Conditions: Chronic Kidney Disease
Keywords: Chronic Kidney Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 861
Healthy volunteers: no

Brief summary:
The purpose of this clinical research study is to establish the dose of verinurad combined with allopurinol 300 mg once daily that will elicit the desired response; ie, reduction in urinary albumin to creatinine ratio (UACR) at 6 months.

Detailed description:
Evidence shows independent associations between hyperuricaemia and the risk of hypertension, myocardial infarction, chronic kidney disease (CKD), type 2 diabetes, heart failure, and metabolic syndrome, including obesity Furthermore, gout, an inflammatory arthritis caused by deposition of monosodium urate crystals in joints, is associated with an increased risk of all-cause death, as well as cardiovascular (CV) death.

Hyperuricaemia is a prerequisite for development of gout, thus linking high levels of sUA to gout and to poor outcomes. However, the causal relationship between hyperuricaemia / gout and the aforementioned diseases and outcomes remains to be proven.

Uric acid transporter 1 (URAT1) is responsible for reabsorption of uric acid (UA in the proximal tubule. Inhibition of URAT1 results in increased urinary excretion of UA.

Verinurad (RDEA3170) is a novel URAT1 inhibitor in Phase 2 development for chronic kidney disease and heart failure.

Verinurad combined with the xanthine oxidase (XO)inhibitor (XOI) febuxostat or allopurinol has been shown to lower sUA in patients with recurrent gout in Phase 2 studies by up to 80%..

The primary objective of this study is to assess the effects of treatment with verinurad and allopurinol, allopurinol alone, and placebo on UACR at 6 months.

In this study, change in UACR at 6 months of treatment is the primary endpoint for the efficacy evaluation of treatment with the combination of verinurad and allopurinol vs. placebo.

A key secondary objective is evaluation of verinurad plus allopurinol on the reduction in UACR at 12 months.

Further, standard safety parameters such as adverse event (AEs), serious adverse event (SAEs), and laboratory evaluations will be employed to assess the safety profile of the study drugs.

Verinurad, allopurinol and oxypurinol plasma concentrations over time will also be measured.

The study will recruit patients with Chronic Kidney Disease and Hyperuricaemia.

Arms:
arm 1: High Dose (mg) (verinurad/allopurinol) Step 1 - titration\_ 3/100 Step 2 - titration\_ 7.5/200 Step 3 - target dose\_ 12/300 arm 2: Intermediate Dose (mg) verinurad/allopurinol Step 1 - titration\_ 3/100 Step 2 - titration\_ 7.5/200 Step 3 - target dose\_ 7.5/300 arm 3: Low Dose (mg) verinurad/allopurinol Step 1 - titration\_3/100 Step 2 - titration\_3/200 Step 3 - target dose\_3/300. As per Protocol Version 5.0, Patients from 3 mg dose will be switched to 24 mg at Visit 9. arm 4: Step 1 - titration\_0/100 Step 2 - titration\_0/200 Step 3 - target dose\_0/300 arm 5: Placebo (mg) in 3 steps\_0/0

Interventions: intervention 1: Verinurad intervention 2: Allopurinol intervention 3: Placebo for Verinurad intervention 4: Placebo for Allopurinol
Intervention descriptions: intervention 1: Study treatments will be titrated in 3 steps for target low dose (3 mg), intermediate dose ( 7.5 mg) and High Dose (12 mg) Verinurad.

As per Protocol Version 5.0, Patients from 3 mg dose will be switched to 24 mg at visit 9 intervention 2: Study treatments will be titrated in 3 steps: Low dose (100 mg), intermediate (200 mg) and High Dose ( 300 mg) Allopurinol intervention 3: Matching Capsule intervention 4: Matching tablet

Protocol document:
Prot_000.pdf: 
Clinical Study Protocol - 5.0 
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CONFIDENTIAL AND PROPRIETARY 
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Clinical Study Protocol 
Drug Substance 
Verinurad / RDEA3170 
Study Code 
D5495C00002 
Version 
5.0 
Date 
18 November 2020 
A Phase 2b, Multicentre, Randomised, Double-blind, Placebo-controlled 
Study of Verinurad and Allopurinol in Patients with Chronic Kidney Disease 
and Hyperuricaemia 
Sponsor: AstraZeneca AB, 151-85 Södertälje, Sweden 
Regulatory Agency Identifying Number(s): USIND 133978 






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• 
In Table 2, for the end of treatment/early discontinuation visit, removed ±7 day window 
as it is not applicable.  Corrected section reference in footnote a.  
• 
In both Table 1 and Table 2, a footnote was added to final (titration step 3) dose 
dispensed at Visits 5 through 14, to state that titration to step-3 target dose will only be 
allowed if the patient’s eGFR was ≥30 mL/min/1.73m2 at Visits 3 and 4. 
 
Section 4.1.2.2, Week -4 to -0 – screening (Visit 2) 
• 
Updated allele testing to be mandatory for all patients prior to randomisation. 
 
Section 4.1.2.12, End of treatment 
• 
Removed reference to patients who discontinue treatment.  Added study drug return 
and accountability to end of treatment tasks. 
 
Section 4.4, End of study definition 
• 
Removed reference to Appendix A6. 
 
Section 5.2, Exclusion criteria 
• 
Exclusion criterion 3 was updated to require mandatory HLA testing for all patients 
prior to randomisation.  This change was made to simplify the decision for the 
investigator to test for the allele on patients with mixed race that could carry the allele. 
• 
Exclusion criterion 11 was updated to refine and clarify the criteria of hepatic 
impairment. 
 
Section 6.1.1, Investigational products, Section 4.1.2.5, Week 8 (Visit 5), 
Section 4.1.2.6, Week 12 (Visit 6), Section 4.1.2.7, Week 20 (Visit 7), Section 4.1.2.8, 
Week 34 (Visit 8), Section 4.1.2.9, Week 47 (Visit 9), Section 4.1.2.10, Week 60 
(Visit 10), Section 4.1.2.11, At 12-week intervals after Visit 10 (Visits 11 through 14) 
• Limited up-titration steps in patients with low eGFR.  This clarification was also added 
to the applicable study procedures section. 
 
Section 6.1.1, Investigational products, Section 6.6, Dose modification 
• Handling of up-titration in error 
 
Section 7.1.3, Procedures for early discontinuation of study treatment 
• 
Updated header to state “early” discontinuation. 
 
Section 8.7.1, Assessment of HLA-B genotype 
• 
Updated allele testing to be mandatory for all patients prior to randomisation. 
 






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Secti o n  8. 5, P h ar m ac o ki netics 
•  
N u m ber of patie nts t o be sa m ple d was i ncrease d  
 
Secti o n  8. 1 0,  G ui deli nes, st u d y asses sme nts, a n d pr oce d ures d uri n g C O VI D - 1 9 
p a n de mic  
•  
Secti o n a d de d 
 
 
 
 
 
Secti o n  9. 4. 2, Effic ac y a n al ysis 
•  
F or m ula f or p er ce nt c h a n ge fr o m baseli ne  was c orrecte d 
•  
Directi o n was pr o vi de d t o a p pl y t he s a me a n al ys es f or U A C R t o  t he e n d p oi nts s U A, 
esti mate d gl o mer ular filtr ati o n rate ( e G F R), creati ni ne, a n d c ystati n- C 
 
Secti o n  9. 5, I nteri m a n al yses 
•  
Se nte nce s pecif yi n g wit h first i nteri m a nal ysis will be perf or m e d was re vis e d 
 
Secti o n  1 0, Ref ere nces  
•  
T he S u m mar y of Pr o d uct C haracteristics f or all o p uri n ol was a d de d t o t he list of 
refere nces 
 
A p pe n di x A  9, St u d y a n d site st art a n d cl os ure 
•  
T his s u b-a p pe n di x was a d de d 
 
A p p e n di x B  2, Defi niti o ns of seri o us a d verse e v e nt  
•  
A para gra p h o n t he re p orti n g of mali g na nt t u m o urs was a d de d 
 
A p pe n di x E 4. 1, P ote nti al H y’s L a w criteri a n ot met 
•  
T he se nte nce stati n g t h at t he Astra Ze n eca re prese ntati ve has t o be i nf or me d was delete d  
 
A p pe n di x E 4. 2, P ote nti al H y’s L a w criteri a met 
•  
A se nte nce a b o ut deter mi ni n g w het h er p ote ntial H y’s La w criteria w ere m et pri or t o 
starti n g st u d y treat me nt was a d ded 
 
A p pe n di x F 2. 2. 1, If e G F R dr o ps t o < 7 5 % of t he b aseli ne v al ue 
•  
All t he si g ns “ >” were r e place d wit h “ <” i n t he ta ble of E x a m ples of e G F R c ha n ges a n d 
tri g gere d acti o ns 
 
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This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures.  The Clinical Study Protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations. 


