatment 2 versus Treatment 1, ie, “verinurad/allopurinol FDC capsule, fasted” versus
“verinurad HPMC capsule and allopurinol tablet, free combination, fasted”. 


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
Treatment 3 versus Treatment 2, ie “verinurad/allopurinol FDC capsule, fed” versus
“Verinurad/allopurinol FDC capsule. fasted”. 

Treatment 4 versus Treatment 1, ie. “verinurad HPMC capsule and allopurinol tablet, free 
combination, fed” versus “verinurad HPMC capsule and allopurinol tablet, free 
combination, fasted”.

Treatment 3 versus Treatment 4, ie. “verinurad/allopurinol FDC capsule, fed” versus 
“verinurad HPMC capsule and allopurinol tablet, free combination, fed”.

Treatment 5 versus Treatment 2 (for verinurad only), ie., “verinurad gelatin capsule,
fasted” versus “verinurad/allopurinol FDC capsule, fasted”.
The analyses will be performed using a linear mixed-effects analysis of variance model using 
the natural logarithm of Cmax, AUCinf and AUClast as the response variables, sequence, 
period and treatment as mixed-effects, volunteer nested within sequence as a random effect. 
Transformed back from the logarithmic scale, geometric means together with CIs (2-sided 
95%) for Cmax, AUCinf and AUClast will be estimated and presented. Also, ratios of 
geometric means together with CIs (2-sided 90%) will be estimated and presented.
11.2.8.
Presentation and Statistical Analysis of Pharmacodynamic Data
A listing of sUA sample collection times, as well as derived sampling time deviations will be 
provided. Serum UA observed and time-matched percentage change from baseline will be 
listed by treatment and summarized descriptively by treatment and time point. Emax CB and 
tEmax CB data will be listed by treatment. For observed and time-matched percentage change 
from baseline, the descriptive statistics will include n, geometric mean, geometric CV, 
arithmetic mean, arithmetic SD, median, minimum, and maximum. Geometric CV will be 
calculated as 100 × (square root [exp(s2)-1]) where s is the SD of the log-transformed data.
Individual and mean (with corresponding error bars) serum concentration curves (both linear 
and log scale) will also be generated. All the results will be based on the PD analysis set.
11.3.
Protocol Deviations
Protocol deviations are considered any deviation from the CSP relating to a subject, and 
include the following:

Inclusion/exclusion criteria deviations

Dosing deviations (eg, incorrect treatment received, subject was not fasted as per the 
protocol requirements prior to and after dosing)

Time window deviations for safety and/or PK assessments

Subjects receiving prohibited concomitant medications

Other procedural and study conduct deviations recorded by the Clinical Unit on a protocol 
deviation log


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The criteria for the assessment and reporting of protocol deviations will be stipulated in a 
separate study specific protocol deviation specification document. This will include a WAD
which stipulates tolerance windows for safety and PK assessments. Measurements performed 
within these tolerance windows will not be considered as protocol deviations and will not be 
reported.
All protocol deviations will be discussed at the data review meeting prior to database hard 
lock in order to define the analysis sets for the study.
Important protocol deviations will be listed by subject.
Protocol deviations (missing assessments/visits) related to COVID-19 will be listed 
separately.
Protocol deviations will be handled in accordance with Parexel SOPs.
For handling of protocol amendments, see Section 8.6.
11.4.
Determination of Sample Size
The sample size was chosen to obtain reasonable assessment of relative bioavailability 
between different formulations of verinurad and/or allopurinol without exposing undue 
numbers of subjects to the compound at this phase of clinical development. It is estimated that 
20 subjects randomised to 5 sequences in a reduced Latin square will provide a 90% CI within 
0.7 and 1.43, with a probability of >90% if the estimated treatment ratio is 1 for Cmax. This is 
based on an intra-subject variability of 24% for Cmax of verinurad in Study D5495C00001. 
Similarly, it is estimated that 20 subjects will provide a 90% CI within 0.8 and 1.25, with a 
probability of >95% if the estimated treatment ratio is 1 for AUC. This is based on an 
intra-subject variability of 14.7% for AUC of verinurad in Study D5495C00001.
Twenty-five subjects will be equally randomised to 5 treatment sequences: 12345, 23451,
34512, 45123, and 51234 in order to ensure at least 20 evaluable subjects at the end of the last 
treatment period.