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TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................. 1 
VERSION HISTORY ............................................................................................................... 2 
TABLE OF CONTENTS ........................................................................................................ 10 
1 
PROTOCOL SUMMARY.................................................................................... 14 
1.1 
Schedule of activities (SoA) ................................................................................. 14 
1.2 
Synopsis ................................................................................................................ 22 
1.3 
Schema .................................................................................................................. 29 
2 
INTRODUCTION ................................................................................................ 31 
2.1 
Study rationale ...................................................................................................... 31 
2.2 
Background ........................................................................................................... 32 
2.2.1 
Verinurad in combination with allopurinol .......................................................... 33 
2.3 
Benefit/risk assessment ......................................................................................... 33 
3 
OBJECTIVES AND ENDPOINTS ...................................................................... 35 
4 
STUDY DESIGN ................................................................................................. 37 
4.1 
Overall design ....................................................................................................... 37 
4.1.1 
Overview............................................................................................................... 37 
4.1.2 
Study procedures .................................................................................................. 38 
4.1.2.1 
Week -6 to -1 – prescreening (Visit 1) ................................................................. 38 
4.1.2.2 
Week -4 to -0 – screening (Visit 2) ...................................................................... 38 
4.1.2.3 
Week 0 (Visit 3).................................................................................................... 39 
4.1.2.4 
Week 4 (Visit 4).................................................................................................... 40 
4.1.2.5 
Week 8 (Visit 5).................................................................................................... 40 
4.1.2.6 
Week 12 (Visit 6).................................................................................................. 41 
4.1.2.7 
Week 20 (Visit 7).................................................................................................. 41 
4.1.2.8 
Week 34 (Visit 8).................................................................................................. 42 
4.1.2.9 
Week 47 (Visit 9).................................................................................................. 42 
4.1.2.10 
Week 60 (Visit 10) (prior to Protocol Version 5.0) .............................................. 43 
4.1.2.11 
At 12-week intervals after Visit 10 (Visits 11 through 14) (prior to Protocol 
Version 5.0) .......................................................................................................... 44 
4.1.2.12 
End of treatment (occurs at 60 weeks for patients on new dosing regimen 
following Protocol Version 5.0 implementation)/early discontinuation .............. 45 
4.1.2.13 
Follow up visit (4 weeks after end of treatment/early discontinuation/last 
scheduled, numbered visit) ................................................................................... 45 
4.2 
Scientific rationale for study design ..................................................................... 46 
4.3 
Justification for dose ............................................................................................. 46 
4.4 
End of study definition ......................................................................................... 48 
5 
STUDY POPULATION ....................................................................................... 48 
5.1 
Inclusion criteria ................................................................................................... 48 
5.1.1 
Pre-screening criteria ............................................................................................ 48 






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9.5 
Interim analyses .................................................................................................... 89 
10 
REFERENCES ..................................................................................................... 91 
11 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................ 94 
 
LIST OF TABLES 
Table 1 
Schedule of activities (SoA), screening and treatment period .................... 15 
Table 2 
Schedule of activities – Extension treatment, end of treatment, and 
follow-up period (Visits 11 through 14 applicable only to patients who 
passed Week 60 prior to Protocol Version 5.0 implementation) ................ 19 
Table 3 
Titration schedule ........................................................................................ 27 
Table 4 
Objectives and endpoints ............................................................................ 35 
Table 5 
Acceptable methods of contraception (<1% failure rate) ........................... 53 
Table 6 
Study treatments (prior to Protocol Version 5.0) ........................................ 54 
Table 7 
Study treatments (after implementation of Protocol Version 5.0) .............. 55 
Table 8 
Titration schedule ........................................................................................ 56 
Table 9 
Restricted medications ................................................................................ 59 
Table 10 
Prohibited medications ................................................................................ 60 
Table 11 
Laboratory efficacy variables ...................................................................... 66 
Table 12 
MRI assessments ......................................................................................... 68 
Table 13 
Patient information to capture at each visit for analysis of confounding 
factors for reactive hyperaemia assessments ............................................... 69 
Table 14 
Laboratory safety variables ......................................................................... 71 
Table 15 
Biomarker collections ................................................................................. 81 
Table 16 
Analysis populations ................................................................................... 84 
 
LIST OF FIGURES 
Figure 1 
Study design ................................................................................................ 30 
 
LIST OF APPENDICES 
Appendix A 
Regulatory, ethical and study oversight considerations .............................. 94 
Appendix B 
Adverse event definitions and additional safety information ................... 100 


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A p pe n di x  C 
Ha n dli n g of H u ma n Bi ol o gical Sa m ples  ................................................... 1 0 5 
 
 
A p pe n di x  E  
Acti o ns re q uire d i n cases of i ncreases i n li ver bi oc he mistr y a n d 
e val uati o n of H y’s La w ............................................................................. 1 1 2  
A p pe n di x  F 
Acti o ns re q uire d i n cases of a re n al -relate d or ki d n e y st o ne treat me nt-
e mer ge nt a d v erse e ve nt or a ser u m creati ni ne ele v ati o n  ........................... 1 1 8 
A p pe n di x  G  
A b bre viati o ns ............................................................................................ 1 2 1 
1  
P R O T O C O L S U M M A R Y  
1. 1  
Sc he d ule of acti vities ( S o A)  
 
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g 
Regardless of dosing regimen, a PK sample is to be collected post-dose during the visit. 
h 
Study medication should be dispensed at end of visit. 
i 
At Visit 5 (approximately 8 weeks after randomisation) through Visit 14, as applicable, titration to step-3 target dose will only be allowed if the patient’s 
eGFR was ≥30 mL/min/1.73m2 at Visits 3 and 4. 
 


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1.2 
Synopsis 
Protocol title 
A Phase 2b, Multicentre, Randomised, Double-blind, Placebo-controlled Study of VerinurAd 
and AlloPurinol in Patients with CHronic KIdney Disease and HyperuRicaEmia 
Short Title: SAPPHIRE 
Rationale 
Evidence shows independent associations between hyperuricaemia (elevated serum uric 
acid [sUA]) and the risk of hypertension, myocardial infarction, chronic kidney disease 
(CKD), type 2 diabetes, heart failure, and metabolic syndrome, including obesity (Nakagawa 
et al 2006, Grayson et al 2011, Kodama et al 2009, Leyva et al 1998, Anker et al 2003).  
Furthermore, gout, an inflammatory arthritis caused by deposition of monosodium urate 
crystals in joints, is associated with an increased risk of all-cause death, as well as 
cardiovascular (CV) death (Iochimescu et al 2008, Kim et al 2008, Niizeki et al 2006, 
Jankowska et al 2007).  Hyperuricaemia is a prerequisite for development of gout, thus linking 
high levels of sUA to gout and to poor outcomes.  However, the causal relationship between 
hyperuricaemia and/or gout and the aforementioned diseases and outcomes remains to be 
proven. 
Uric acid transporter 1 (URAT1) is responsible for reabsorption of uric acid (UA in the 
proximal tubule.  Inhibition of URAT1 results in increased urinary excretion of UA.  
Verinurad (RDEA3170) is a novel URAT1 inhibitor in Phase 2 development for chronic 
kidney disease and heart failure.  Verinurad combined with the xanthine oxidase (XO) 
inhibitors (XOI) febuxostat or allopurinol has been shown to lower sUA in patients with 
recurrent gout in Phase 2 studies by up to 80% (see Investigator’s Brochure, Section 5.2.1.3-
4 for details on Studies 204, 205, and 206).  The extensive lowering of sUA delivered presents 
a unique opportunity to explore whether intensive urate lowering therapy can improve kidney 
function and/or cardiac health. 
Potent URAT1 inhibition has been associated with creatinine elevation in some patients, 
potentially related to increased peak concentrations of urinary uric acid (uUA) in the proximal 
tubuli of the kidney.  Verinurad is therefore given as an extended release formulation as a low 
maximum concentration is expected to further reduce or eliminate the risk of creatinine 
elevations.  Moreover, verinurad is to be developed exclusively in a fixed-dose combination 
with an XOI, reducing also the production of UA. 
The Phase 2a study D5495C00007 was performed using 9 mg verinurad given as the ER8 
capsule and 80 mg febuxostat administered once daily in combination for 24 weeks.  The 
primary endpoint was change in urinary albumin to creatinine ratio (UACR) at 12 weeks. 


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Si xt y p atie nts wer e ra n d o mise d.  At e nr ol me nt, t he treat me nt ar ms i n st u d y D 5 4 9 5 C 0 0 0 0 7 
were ge ner all y b ala nce d wit h re gar ds t o c o m m o n cli nical para m eters.  
T he st u d y met t he pri mar y e n d p oi nt at 1 2 w ee ks.  U A C R was si g nifica ntl y re d uce d b y 3 9. 4 % 
f or patie nts ra n d o mise d t o be treate d wit h veri n ura d a n d fe b u x ostat c o m pare d t o place b o 
( p = 0. 0 7 4 7).  T h e c o m paris o n bet wee n t he acti ve ar m a n d t he c o ntr ol ar m i n dicate d statistical 
si g nifica n ce w as ac hi e ve d, c o nsi deri n g t he pre d et er mi ne d al p ha ( 0. 1).  T he effect o n U A C R 
was ra pi d, wit h f ull effect ac hie ve d at t he first o n -treat me nt assess me nt ti me p oi nt at 1 wee k, 
a n d di d n ot a p pear t o b e dri ve n b y o utliers. 
Mea n baseli ne esti mate d g l o mer ular filtrati o n rat e (e G F R) i n t he trial was 5 9 a n d 
6 8 m L/ mi n/ 1. 7 3 m 2 i n t he acti ve a n d c o ntr ol ar ms, res pecti vel y.  T h ere were n o c ha n ges i n 
e G F R i n eit her ar m, eit her at t he earl y or late assess me nt ti me p oi nts.  H o we ver, c o nsi d eri n g 
t he li mite d sa mple size, e G F R varia bilit y, a n d s h ort d urati o n of treat me nt, t his is n ot 
u ne x pecte d.  
F or f ull data, i n cl u di n g s afet y r es ults, see t he I n v esti gat or's Br oc h ure. 
O bjecti ves a n d e n d p oi nts  
O bjecti ves  
E n d p oi nt/ v ari a ble:  
Pri m ar y o bjecti ve : 
T o assess t he effects  of treat me nt wit h veri n ura d a n d 
all o p uri n ol, allo p uri n ol al o ne , a n d place b o o n U A C R 
at 6 m o nt hs  
C ha n ge fr o m baseli ne i n U A C R at 6  m o nt hs  
Sec o n d ar y o bjecti ves:  
T o assess t he effects of treat me nt wit h veri n ura d a n d 
all o p uri n ol, all o p uri n ol al o ne , a n d place b o o n U A C R 
at 1 2 m o nt hs  
C ha n ge fr o m baseli ne i n U A C R at 1 2 m o nt hs  
T o assess t he effects of veri n ura d a n d all o p uri n ol, 
all o p uri n ol al o ne , a n d place b o o n s U A  
C ha n ge fr o m baseli ne i n s U A at 6 a n d 1 2  m o nt hs  
T o esti mate t he d ose -res p o nse relati o ns hi p a m o n g 3 
d oses of veri n ura d a n d all o p uri n ol a n d place b o o n 
U A C R a n d s U A  
C ha n ge fr o m baseli ne i n U A C R a n d s U A at 6  m o nt hs  
T o assess t he effects of veri n ura d a n d all o p uri n ol 
vers us place b o o n ki d ne y f u ncti o n  
C ha n ge fr o m baseli ne i n esti mate d gl o mer ular 
filtrati o n rate at 6 a n d 1 2 m o nt hs   
C ha n ge fr o m baseli ne i n creati ni ne at 6 a n d 
1 2  m o nt hs  
C ha n ge fr o m baseli ne i n c ystati n -C at 6 a n d 
1 2  m o nt hs  
 
 
 
 
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As of Protocol Version 5.0 and following a blinded interim analysis in September 2020, the 
study design was modified to include a new dosing regimen.  All patients with Visit 9 
(47 weeks) occurring after implementation of the amendment and investigational product (IP) 
is available (approximately 01 May 2021, ie, approximately half of planned patients 
randomized) will be treated with the new dosing regimen.  Under the new dosing regimen all 
patients will continue with the same dose of verinurad and allopurinol as previously, except 
patients randomized to the low dose of verinurad (3 mg), which will be switched to treatment 
with 24 mg verinurad.  Also, following implementation of the amendment, all subjects will 
discontinue therapy after 60 weeks (Visit 10).  Patients that have conducted Visit 10 before 
the implementation of the amendment will discontinue therapy at their next scheduled visit. 
The new treatment regimen will be dispensed to patients for which Visit 9 falls on or after the 
last of the following dates: 
• 
the date of availability at site of IP suitable for the new treatment regimen, 
• 
the date of the Regulatory Authority approval of Protocol Version 5.0 in the respective 
country, and 
• 
the date of the Ethics Committee/Independent Review Board approval of Protocol 
Version 5.0 in the respective country/site.  
A patient in the new dosing regimen who is still on treatment, who has not been down-titrated 
and has signed Informed Consent Form for the new dosing regimen, will receive the new 
treatment at Visit 9.  Patients who do not consent should be discontinued from the study at a 
subsequent visit.  If the patient has passed Visit 9 before the dates listed above, they will 
remain on the initial dosing regimen. 
Additional details on treatment administration are included in Section 6.1. 
Target patient population 
The study will be conducted in male and female adults (≥18 years of age) with documented 
CKD who provide informed consent to participate in the study and are not pregnant.  Eligible 
patients will have sUA concentrations ≥6.0 mg/dL, eGFR ≥25 mL/min/1.73 m2 and a UACR 
between 30 mg/g and 5000 mg/g (inclusive).  Patients should be receiving stable treatment of 
angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) for at 
least 1 month prior to entry into the study.  
Patients with a prior history of gout will receive gout prophylaxis treatment with colchicine up 
to 0.6 mg once daily, as outlined in gout guidelines.  If intolerance or other sound medical 
rationale exists for not using colchicine, the investigator may instead prescribe gout flare 
prophylaxis with steroids or non-steroidal anti-inflammatory drugs (NSAIDs), or avoid 
administering prophylaxis altogether.  Prophylaxis against flares will be fully explained and 
discussed with the patient. 


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Study period 
Estimated date of first patient enrolled: Q3 2019 
Estimated date of last patient completed: Q4 2021 
Number of patients 
Total of 725 patients (145 per arm [initial dosing regimen]) at around 200 sites in 
approximately 15 countries will be randomised with equal probability to 1 of 5 treatment 
arms. 
Treatments and treatment duration 
Each patient will be treated as randomised with placebo, allopurinol, and/or verinurad plus 
allopurinol (3 doses) for 26 weeks at target dose after 8 weeks of titration to allow for 
assessment of the primary endpoint, UACR at 6 months.  After Protocol Version 5.0 is 
implemented, patients will continue treatment at target dose for approximately 12 weeks after 
Visit 9, and will discontinue therapy at Visit 10.  Patients who have already had IP 
administered at Visit 9 or a subsequent visit before Protocol Version 5.0 is implemented will 
discontinue IP at the next subsequent visit. 
Study treatments will be titrated in discrete steps as shown in Table 3.  Titration steps will be 
spaced at 4-week intervals to minimise the risk of skin reactions to allopurinol.  Patients 
unable to tolerate the stepped dosage may be down-titrated only by reversing the assigned 
steps within treatment group, and verinurad and allopurinol dosages cannot be unpaired from 
the titration schedule.  Patients who cannot tolerate the step-1 titration will be discontinued 
from IP and be followed for the remainder of the study. 
Table 3 
Titration schedule 
 
Step 1 - titration 
(verinurad/ 
allopurinol) 
Step 2 - titration 
(verinurad/ 
allopurinol) 
Step 3 - target dose 
(verinurad/ 
allopurinol) 
High Dose (mg) 
3/100 
7.5/200 
12/300 
Intermediate Dose (mg) 
3/100 
7.5/200 
7.5/300 
Low Dose (mg) 
3/100 
3/200 
3/300 
Allopurinol alone (mg) 
0/100 
0/200 
0/300 
Placebo (mg) 
0/0 
0/0 
0/0 
 
At the time of implementation of Protocol Version 5.0, a new dosing regimen will be 
introduced to assess a higher dose of 24 mg verinurad.  Patients in the 3 mg verinurad cohort 
who will have Visit 9 planned after the amendment implementation in the country/site and 
who have signed ICF for the new dosing regimen will be switched to 24 mg dose at Visit 9.  


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Patients who do not consent should be discontinued from the study at a subsequent visit.  To 
introduce the new 24 mg dose, a new dosing regimen will be initiated across treatment arms to 
maintain blinding.  For verinurad dosing, all patients in the new dosing regimen will receive 
2 capsules through addition of a matching placebo capsule, with the exception of those who 
switched from the 3 mg to 24 mg dose, where two 12-mg verinurad capsules will be given.  
Allopurinol dosing will remain the same.  
When the new dosing regimen is introduced under Protocol Version 5.0, patients who were 
down-titrated due to intolerance in the initial dosing regimen will not switch treatment to the 
new dosing regimen.  These patients will instead remain on the same treatment after Visit 9.  
Patients who do not tolerate the new dosing regimen will be down-titrated to the initial dosing 
regimen (ie, patients on 24 mg will be down-titrated to 3 mg, and patients in other cohorts will 
not be dispensed the matching placebo capsule).  If there is a need for further down-titration, 
patients will follow the down-titration steps outlined in the initial dosing regimen 
(Section 6.1).  Additionally, patients in the initial dosing regimen will follow down-titration 
steps outlined for the initial dosing regimen (Section 6.1).  
Data monitoring committee 
An independent data monitoring committee (DMC) will be appointed and will report to 
AstraZeneca and the contract research organisation (CRO).  The DMC will be responsible for 
ensuring patient safety by assessing the safety of the IP during the study, and for reviewing the 
overall conduct of the study.  The DMC will have access to the individual treatment codes and 
be able to merge these with the collected study data while the study is ongoing.  
Clinical event adjudication committee  
The role of the clinical event adjudication committee (CEA) is to independently review, 
interpret and adjudicate potential CV events that are experienced by the patients.  CV events 
will be identified preliminarily by the investigators, and also by AstraZeneca personnel, CRO 
personnel or in the CEA process as specified in the CEA charter.  The CEA member/s will not 
have access to individual treatment codes for any patient or clinical efficacy endpoint and 
safety event. 
Statistical methods 
The estimated sample size of 145 patients per arm (initial dosing regimen) will yield 80% 
power to detect a 25% reduction in UACR for the high dose of verinurad + allopurinol 
compared to placebo (treatment difference of approximately -0.29 on natural log scale) at the 
two-sided alpha level of 0.1, assuming a standard deviation of 1.0 on the natural log-scale.  A 
total of 725 patients (145 patients per arm [initial dosing regimen]) need to be randomised. 


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The primary efficacy variable is the change from baseline in UACR at 6 months.  The analysis 
of change in UACR from baseline to Week 34 (including the 8-week titration phase) will be 
conducted on the log-transformed UACR values using repeated measures model.  This 
analysis will be performed on the Full Analysis Set (FAS). 
Three hypotheses will be included in confirmatory testing for the primary objective.  The 
following hypotheses will be tested sequentially at two-sided alpha = 0.1: 
• 
Null hypothesis: No difference between high dose verinurad plus allopurinol compared to 
placebo on UACR at 6 months  
• 
Alternative hypothesis: There is a difference between high dose verinurad plus allopurinol 
compared to placebo on UACR at 6 months 
 
• 
Null hypothesis: No difference between high and intermediate dose verinurad combined 
plus allopurinol compared to allopurinol alone on UACR at 6 months  
• 
Alternative hypothesis: There is a difference between high and intermediate dose 
verinurad combined plus allopurinol compared to allopurinol alone on UACR at 6 months 
 
• 
Null hypothesis: No difference between allopurinol alone compared to placebo on UACR 
at 6 months  
• 
Alternative hypothesis: There is a difference between allopurinol alone compared to 
placebo on UACR at 6 months 
 
No other comparisons between treatment groups for the primary and secondary objectives will 
be adjusted for multiplicity. 
1.3 
Schema 
The general study design is summarised in Figure 1. 