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12.
LEGAL AND ADMINISTRATIVE ASPECTS
12.1.
Archiving of Study Documents
All source documents generated in connection with the study will be retained in the limited 
access file storage area, respecting the privacy and confidentiality of all records that could 
identify the subjects. Direct access is allowed only for authorised people for monitoring and 
auditing purposes. Source documents will be handled, stored and archived according to 
in-house procedures.
The Investigator's Site File will be archived by the CRO for 25 years after completion of the 
study.
12.2.
Publication of Study Results
All of the study information and data collected during the study are confidential and the 
property of AstraZeneca. After completion of the study, AstraZeneca may prepare a joint 
publication with the Investigator. The Investigator must undertake not to submit any data from 
this CSP for publication without prior consent of AstraZeneca at a mutually agreed time.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
12.3.
Clinical Study Report
An integrated CSR will be prepared in accordance with the standards of the ICH guideline for 
structure and content of CSRs (ICH E3). Copies of the CSR will be provided to the IEC and 
the national regulatory authority in accordance with regulatory requirements and Parexel
SOPs. In the event of premature termination of the study or other conditions specified in ICH 
E3, an abbreviated CSR may be prepared.


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13.
REFERENCE LIST
1.
Investigator's Brochure Verinurad - Chronic kidney disease (D5495) and heart failure 
(D5496). 2019 November 11. Edition Number 3.
2.
Ambrosy AP, Gheorghiade M, Chioncel O, Mentz RJ, Butler J. Global perspectives in 
hospitalised heart failure: regional and ethnic variation in patient characteristics, 
management, and outcomes. Current Heart Failure Reports. 2014; 11(4): p. 416-27.
3.
Anker SD, Doehner W, Rauchhaus M, Sharma R, Francis D, Knosalla C, et al. Uric Acid 
and Survival in Chronic Heart Failure: Validation and Application in Metabolic, 
Functional, and Hemodynamic Staging. Circulation. 2003; 107(15): p. 1991-97.
4.
Andrés M, Quintanilla MA, Sivera F, Sánchez-Payá J, Pascual E, Vela P, et al. Silent 
Monosodium Urate Crystal Deposits Are Associated With Severe Coronary Calcification 
in Asymptomatic Hyperuricemia: An Exploratory Study. Arthritis Rheumatol. 2016; 
68(6): p. 1531-39.
5.
Martillo MA, Nazzal L, Crittenden DB. The crystallization of monosodium urate. Curr 
Rheumatol Rep. 2014; 16(2): p. 400-09.
6.
Palazzuoli A, Ruocco G, De Vivo O, Nuti R, McCullough PA. Prevalence of 
hyperuricemia in patients with acute heart failure with either reduced or preserved 
ejection fraction. J. 2017; 120(7): p. 1446-50.
7.
Grayson PC, Kim SY, LaValley M, Choi HK. Hyperuricemia and incident hypertension: 
A systematic review and meta-analysis. Arthritis Care Res. 2011; 63(1): p. 102-10.
8.
Leyva F, Anker SD, Godsland IF, Teixeira M, Hellewell PG, Kox WJ, et al. Uric Acid in 
Chronic Heart Failure: A Marker of Chronic Inflammation. Eur Heart J. 1998; 19(12): p. 
1814-22.
9.
European Medicines Agency. Guidance on the Management of clinical trials during the 
COVID-19 (Coronavirus) pandemic, Version 3.; 2020. Available from: 
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/guidanceclinicaltrials_c
ovid19_en.pdf.
10. Food and Drug Administration. FDA Guidance on conduct of clinical trials of medical 
products during COVID-19 public health emergency, dated March 2020, updated on 16 
April 2020.; 2020. Available from: 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/fda-guidanc
e-conduct-clinical-trials-medical-products-during-covid-19-public-health-emergency.
11. Food and Drug Administration. Statistical Considerations for Clinical Trials During the 
COVID-19 Public Health Emergency, dated June 2020. Available from: 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/statistical-
considerations-clinical-trials-during-covid-19-public-health-emergency-guidance-
industry.


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12. Summary of Product Characteristics - Allopurinol 300 mg Tablets. [Online].; 2018 [cited 
2019 Oct 25]. Available from: https://www.medicines.org.uk/emc/product/6006/smpc.


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14.
APPENDICES
Appendix A
Additional Safety Information
Further Guidance on the Definition of a Serious Adverse Event
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 (eg, hepatitis that resolved without hepatic failure).
Hospitalisation
Outpatient treatment in an emergency room is not in itself a SAE, although the reasons for it 
may be (eg, 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.
Important Medical Event or Medical Intervention
Medical and scientific judgment 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 jeopardise the subject or may require 
medical intervention to prevent 1 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 
judgment must be used.
Examples of such events are:

Angioedema not severe enough to require intubation but requiring intravenous 
hydrocortisone treatment.