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Figure 1 
Study design 
ACEi angiotensin converting enzyme inhibitor; ARB  angiotensin receptor blocker; CKD chronic kidney disease; 
eGFR  estimated glomerular filtration rate; EP endpoint; MRI  magnetic resonance imaging; PK  
pharmacokinetic; sUA  serum uric acid; UACR  urinary albumin to creatinine ratio 


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2 
INTRODUCTION 
Chronic kidney disease is a major public health problem, and its global burden is expected to 
further grow due to an aging population.  Currently CKD management focuses on blood 
pressure, glycaemic control, and treatment with an ACEi or ARB.  Although it is well 
accepted that hyperuricaemia is associated with CKD, the effects of UA-lowering therapy in 
patients with CKD remain uncertain. 
Uric acid is a purine metabolite generated by the liver during turnover of nucleic acids.  It is 
primarily excreted by the kidneys (two thirds) as well as the gastrointestinal tract (one third) 
(reviewed by Hyndman et al 2016).  Numerous cross-sectional and epidemiological studies 
have shown the association of sUA level concentrations and CKD in both the general 
population and in patients with CKD (Mohandas and Johnson 2008).  The harmful effects of 
sUA on kidneys are ascribed to direct cytotoxicity including the proximal tubule of the kidney 
due to its accumulation (and crystallisation) within cells, and activation and upregulation of 
inflammation by sUA (Mohandas and Johnson 2008). 
UA-lowering therapy may prevent progression of CKD but the conclusion is very uncertain.  
Larger well-designed studies are required to study the effect of UA-lowering therapy on CKD 
progression. 
2.1 
Study rationale 
Evidence shows independent associations between hyperuricaemia and the risk of 
hypertension, myocardial infarction, CKD, type 2 diabetes, heart failure, and metabolic 
syndrome, including obesity (Nakagawa et al 2006, Grayson et al 2011, Kodama et al 2009, 
Leyva et al 1998, Anker et al 2003).  Furthermore, gout, an inflammatory arthritis caused by 
deposition of monosodium urate crystals in joints, is associated with an increased risk of all-
cause death, as well as CV death (Iochimescu et al 2008, Kim et al 2008, Niizeki et al 2006, 
Jankowska et al 2007).  Hyperuricaemia (elevated levels of urate in the circulation) is a 
prerequisite for development of gout, an inflammatory arthritis caused by deposition of 
monosodium urate crystals in joints.  Gout occurs in patients with serum urate >6.8 mg/dL, 
which is the solubility limit of monosodium urate.  The prevalence of gout increases with 
higher serum urate (Choi et al 2005).  However, the causal relationship between 
hyperuricaemia / gout and the aforementioned diseases and outcomes remains to be proven. 
URAT1 is responsible for reabsorption of UA in the proximal tubule.  Inhibition of URAT1 
results in increased urinary excretion of UA.  Verinurad is a novel URAT1 inhibitor in 
Phase 2 development for CKD and heart failure.  Verinurad combined with the XOIs 
febuxostat or allopurinol has been shown to lower sUA in patients with recurrent gout in 
Phase 2 studies by up to 80% (see Investigator’s Brochure, Section 5.2.2.3 through Section 
5.2.2.5 for details on Studies 204, 205, and 206).  The extensive lowering of sUA delivered 


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presents a unique opportunity to explore whether intensive urate lowering therapy can 
improve kidney function and/or cardiac health.  Currently no sUA-reducing drug is approved 
to treat CKD, thus presenting a potential to target a novel therapeutic pathway. 
Potent URAT1 inhibition has been associated with creatinine elevation in some patients, 
potentially related to increased sUA peak concentrations of uUA in the proximal tubuli of the 
kidney.  Verinurad is therefore given as an extended release formulation as a low maximum 
concentration is expected to further reduce or eliminate the risk of creatinine elevations.  
Moreover, verinurad is to be developed exclusively in a fixed-dose combination with an XOI, 
reducing also the production of UA. 
The Phase 2a study D5495C00007 was performed using 9 mg verinurad given as the ER8 
capsule and 80 mg febuxostat administered once daily in combination for 24 weeks.  The 
primary endpoint was UACR at 12 weeks. 
Sixty patients were randomised.  At enrolment, the treatment arms in study D5495C00007 
were generally balanced with regards to common clinical parameters. 
The study met the primary endpoint at 12 weeks.  UACR was significantly reduced by 39.4% 
for patients randomised to be treated with verinurad and febuxostat compared to placebo 
(p=0.0747).  The comparison between the active arm and the control arm indicated statistical 
significance was achieved, considering the predetermined alpha (0.1).  The effect on UACR 
was rapid, with full effect achieved at the first on-treatment assessment time point at 1 week, 
and did not appear to be driven by outliers.  The therapeutic effect persisted with an LS mean 
of percent change from baseline in UACR compared to placebo (90% CI) -49.26 
(-68.206, -19.009) at Week 24.  
Mean baseline eGFR in the trial was 59 and 68 mL/min/1.73 m2 in the active and control 
arms, respectively.  There were no changes in eGFR in either arm, either at the early or late 
assessment time points.  However, considering the limited sample size, eGFR variability, and 
short duration of treatment, this is not unexpected.  Overall the treatment was well tolerated 
and safety findings in the study were consistent with the known safety profile of the drug. 
The overall clinical evidence suggests that the combination of verinurad and XOI has clinical 
benefit and an acceptable safety profile in CKD patients and that further development is 
warranted.  Hence, a global, randomised, Phase 2b study is planned to evaluate the efficacy 
and safety of verinurad and allopurinol in patients with CKD and hyperuricaemia. 
2.2 
Background 
Verinurad is a novel URAT1 inhibitor in Phase 2 development.  Verinurad combined with the 
XOI febuxostat has been shown to lower UACR in patients with diabetes and albuminuria, 


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and to lower sUA by >80% in patients with recurrent gout in Phase 2 studies.  Please refer to 
the Investigator's Brochure for full details on safety and efficacy of verinurad. 
2.2.1 
Verinurad in combination with allopurinol 
Study RDEA3170-206 was a Phase 2a, randomised, open-label, multicentre study to assess 
the pharmacokinetics (PK), pharmacodynamics (PD), and safety of verinurad administered in 
combination with allopurinol (300 mg qd) compared with allopurinol administered alone 
(300 mg once daily, 300 mg twice daily, or 600 mg once daily) in adult patients with gout.  
There were 40 male patients and 1 female patient randomised into the study. sUA was 
decreased in a dose-dependent manner in patients treated with multiple once daily doses of 
verinurad ranging from 2.5 to 20 mg given as the MR4 tablet in combination with allopurinol 
300 mg.  All verinurad and allopurinol 300 mg combination treatments resulted in greater 
reductions in sUA compared with allopurinol 300 mg dosed alone. 
2.3 
Benefit/risk assessment 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of verinurad and allopurinol may be found in the Investigator’s 
Brochure. 
The study design aims to minimise potential risks to patients and to ensure adequate 
monitoring.  A dual-inhibition approach using lower doses of 2 agents with complementary 
mechanisms of action is expected to synergistically improve efficacy outcomes while reducing 
potential safety issues that would be of concern with higher doses of each agent alone. 
The main toxicity of concern noted with verinurad monotherapy is creatinine elevations >1.5x 
baseline occurring in 6.2% of Caucasian patients in Study RDEA3170-201, and in 17.1% of 
Japanese patients in Study RDEA3170-203.  When verinurad was combined with XOI in 
Studies RDEA3170-204, RDEA3170-205 and RDEA3170-206, no creatinine elevations were 
reported.  In the current study, verinurad will therefore exclusively be administered in 
combination with allopurinol.  In the CKD Phase 2a study D5495C00007, in which a similar 
patient population was recruited as in this study, the combination of verinurad and febuxostat 
resulted in the same rate of creatinine elevations in both the active treatment group and in the 
placebo control group. 
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. 
CKD with hyperuricaemia represents a significant unmet medical need and underlines the 
need for novel therapies for this patient population.  Verinurad combined with allopurinol may 
demonstrate a meaningful clinical benefit and an acceptable safety profile.  The overall 


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benefit-risk profile of verinurad combined with allopurinol is expected to be favourable, 
therefore supporting the current study design. 
Patients with CKD are at increased risk to experience CV events, and several studies showed 
that both reduced renal function and proteinuria are associated with such events.  Furthermore, 
CV events have been identified as a risk for lesinurad, which is an approved drug with a 
similar mechanism of action as verinurad.  Few CV events were reported in the verinurad 
clinical programme.  Important actions aiming to minimise the CV risk to patients in this 
study include using allopurinol instead of febuxostat, as allopurinol treatment is associated 
with a lower risk of CV death (White et al 2018).  Also, high-risk patients such as patients 
with recent CV events or inadequate blood pressure control will be excluded. 
The main risk from allopurinol, skin reaction, will be minimised by excluding patients 
carrying the high risk Human Leukocyte Antigen-B (HLA-B) *58:01 allele and administration 
of allopurinol via a slow dose titration.  
Patients with gout may experience an acute gout flare event with initiation or an increase in 
dose of urate-lowering therapies (Borstad et al 2004).  To prevent this, the manufacturer’s 
prescribing information for urate-lowering therapies like lesinurad, allopurinol and febuxostat, 
as well as the European League Against Rheumatism (EULAR), American College of 
Rheumatology (ACR), and British Society of Rheumatology treatment guidelines Zhang et al 
2006; Jordan et al 2007; Khanna et al 2012), recommend acute gout flare prophylaxis with 
colchicine, steroids, or a NSAID when initiating or increasing the dose of such therapies.  The 
protocol lists options for gout prophylaxis to the investigators to allow for appropriate 
management (Section 6.5.1). 
Following a blinded interim analysis in September 2020, the study was modified (via Protocol 
Version 5.0) to explore a broader range of doses, and a 24 mg dose of verinurad will be 
introduced to a subset of patients in the 3 mg cohort.  This subset will consist of patients 
randomized to 3 mg verinurad who have a planned Visit 9 after Protocol Version 5.0 is 
implemented in the respective territories and once IP is available.  
Testing a higher dose of verinurad requires careful consideration.  Based on the safety 
information from the blinded interim analysis, as well as the evidence accumulated throughout 
the verinurad clinical development program, there are no major concerns precluding testing 
24 mg verinurad with regards to safety.  Verinurad has previously been administered to 
healthy subjects for 7 days using the same formulation (ER8) at 12 and 24 mg in the JADE 
study (D5495C00006) without safety concerns (refer to Investigator’s Brochure).  
In the new dosing regimen, all subjects will end treatment at Visit 10, therefore no patients 
will be treated with 24 mg verinurad for longer than approximately 13 weeks. 








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Also, following implementation of the amendment, all subjects will discontinue therapy after 
60 weeks (Visit 10).  Patients that have conducted Visit 10 before the implementation of the 
amendment will discontinue therapy at their next scheduled visit. 
The new treatment regimen will be dispensed to patients for which Visit 9 falls on or after the 
last of the following dates: 
• 
the date of availability at site of IP suitable for the new treatment regimen, 
• 
the date of the Regulatory Authority approval of Protocol Version 5.0 in the respective 
country, and 
• 
the date of the Ethics Committee/Independent Review Board approval of Protocol 
Version 5.0 in the respective country/site.  
A patient in the new dosing regimen who is still on treatment, who has not been down-titrated 
and has signed Informed Consent Form (ICF) for the new dosing regimen, will receive the 
new treatment at Visit 9.  Patients who do not consent should be discontinued from the study 
at a subsequent visit.  If the patient has passed Visit 9 before the dates listed above, they will 
remain on the initial dosing regimen. 
A total of 725 patients (145 per initial dosing regimen arm) at around 200 sites in around 15 
countries will be randomised with equal probability to 1 of the initial dosing regimens 5 
treatment arms. 
For an overview of the study design see Figure 1, Section 1.3.  For details on treatments given 
during the study, see Section 6.1 Treatments Administered. 
For details on what is included in the efficacy and safety endpoints, see Section 8, Study 
Assessments and Procedures. 
4.1.2 
Study procedures 
4.1.2.1 
Week -6 to -1 – prescreening (Visit 1) 
• 
Obtain signed abbreviated ICF 
• 
Obtain blood sample to assess sUA and eGFR, and spot UACR to determine eligibility 
• 
Dispense containers for morning voids (patients not meeting criteria for enrolment will be 
notified before collection of morning voids begins) 
 
4.1.2.2 
Week -4 to -0 – screening (Visit 2) 
• 
Collect first morning void samples from 3 days before visit 
• 
Obtain signed full ICF 
• 
Record serious adverse events (SAEs) 
• 
Obtain demography information 


Cli nical St u d y Pr ot oc ol - 5. 0  
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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  
3 9  of 1 2 2  
 
•  
O btai n f ull me dical hist or y wit h n ote of c o m or bi dities  
•  
Rec or d c o n c o mita nt me dicati o n  
•  
Perf or m f ull p h ysical e x a mi nati o n ( P E)  
•  
O btai n vital si g n s 
•  
O btai n hei g ht a n d wei g ht 
•  
O btai n 1 2- lea d el ectr o car di o gra m ( E C G) 
•  
O btai n bl o o d sa m ples f or cli nical c he mistr y a n d h ae mat ol o g y, a n d efficac y assess me nts 
(s- U A, creati ni ne, e G F R, C ystati n C, N T-pr o B N P)  
•  
O btai n bl o o d sa m ple f or H L A- B * 5 8 0 1 allele ge n ot y pi n g f or all patie nts pri or t o 
ra n d o misati o n  
•  
O btai n uri ne sa m ples f or safet y assess me nt ( di pstic k uri nal ysis) 
•  
Perf or m pre g n a nc y uri ne di pstic k test f or w o me n of c hil d beari n g p ote ntial; after 
2 p ositi ve uri ne tests, a ser u m pre g n a nc y test is t o be d o ne b y ce ntral la b orat or y 
•  
E val uate all i ncl usi o n/e x cl usi o n criteria  
•  
C o nfir m eli gi bilit y f or re nal M RI e val uati o n f or p atie nts w h o c o nse nte d t o partici pate i n 
M RI s u b -st u d y pri or t o r a n d o misati o n 
•  
I V R S/I W R S (I nteractive V oice/ We b Res p o nse s yste m) tra nsacti o n  
•  
Dis pe nse c o ntai ners f or m or ni n g v oi ds 
 
4. 1. 2. 3  
Wee k 0 ( Visit 3) 
•  
C ollect first m or ni n g v oi d sa m ples fr o m 3  da ys bef ore visit (f or pri mar y 
 
bi o mar kers) 
•  
Re vie w de m o gra p h y i nf or mati o n  
•  
U p date c o n c o mita nt me dicati o n 
•  
Rec or d me dicall y i m p ort a nt e ve nts as me dical hist or y  
•  
Perf or m brief P E  
•  
Rec or d vital si g ns 
•  
Rec or d wei g ht  
•  
O btai n electr o car di o gr a m ( E C G)  
 
 
•  
O btai n bl o o d sa m ples f or cli nical c he mistr y a n d h ae mat ol o g y, efficac y ass ess me nts 
(s-U A, c reati ni ne, e G F R, C ystati n C, N T- pr o B N P),
 
•  
Ge netics sa m pli n g f or s o me patie nts  
•  
O btai n uri ne sa m ples f or safet y assess me nt ( di pstic k uri nal ysis 
•  
C o n d uct re nal M RI a n d P W V e val uati o n f or patie nts w h o c o nse nte d t o partici pate i n M RI 
s ub-st u d y pri or t o r a n d o misati o n 
•  
Reacti ve h y per ae mia e val uati o n  
C CI
C CI
C CI


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•  
Perf or m pre g n a nc y uri ne di pstic k test f or w o me n of c hil d beari n g p ote ntial; after 
2 p ositi ve uri ne tests, a ser u m pre g n a nc y test is t o be d o ne b y ce ntral la b orat or y 
•  
Re vie w i ncl usi o n/e x cl usi o n criteria  
•  
Ra n d o mise patie nts via I V R S/I W R S tra nsacti o n  
•  
Dis pe nse titrati o n Ste p - 1 d ose 
•  
Dis pe nse c o ntai ners f or m or ni n g v oi ds 
 
4. 1. 2. 4  
Wee k 4 ( Visit 4) 
•  
C ollect first m or ni n g v oi d sa m ples fr o m 3  da ys bef ore visit 
•  
C ollect u nta ke n st u d y me dicati o n  
•  
U p date c o n c o mita nt me dicati o n  
•  
Rec or d A Es  
•  
Perf or m brief P E  
•  
Rec or d vital si g ns 
•  
Rec or d wei g ht  
•  
O btai n bl o o d sa m ples f or cli nical c he mistr y a n d h ae mat ol o g y, a n d efficac y assess me nts 
(s- U A, creati ni ne, e G F R, C ystati n C, N T-pr o B N P)  
•  
O btai n uri ne sa m ples f or safet y assess me nt ( di psti c k uri nal ysis)  
•  
I V R S/I W R S tra nsacti o n a n d dis pe nse titrati o n Ste p- 2 d ose 
•  
Dis pe nse c o ntai ners f or m or ni n g v oi ds 
 
4. 1. 2. 5  
Wee k 8 ( Visit 5) 
•  
C ollect first m or ni n g v oi d sa m ples fr o m 3  da ys bef ore visit 
•  
C ollect u nta ke n st u d y me dicati o n  
•  
U p date c o n c o mita nt me dicati o n  
•  
Rec o r d A Es 
•  
Perf or m brief P E  
•  
Rec or d vital si g ns 
•  
Rec or d wei g ht  
 
 
•  
O btai n bl o o d sa m ples f or cli nical c he mistr y a n d h ae mat ol o g y, a n d efficac y assess me nts 
(s- U A, creati ni ne, e G F R, C ystati n C, N T-pr o B N P)  
•  
O btai n uri ne sa m ples f or safet y asse ss me nt ( di pstic k uri nal ysis 
•  
I V R S/I W R S tra nsacti o n a n d dis pe nse titrati o n Ste p- 3 d ose ( N ote: Titrati o n t o ste p- 3 
tar get d ose will o nl y b e all o we d if t he patie nt’s e G F R was ≥3 0 m L/ mi n/ 1. 7 3 m2 at Visits 3 
a n d 4.) 
•  
Dis pe nse c o ntai ners f or m or ni n g v oi ds 
 
C CI


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4 1  of 1 2 2  
 
4. 1. 2. 6  
Wee k 1 2 ( Visit 6) 
•  
Place p h o ne calls o n t he da y b ef ore t he visit t o re mi n d patie nts t o n ot ta ke dr u g at h o me 
bef ore t his visit a n d t o rec or d t he ti me a n d dat e of t he last d ose ta ke n 
•  
Visit t o be sc he d ule d i n t he m or ni n g t o per mit P K bl o o d c ollecti o n 
•  
C ollect first m o r ni n g v oi d sa m ples fr o m 3 da ys bef ore visit (f or pri mar y 
 
bi o mar kers) 
•  
C ollect u nta ke n st u d y me dicati o n  
•  
U p date c o n c o mita nt me dicati o n  
•  
Rec or d A Es  
•  
Perf or m brief P E  
•  
Rec or d vital si g ns 
•  
Rec or d wei g ht  
•  
O btai n E C G 
•  
O btai n bl o o d sa m ples f or cli nical c he mistr y a n d h ae mat ol o g y, efficac y ass ess me nts 
(s- U A, creati ni ne, e G F R, C ystati n C, N T- pr o B N P) 
 
•  
O btai n pre- d os e P K bl o o d sa m ples ( P K s h o ul d be c ollecte d t o get her wit h s U A) i n all 
patie nts  
•  
Patie nts ta ke dr u g at cli nic (ti me of dr u g i nta ke s h o ul d be rec or de d) 
•  
O btai n p ost- d ose P K a n d s U A bl o o d sa m ples i n eac h of t he f o ur f oll o wi n g ti me wi n d o ws: 
( 1) 3 t o 4, ( 2) 4 t o 5, ( 3) 5 t o 6 a n d ( 4) 8 t o 9 h i n patie nts partici pati n g i n t he P K s u b-
st u d y  
•  
C ollect u nta ke n st u d y me dicati o n  
•  
O btai n ur i ne sa m ples f or safet y assess me nt ( di pstic k uri nal ysis 
•  
Perf or m pre g n a nc y uri ne di pstic k test f or w o me n of c hil d beari n g p ote ntial; after 
2 p ositi ve uri ne tests, a ser u m pre g n a nc y test is t o be d o ne b y ce ntral la b orat or y 
•  
I V R S/I W R S tra nsacti o n a n d dis pe nse titrati o n Ste p- 3 d ose ( N ote: Titrati o n t o ste p- 3 
tar get d ose will o nl y b e all o we d if t he patie nt’s e G F R was ≥3 0 m L/ mi n/ 1. 7 3 m2 at Visits 3 
a n d 4.) 
•  
Dis pe nse c o ntai ners f or m or ni n g v oi ds 
 