Hepatotoxicity caused by paracetamol/acetaminophen overdose requiring treatment with 
N-acetyl cysteine.

Intensive treatment in an emergency room or at home for allergic bronchospasm.

Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion) or convulsions 
that do not result in hospitalisation.

Development of drug dependency or drug abuse.


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A Guide to Interpreting the Causality Question
The following factors should be considered when deciding if there is a “reasonable 
possibility” that an AE may have been caused by the IMP.

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?

Dechallenge 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 other etiology such as the underlying disease, 
other drugs, other host or environmental factors.

Rechallenge experience:
Did the AE reoccur if the suspected drug was reintroduced after having been stopped?
Note: AstraZeneca would not normally recommend or support a rechallenge.

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 recognised 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”.


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Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.


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Appendix B
International Airline Transportation Association 6.2 
Guidance Document
Labelling and Shipment of Biohazard Samples
International Airline Transportation Association classifies biohazardous agents into 
3 categories (http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.ht
m). 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 for example, Ebola and Lassa 
Fever viruses. Category A pathogens:
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 for example, hepatitis A, B, C, D and E 
viruses, and HIV 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 Instruction 650.
Exempt refers to 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.

International Airline Transportation Association compliant courier and packaging 
materials should be used for packing and transportation. 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 C
Actions Required in Cases of Combined Increase of 
Aminotransferase and Total Bilirubin - Hy’s Law
C 1
Introduction
This Appendix describes the process to be followed in order to identify and appropriately 
report PHL cases and HL cases. 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 PHL criteria at any point during the study.
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including central and all 
local laboratory evaluations even if collected outside of the study visits; for example, PHL 
criteria could be met by an elevated ALT from a central laboratory and/or elevated total 
bilirubin (TBL) from a local laboratory. 
The Investigator will also review AE data (for example, for AEs that may indicate elevations 
in liver biochemistry) for possible PHL events.
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether 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 IMP. 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting SAEs and AEs according to the outcome of the review and assessment in line with 
standard safety reporting processes.
C 2
Definitions
Potential Hy’s Law
AST or ALT ≥3 × ULN together with TBL ≥2 × ULN at any point during the study 
following the start of study medication irrespective of an increase in ALP.
Hy’s Law
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.


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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 timeframe within which the 
elevations in transaminases and TBL must occur.
C 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:

AST ≥3 × ULN

ALT ≥3 × ULN

TBL ≥2 × ULN
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 Section 2 
within this appendix for definition) by reviewing laboratory 
reports from all previous visits

Promptly enter the laboratory data into the laboratory CRF 
module(s)
C 4
Follow-Up
C 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 CSP
C 4.2
Potential Hy’s Law Criteria met
If the subject does meet PHL criteria the Investigator will:

Notify the AstraZeneca representative who will then inform the central Study Team

Within 1 day of PHL criteria being met, the Investigator will report the case as an SAE of 
PHL; serious criteria “Important medical event” and causality assessment “yes/related”
according to CSP process for SAE reporting


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
For subjects that met PHL criteria prior to starting IMP, the Investigator is not required to 
submit a PHL SAE unless there is a significant change‡ in the subject’s condition

The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study subjects’ follow-up (including any further laboratory testing) and 
the continuous review of data

Subsequent to this contact the Investigator will:
o
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. Completes follow-up SAE Form as required.
o
Investigate the etiology of the event and perform diagnostic investigations as 
discussed with the Study Physician. This includes deciding which the tests 
available in the HL laboratory kit should be used (if applicable).
o
Complete the 3 liver CRF modules as information becomes available.
C 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.
As soon as possible 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, to ensure timely analysis and reporting to health authorities within 15 calendar days 
from the date the PHL criteria were met. 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.
Where there is an agreed alternative explanation for the AST or ALT and TBL elevations, 
a determination of whether the alternative explanation is an AE will be made and 
subsequently whether the AE meets any criteria for a SAE:

If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF module(s)
                                               
‡ 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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
If the alternative explanation is an AE/SAE: update the previously submitted PHL SAE 
and AE CRF entries accordingly with the new information (reassessing event term; 
causality and seriousness criteria) following the AstraZeneca standard processes
If it is agreed that there is no explanation that would explain the AST or ALT and TBL 
elevations other than the IMP:

Send updated SAE (report term “Hy’s Law”) according to AstraZeneca standard 
processes