4. 1. 2. 7  
Wee k 2 0 ( Visit 7) 
•  
Place p h o ne calls o n t he da y b ef ore t he visit t o re mi n d patie nts t o rec or d t he ti me a n d date 
of t he st u d y me di cati o n i nta ke o n t he da y of t h e visit 
•  
C ollect first m or ni n g v oi d sa m ples fr o m 3  da ys bef ore visit 
•  
C ollect u nta ke n st u d y me dicati o n  
•  
U p date c o n c o mita nt me dicati o n  
•  
Rec or d A Es  
•  
Rec or d vital si g ns 
•  
Rec or d wei g ht  
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Astra Ze neca  
Veri n ura d / R D E A 3 1 7 0  - D 5 4 9 5 C 0 0 0 0 2  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
4 2  of 1 2 2  
 
•  
O btai n bl o o d sa m ples f or p ost- d ose P K a n d s U A ( dr u g ta k e n at h o me, d ate a n d ti me of 
dr u g i nta k e s h o ul d be rec or de d) 
•  
O btai n bl o o d sa m ples f or efficac y ass ess me nts (s- U A, creati ni ne, e G F R, C ystati n  C, N T -
pr o B N P) 
•  
Perf or m pre g n a nc y uri ne di pstic k test f or w o me n of c hil d beari n g p ote ntial; after 
2 p ositi ve uri ne tests, a ser u m pre g n a nc y test is t o be d o ne b y ce ntral la b orat or y 
•  
I V R S/I W R S a n d dis pe ns e titrati o n Ste p- 3 d ose ( N ote: Titrati o n t o ste p-3 tar get d ose will 
o nl y be all o we d if t he patie nt’s e G F R w as ≥3 0 m L/ mi n/ 1. 7 3 m 2 at Visits 3 a n d 4 .) 
•  
Dis pe nse c o ntai ners f or m or ni n g v oi ds 
 
4. 1. 2. 8  
Wee k 3 4 ( Visit 8) 
•  
Place p h o ne calls o n t he da y b ef ore t he visit t o re mi n d patie nts t o rec or d t he ti me a n d date 
of t he st u d y me di cati o n i nta ke o n t he da y of t h e visit 
•  
C ollect first  m or ni n g v oi d sa m ples fr o m 3 da ys bef ore visit (f or pri mar y 
 
bi o mar kers) 
•  
C ollect u nta ke n st u d y me dicati o n  
•  
U p date c o n c o mita nt me dicati o n  
•  
Rec or d A Es  
•  
Perf or m brief P E  
•  
Rec or d vital si g ns 
•  
Rec or d wei g ht  
•  
O btai n E C G 
 
 
•  
O btai n bl o o d sa m ples f or cli nical c he mistr y a n d h ae mat ol o g y, efficac y ass ess me nts 
(s- U A, creati ni ne, e G F R, C ystati n C, N T- pr o B N P) 
 
•  
O btai n bl o o d sa m ples f or p ost- d ose P K a n d s U A ( dr u g ta k e n at h o me, d ate a n d ti me of 
dr u g i nta k e s h o ul d be rec or de d) 
•  
O btai n uri ne sa m ples f or safet y assess me nt ( di pstic k uri nal ysis 
•  
O btai n res ults/c o nfir m a v aila bilit y of M RI re n al a n d P W V e val uati o n f or s o me patie nts  
•  
Reacti ve h y perae mia e val uati o n f or s o me patie nts  
•  
Perf or m pre g n a nc y uri ne di pstic k test f o r w o me n of c hil d beari n g p ote ntial; after 
2 p ositi ve uri ne tests, a ser u m pre g n a nc y test is t o be d o ne b y ce ntral la b orat or y 
•  
I V R S/I W R S a n d dis pe ns e titrati o n Ste p- 3 d ose ( N ote: Titrati o n t o ste p-3 tar get d ose will 
o nl y be all o we d if t he patie nt’s e G F R w as ≥3 0 m L/ mi n/ 1. 7 3 m 2 at Visits 3 a n d 4 .) 
•  
Dis pe nse c o ntai ners f or m or ni n g v oi ds 
 
4. 1. 2. 9  
Wee k 4 7 ( Visit 9) 
At t he ti me of i m ple me ntati o n  of Pr ot oc ol Versi o n 5. 0, a ne w d osi n g re gi m e n will be 
i ntr o d uce d t o assess t he hi g her d os e of 2 4 m g veri n ura d.  Patie nts  i n t he 3 mg veri n ura d  c o h ort 
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who will have Visit 9 planned after the amendment implementation in the respective 
country/site and who have signed ICF for the new dosing regimen will be switched to 24 mg 
dose at Visit 9.  Patients who do not consent should be discontinued from the study at a 
subsequent visit. 
To introduce the new 24 mg dose, a new dosing regimen will be initiated across treatment 
arms to maintain blinding.  For verinurad dosing, all patients in the new dosing regimen will 
receive 2 capsules through addition of a matching placebo capsule, with the exception of those 
who switched from the 3 mg to 24 mg dose, where two 12-mg verinurad capsules will be 
given.  Allopurinol dosing will remain the same. 
Note: Patients will only be allowed to switch to the new dosing regimen’s treatments 
introduced under Protocol Version 5.0 if the patient’s eGFR was ≥30 mL/min/1.73m2 at 
Visit 8.  Management of patients with eGFR <30 mL/min/1.73m2 at Visit 9 should be 
discussed with the medical monitor. 
• 
Place phone calls on the day before the visit to remind patients to record the time and date 
of the study medication intake on the day of the visit 
• 
Collect first morning void samples from 3 days before visit 
• 
Collect untaken study medication 
• 
Update concomitant medication 
• 
Record AEs 
• 
Record vital signs 
• 
Record weight 
• 
Obtain blood samples for post-dose PK and sUA (drug taken at home, date and time of 
drug intake should be recorded) 
• 
Obtain blood samples for efficacy assessments (s-UA, creatinine, eGFR, Cystatin C, NT-
proBNP) 
• 
Perform pregnancy urine dipstick test for women of childbearing potential; after 
2 positive urine tests, a serum pregnancy test is to be done by central laboratory 
• 
Prior to Protocol Version 5.0, IVRS/IWRS and dispense titration Step-3 dose 
(Note: Titration to step-3 target dose will only be allowed if the patient’s eGFR was 
≥30 mL/min/1.73m2 at Visits 3 and 4.) 
• 
Dispense containers for morning voids 
 
4.1.2.10 
Week 60 (Visit 10) (prior to Protocol Version 5.0) 
Prior to Protocol Version 5.0, patients were expected to continue treatment beyond Visit 10 
with visits every 12 weeks.  Patients who have conducted Visit 10 before the implementation 
of the amendment will continue the currently dispensed IP, and at the subsequent visit will 
conduct an end of treatment visit (see Section 4.1.2.12).  


Cli nical St u d y Pr ot oc ol - 5. 0  
Astra Ze neca  
Veri n ura d / R D E A 3 1 7 0  - D 5 4 9 5 C 0 0 0 0 2  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
4 4  of 1 2 2  
 
P ati e nts w h o s witc h t o t he ne w d osi n g re gi me n, wit h Visit 9 pl a n ne d after 
i m ple me nt ati o n of Pr ot oc ol Versi o n 5. 0, will f oll o w Visit 1 0 assess me nts as descri be d i n 
Secti o n  4. 1. 2. 1 2. 
P atie nts n ot s witc hi n g t o t he ne w d osi n g re gi me n will u n d er g o t he f oll o wi n g ass ess me nts. 
•  
Place p h o ne calls o n t he da y b ef ore t he visit t o re mi n d patie nts t o rec or d t he ti me a n d date 
of t he st u d y me di cati o n i nta ke o n t he da y of t h e visit 
•  
C ollect first m or ni n g v oi d sa m ples fr o m 3  da ys bef ore visit 
•  
C ollect u nta ke n st u d y me dicati o n 
•  
U p date c o n c o mita nt me dicati o n  
•  
Rec or d A Es  
•  
Perf or m f ull  P E  
•  
Rec or d vital si g ns 
•  
Rec or d wei g ht  
•  
O btai n E C G 
 
 
•  
O btai n bl o o d sa m ples f or cli nical c he mistr y a n d h ae mat ol o g y, efficac y ass ess me nts 
(s-U A, creati ni ne, e G F R, C y stati n C, N T-pr o B N P)  
•  
O btai n bl o o d sa m ples f or p ost- d ose P K a n d s U A ( dr u g ta k e n at h o me, d ate a n d ti me of 
dr u g i nta k e s h o ul d be rec or de d) 
•  
O btai n uri ne sa m ples f or safet y assess me nt ( di pstic k uri nal ysis) 
•  
Reacti ve h y per ae mia e val uati o n f or s o me patie nts  
•  
Perf or m pre g n a nc y uri ne di pstic k test f or w o me n of c hil d beari n g p ote ntial; after 
2 p ositi ve uri ne tests, a ser u m pre g n a nc y test is t o be d o ne b y ce ntral la b orat or y 
•  
Dis pe nse c o ntai ners f or m or ni n g v oi ds 
 
4. 1. 2. 1 1  
At 1 2 - w ee k i nter v als after Visit 1 0 ( Visits 1 1 t hr o u g h 1 4) ( pri or t o Pr ot o c ol 
Versi o n 5. 0) 
Pri or t o Pr ot oc ol Versi o n 5. 0, patie nts were e x pecte d t o c o nti n ue treat me nt be y o n d Visit 1 0 
wit h visits e ver y 1 2 w ee ks.  After i m ple me ntati o n of t he a me n d me nt, patie nts w h o ha ve 
passe d  Wee k 6 0  will dis c o nti n ue I P  at t he s u bse q u e nt visit (e n d of treat me nt visit ) (see 
Secti o n  4. 1. 2. 1 2 ). 
•  
C ollect first m or ni n g v oi d sa m ples fr o m 3  da ys bef ore visit 
•  
C ollect u nta ke n st u d y me dicati o n 
•  
U p date c o n c o mita nt me dicati o n  
•  
Rec or d A Es  
•  
Perf or m brief P E ( Visits 1 1 a n d 1 4) 
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Astra Ze neca  
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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  
4 5  of 1 2 2  
 
•  
Rec or d vital si g ns 
•  
Rec or d wei g ht  
•  
O btai n bl o o d sa m ples f or cli nical c he mistr y a n d h ae mat ol o g y, efficac y ass ess me nts 
(s- U A, creati ni ne, e G F R, C ystati n C, N T-pr o B N P)   
•  
Dis pe nse c o ntai ners f or m or ni n g v oi ds 
 
4. 1. 2. 1 2  
E n d of tre at me nt  (occ u rs at 6 0 w ee ks  f or p atie nts o n ne w d osi n g re gi me n 
f oll o wi n g Pr ot oc ol Versi o n 5. 0 i m ple me nt ati o n)/e arl y disc o nti n u ati o n 
F oll o wi n g t he i m ple me nt ati o n of Pr ot oc ol Versi o n 5 . 0, all patie nts will disc o nti n ue treat me nt 
at Visit 1 0.  T he f oll o wi n g ass ess me nts will be c o n d ucte d at t he e n d of treat me nt/earl y 
disc o nti n uati o n visit . 
•  
C ollect first m or ni n g v oi d sa m ples fr o m 3  da ys bef ore visit (f or pri mar y 
 
bi o mar kers) 
•  
Rec or d A Es  
•  
U p date c o n c o mita nt me dicati o n  
•  
Perf or m f ull P E  
•  
Rec or d vital si g ns 
•  
Rec or d wei g ht  
 
 
•  
O btai n 1 2- lea d E C G 
•  
O btai n bl o o d sa m ples f or cli nical c he mistr y a n d h ae mat ol o g y , efficac y ass ess me nts 
(s- U A, creati ni ne, e G F R, C ystati n C, N T-pr o B N P) , P K, 
 
•  
O btai n uri ne f or s afet y assess me nt ( di pstic k uri nal ysis) 
•  
St u d y dr u g ret ur n a n d acc o u nta bilit y  
 
4. 1. 2. 1 3  
F oll o w u p visit ( 4 w ee ks after e n d of tre at me nt/ e arl y disc o nti n u ati o n/l ast 
sc he d ule d, n u m bere d visit) 
•  
All patie nts (i ncl u di n g a n y patie nts w h o h a ve disc o nti n ue d treat me nt wit h i n vesti gati o nal 
pr o d uct [ I P]) s h o ul d ret ur n f or t heir Visit. 
•  
C ollect first m or ni n g v oi d sa m ples fr o m 3  da ys bef ore visit (f or pri mar y 
 
bi o mar kers) 
•  
U p date c o n c o mita nt me dicati o n  
•  
Rec or d A Es  
•  
Perf or m f u ll P E 
•  
Rec or d vital si g ns 
•  
Rec or d wei g ht  
 
 
•  
O btai n 1 2- lea d E C G 
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Cli nical St u d y Pr ot oc ol - 5. 0  
Astra Ze neca  
Veri n ura d / R D E A 3 1 7 0  - D 5 4 9 5 C 0 0 0 0 2  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
4 6  of 1 2 2  
 
•  
O btai n bl o o d sa m ples f or cli nical c he mistr y a n d h ae mat ol o g y , efficac y ass ess me nts 
(s- U A, creati ni ne, e G F R, C ystati n C, N T- pr o B N P) 
 
•  
O btai n uri ne sa m ples f or safet y assess me nt ( di pstic k uri nal ysis)  
•  
Perf or m pre g n a nc y uri ne di pstic k test f or w o me n of c hil d beari n g p ote ntial; after 
2 p ositi ve uri ne tests, a ser u m pre g n a nc y test is t o be d o ne b y ce ntral la b orat or y 
 
4. 2  
Scie ntific r ati o n ale f or st u d y desi g n  
T he p ur p ose of t h e st u d y is t o esta blis h t he d ose of veri n ura d c o m bi ne d wit h all o p uri n ol 
3 0 0 m g o nce dail y t hat will elicit t he desire d res p o nse; ie, re d ucti o n i n U A C R at 6  m o nt hs.  
U A C R is a meas ure me nt of al b u mi n uria, it was c h ose n beca us e c h a n ges i n U A C R ca n be 
detecte d earl y i n res p o ns e t o treat me nt, a n d t hes e c ha n ges, if s u bsta ntial, c orrelate wit h 
pr o gressi o n of C K D, det eri orati o n i n e G F R, a n d har d o utc o mes.  T heref ore, c ha n ge i n U A C R 
is re gar de d as a n a p pr o priate e n d p oi nt.  I n t his st u d y, c h a n ge i n U A C R at 6  m o nt hs of 
treat me nt is t he pri mar y e n d p oi nt f or t he efficac y e val uati o n of treat me nt wit h t he 
c o m bi nati o n of veri n ura d a n d all o p uri n ol vs. place b o.  A ke y sec o n d ar y o bj ecti ve is 
e val uati o n of veri n ura d pl us all o p uri n ol o n t he re d ucti o n i n U A C R at 1 2 m o nt hs.  A d diti o nal 
sec o n dar y e n d p oi nts i ncl u de c ha n ges fr o m bas eli ne i n  s U A, e G F R, c ystati n C, creati ni ne a n d 
N T - pr o B N P.  F urt h er, st a n dar d safet y para meters s uc h as A Es, S A Es, a n d la b orat or y 
e val uati o ns will be e m pl o ye d t o assess t he safet y pr ofile o f t he st u d y dr u gs.  Veri n ura d, 
all o p uri n ol a n d o x y p uri n ol plas ma c o nce ntrati o ns o ver ti me will als o be meas ure d. 
4. 3  
J ustific ati o n f or d ose  
T he veri n ur a d a n d all o p uri n ol c o m bi nati o n t hera p y d oses a n d re gi me n s electe d f or t his st u d y 
are bas e d o n t he g oal of c ha ract erisi n g t h e d ose-res p o nse f or U A C R a n d e val uati n g safet y i n 
t his patie nt p o p ulati o n. 
T he s u g geste d d ose ra n ge ( 3 t o 2 4 m g) of veri n ura d i n t his st u d y is c h ose n t o e na ble a test of a 
wi de ra n ge of d oses a n d is base d o n p har m ac o ki netic, p har mac o d y n a mic, a n d safet y data fr o m 
pre vi o us st u dies i n healt h y v ol u nteers a n d i n patie nts wit h g o ut or h y per uricae mia wit h 
al b u mi n uria.  T he l o west d ose of 3 m g is sel ecte d t o ha ve li mite d effect o n s U A a n d is 
t heref or e li kel y t o ha ve n o or mi ni mal effect o n U A C R.  T he hi g hest d ose of 2 4 m g is selecte d 
t o ma xi mise t he effect o n s U A a n d i n hi biti o n of U R A T 1. 
A ne w d osi n g re gi me n of veri n ura d 2 4 m g will be i ntr o d uce d t o patie nts i n t he 3 m g c o h ort at 
Visit 9 ( 4 7 wee ks).  D ata fr o m t he S A P P HI R E i nt eri m a nal ysis, i n dicate a l o wer t ha n 
a ntici pate d s U A r e d ucti o n .  T he i nteri m a nal ysis als o s h o ws a sl o wer rat e of a bs or pti o n of 
veri n ura d t ha n a ntici pate d wit h a mai ntai ne d veri n ura d A U C b ut less t ha n h alf t he e x pecte d 
veri n ura d C ma x.  T o f ull y e x pl ore t he h y p ot hesis of i n hi biti o n of U R A T 1 i n hi biti o n, t he 
hi g hest veri n ura d d ose assesse d i n t he st u d y is t heref ore i n crease d t o 2 4 m g. 
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Testing a higher dose of verinurad (24 mg) requires careful consideration.  Based on the 
current safety information from the blinded SAPPHIRE interim analysis, as well as evidence 
accumulated throughout the verinurad clinical development program, there are no major 
concerns precluding testing verinurad 24 mg in this study.  To maintain the scientific integrity 
of the SAPPHIRE study, further details of the interim analysis will not be shared at this time. 
Verinurad has previously been administered to healthy subjects for 7 days using the same 
formulation (ER8) at 12 and 24 mg in the JADE study (D5495C00006) without safety 
concerns (refer to the Investigator’s Brochure). In the JADE study, the observed verinurad 
Cmax was higher than the verinurad Cmax expected to be achieved after 24 mg verinurad in 
the SAPPHIRE study.  The verinurad AUC after 24 mg in the SAPPHIRE study is expected to 
be slightly above the observed AUC in the JADE study, as patients with low renal function 
have higher exposure compared to those with normal renal function.  The highest observed 
verinurad Cmax and AUC are 760 ng/mL and 1270 ng*h/mL, respectively, after 40 mg 
verinurad given as an immediate-release formulation to healthy subjects. Details on Cmax and 
AUC achieved in earlier verinurad studies are provided in the Investigator’s Brochure.   
Verinurad combined with allopurinol (300 mg once daily) dose-dependently lower sUA from 
47% up to 74% at verinurad doses of 2.5 to 20 mg (given as the MR4 tablet) in patients with 
recurrent gout (Fleischmann et al 2018a).  A dose of 20 mg of the MR4 tablet is equivalent to 
12 mg of the ER8 capsule used in this study.  Allopurinol alone given as 300 mg once daily 
lowered sUA by 40% in the same study. 
Verinurad dose-dependently increased the uUA excretion (Hall et al 2018).  The uUA 
excretion is comparable to baseline when verinurad is given in combination with an XOI 
(Fleischmann et al 2018a, Fleischmann et al 2018b).  Verinurad is therefore combined with 
allopurinol (XOI) to further reduce the peak uUA excretion, as high fractional excretion of 
UA has been associated with renal AEs in the setting of high UA production. 
A dose of 9 mg verinurad (ER8 capsule) given in combination with 80 mg febuxostat reduced 
UACR (primary endpoint) by 39.4% compared to placebo (p=0.0747) at 12 weeks in the 
Phase 2a study D5495C00007. 
Allopurinol will be titrated every 4 weeks in the initial phase of the study (Table 8) to 
minimise the risk for skin reactions.  The starting dose of allopurinol will be 100 mg once 
daily, titrated up to 200 mg once daily, and finally titrated to 300 mg once daily, the target 
dose, which is in line with the guideline recommendation (Khanna et al 2012, Stamp et al 
2016, Richette et al 2017).  Verinurad will be titrated along with allopurinol (up to 300 mg 
allopurinol) in order to avoid oversaturation of urate in the urine. 