The “Medically Important” seriousness criterion should be used if no other 
seriousness 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 15 calendar days in obtaining the information 
necessary to assess whether 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:

Provide any further update to the previously submitted SAE of PHL (report term now 
“Hy’s Law case”), ensuring causality assessment is “related to IMP” and seriousness 
criterion is “medically important”, according to CSP process for SAE reporting

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 still met. Update the previously submitted PHL SAE report 
following CSP process for SAE reporting, according to the outcome of the review and 
amending the reported term if an alternative explanation for the liver biochemistry 
elevations is determined.
C 6
Laboratory Tests
The list below represents the standard, comprehensive list of follow-up tests which are 
recommended but not mandatory when using a central laboratory. For studies using a local 
laboratory, the list may be modified based on clinical judgment. Any test results need to be 
recorded.


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Hy’s Law laboratory kit for central laboratories (18 December 2018)
Additional standard biochemistry and 
coagulation tests
GGT
LDH
Prothrombin time
INR
Viral hepatitis
IgM anti-HAV 
IgG anti-HCV
IgM and IgG anti-HBc
HCV RNA*
HBsAg
IgM anti-HEV
HBV DNA
HEV RNA
Other viral infections
IgM & IgG anti-CMV
IgM & IgG anti-HSV
IgM & IgG anti-EBV
Alcoholic hepatitis
Carbohydrate deficient transferrin (CD-transferrin)
Autoimmune hepatitis
Antinuclear antibody (ANA)
Anti-Liver/Kidney Microsomal Ab (Anti-LKM)
Anti-Smooth Muscle Ab (ASMA)
Metabolic diseases
alpha-1-antitrypsin
Ceruloplasmin
Iron
Ferritin
Transferrin
Transferrin saturation
* HCV RNA is only tested when anti-HCV is positive or inconclusive
REFERENCES
Aithal GP, Watkins PB, Andrade RJ, et al. Case definition and phenotype standardization in 
druginduced liver injury. Clinical Pharmacology & Therapeutics 2011;89(6):806–15.


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Appendix D
Actions Required in Cases of a Renal-related or Urolithiasis 
Treatment-emergent Adverse Event or a Serum Creatinine 
Elevation
During the course of the study, the Investigator will remain vigilant for symptoms or signs of 
renal-related events, kidney stone events or changes in renal function.
D 1
Signs and Symptoms Suggestive of Urolithiasis
After initiation of study medication, if a subject experiences signs or symptoms suggestive of 
nephrolithiasis (eg, flank pain or haematuria), he/she should be evaluated by a physician and 
serum creatinine, blood urea nitrogen, and urinalysis should be measured via central 
laboratory testing (preferred) and/or local laboratory testing, as appropriate, to determine renal 
function. Imaging (intravenous urogram, renal ultrasound, or magnetic resonance imaging) is 
recommended to confirm or exclude any urinary tract calculus. Abnormal results should be 
treated as medically appropriate by the treating physician. All symptoms, testing, and results 
will be documented in source documents and ClinBase™.
If a subject develops a urinary tract calculus (as confirmed and documented by imaging or 
passage of a stone) at any time during the study, the subject will discontinue randomised study 
medication and be encouraged to remain in the study for continued safety assessments. If the 
urinary tract calculus is passed, it should be collected and submitted to pathology for analysis 
of chemical composition.
D 2
Deterioration of Renal Function
The Investigator should assess subjects exhibiting elevated serum creatinine carefully to 
determine the most likely cause for the deterioration of renal function. Following a thorough 
assessment, the subject should be managed according to local medical practice. 
Potentially-treatable causes such as volume depletion, hypotension etc., should be corrected 
before following the recommendations given below.
Serum Creatinine Increase to ≥ 1.5-fold from Baseline

Assess the subject to identify and manage any potential contributing factor. Correct any 
dehydration and ensure the subject is well hydrated prior any future evaluation.

Contact the Sponsor’s lead physician for advice and to discuss discontinuation of study 
medication.

Assess creatinine daily if the elevation is detected while the subject is admitted to the 
Clinical Unit, and otherwise weekly.

Subsequent management will depend on the repeat measurement(s):

If serum creatinine < 1.5-fold of baseline value for 2 successive measurements, the 
subject may restart/continue with study treatment on the original study visit schedule.


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
If repeat serum creatinine is ≥ 1.5-fold of baseline, the subject should be evaluated 
every week until normalisation. The randomised treatment should be permanently 
discontinued.