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4.4 
End of study definition 
The end of study is defined as the last expected visit/contact of the last patient undergoing the 
study. 
A patient is considered to have completed the study when he/she has completed his/her last 
scheduled visit or last scheduled procedure shown in the SoA. 
5 
STUDY POPULATION 
The current protocol is intended to enrol a broad patient population with CKD and residual 
kidney function that is expected to benefit from the treatment while minimising risks for 
treatment-related AEs.  Prospective approval of protocol deviations to recruitment and 
enrolment criteria, also known as protocol waivers or exemptions, is not permitted. 
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study in order to be assigned/randomised to a study intervention.  Under no circumstances can 
there be exceptions to this rule.  Patients who do not meet the entry requirements are defined 
as screen failures, refer to Section 5.4. 
In this protocol, “enrolled” patients are defined as those who signed the full informed consent 
at Visit 2.  “Randomised” patients are defined as those who undergo randomisation and 
receive a randomisation number. 
For procedures for withdrawal of incorrectly enrolled patients see Section 7.3. 
5.1 
Inclusion criteria 
5.1.1 
Pre-screening criteria 
(a) Provision of signed and dated, brief written ICF prior to any mandatory study- 
specific procedures, sampling, and analyses 
(b) Enrol if: 
− 
sUA ≥6 mg/dL and 
− 
eGFR ≥25 mL/min/1.73 m2 and 
− 
UACR ≥30 mg/g and ≤5000 mg/g 
 
5.1.2 
Full eligibility criteria 
Patients are eligible to be included in the study only if all of the following inclusion criteria 
and none of the exclusion criteria apply: 


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Informed consent 
1 
Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the ICF and in this protocol. 
2 
Provision of signed and dated, written ICF prior to any mandatory study-specific 
procedures, sampling, and analyses.  
3 
Provision of signed and dated written genetic informed consent prior to collection of 
sample for genetic analysis 
 
The ICF process is described in Appendix A 3. 
Age 
4 
Patient must be ≥18 years of age at the time of signing the ICF. 
 
Type of patient and disease characteristics 
5 
Patients with CKD.  CKD as defined in the Kidney Disease: Improving Global Outcomes 
(KDIGO) guidelines as abnormalities in kidney structure or function present for >3 
months; ie, there must be a documented occurrence at least 3 months before 
randomisation of either of the following eGFR <60 mL/min/1.73 m2, UACR ≥30 mg/g, 
and/or one or more other markers of kidney damage (including abnormalities detected by 
histology or imaging, urine sediments, urine protein dipstick ≥1+, positive urine albumin 
dipstick, or urinary protein to creatinine ratio ≥84 mg/g). 
6 
Patients should receive background standard of care treatment for albuminuria and/or 
T2DM and be treated according to locally recognised guidelines, as appropriate.  
Guideline-recommended medications should be used at recommended doses.  Therapy 
should have been optimised and stable for ≥4 weeks before study entry and include an 
ACEi or an ARB, unless contraindicated, not tolerated, or in the opinion of the 
investigator not practically available or suitable. 
7 
If treated with a sodium-glucose transport protein (SGLT2) inhibitor, the SGLT2 inhibitor 
dose must have been stable for ≥4 weeks before randomisation. 
8 
Meeting screening criteria for sUA and eGFR (Visit 2) 
(a) sUA ≥6.0 mg/dL 
(b) eGFR ≥25 mL/min/1.73 m2 (CKD-EPI formula) 
9 
Mean UACR between 30 mg/g and 5000 mg/g inclusive.  At least 2 first morning void 
samples collected before randomisation will be required. 
 
Sex 
10 Male or female 


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Reproduction 
11 Negative pregnancy test at investigation site (urine or serum) for female patients of 
childbearing potential. 
12 Female patients must be 1 year post-menopausal, surgically sterile, or using an acceptable 
method of contraception (Table 5) for the duration of the study (from the time they sign 
consent) and for 4 weeks after the last dose of study treatment to prevent pregnancy. In 
addition, oral contraceptives, approved contraceptive implant, long-term injectable 
contraception, intrauterine device, or tubal ligation are allowed. Patients agreeing to total 
sexual abstinence can also be included, assuming it is their usual lifestyle. 
 
5.2 
Exclusion criteria  
Medical conditions 
1 
Autosomal dominant or autosomal recessive polycystic kidney disease, lupus nephritis or 
anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (granulomatosis with 
polyangiitis [Wegener's granulomatosis], microscopic polyangiitis, or eosinophilic 
granulomatosis with polyangiitis [Churg-Strauss syndrome]). 
2 
History of renal transplantation 
3 
Known carrier of the Human Leukocyte Antigen-B (HLA-B) *58:01 allele.  
HLA-B *58:01 genotyping is mandatory prior to randomisation for all patients.  
4 
Patients diagnosed with tumor lysis syndrome or Lesch-Nyhan syndrome 
5 
Patients who are severely physically or mentally incapacitated and who in the opinion of 
investigator are unable to perform the patients’ tasks associated with the protocol 
6 
Presence of any condition which, in the opinion of the investigator, places the patient at 
undue risk or potentially jeopardises the quality of the data to be generated 
7 
History of stroke, myocardial infarction, percutaneous coronary intervention, coronary 
artery bypass graft in the past 6 months 
8 
Uncontrolled hypertension presenting with systolic blood pressure >180 mm Hg and/or 
diastolic blood pressure >100 mm Hg 
9 
Diagnosed with heart failure and New York Heart Association Functional Classification 
(NYHA) Class IV (refer to Appendix E) at the time of randomisation  
10 QT interval corrected by the Fridericia formula (QTcF)  >470 msec; patients diagnosed 
with long QT syndrome; patients with a family history of long QT syndrome 
11 Evidence of significant liver disease (eg, aspartate transaminase [AST] or alanine 
transaminase [ALT] >3x the upper limit of normal [ULN]; or total bilirubin >1.5x ULN). 
An isolated increase in bilirubin in patients with known Gilbert’s syndrome is not a 
reason for exclusion. 


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Prior/concomitant therapy 
12 Receiving cytotoxic therapy, immunosuppressive therapy or other immunotherapy for 
primary or secondary renal disease within 6 months prior to enrolment  
13 Treated with any drug for hyperuricaemia in the 6 months preceding randomisation. 
Drugs for hyperuricaemia include all XOIs (allopurinol, febuxostat, and topiroxostat), 
URAT1 inhibitors (lesinurad, verinurad, probenecid, and benzbromarone), and urate 
oxidases (pegloticase, rasburicase) 
14 Dose of ACEi, ARBs, fenofibrate, guaifenesin, or SGLT2 inhibitors changed within 
4 weeks of randomisation or further dose titration expected after randomisation 
15 Treated with strong or moderate organic anion transporting polypeptide (OATP) 
inhibitors (See Table 10) 
 
Prior/concurrent clinical study experience 
16 Participation in another clinical study with an investigational product administered during 
the last month prior to randomisation 
17 Known hypersensitivity to any URAT1 inhibitor, allopurinol, or any of its excipients.  
Known intolerance to lactose (an allopurinol excipient) due to hereditary defect. 
 
Other exclusions 
18 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site). 
19 Judgment by the investigator that the patient should not participate in the study if the 
patient is unlikely to comply with study procedures, restrictions and requirements. 
20 Previous randomisation in the present study.  
21 Patients who are pregnant, lactating, or planning to become pregnant. 
22 For the MRI substudy, patients unsuitable or unable to undergo MRI assessment for the 
following reasons are not allowed to participate in the optional MRI substudy: 
− 
Body mass index >40 kg/m2 or abdominal height in the supine position >30 cm  
− 
Claustrophobia 
− 
Pacemaker or aneurysm clips 
− 
Other metallic implants or internal electrical devices (eg, cochlear implant, nerve 
stimulator, gastric pacemaker, bladder stimulator, defibrillator, artificial valves in 
heart, etc), or permanent makeup or tattoos which, in the investigator's opinion, might 
jeopardise the subject's safety or interfere with the imaging measurements 
− 
Arrhythmia 


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− 
Pregnancy 
23 Patients with bilateral upper or lower arm pathology are not allowed to participate in the 
vascular reactivity substudy: 
− 
Presence of fistula / AV Shunt 
− 
Other structural or vascular abnormality 
 
5.3 
Lifestyle restrictions 
There are no life style restrictions, with the exception of contraceptive use and taking alcohol 
and investigational product at the same time.  
5.3.1 
Pregnancy 
The following restrictions apply while the patient is receiving study treatment and for the 
specified times before and after. 
1 
Female patient of childbearing potential 
• 
Female patients of childbearing potential who are not abstinent and intend to be sexually 
active with a non-sterilized male partner must use an acceptable method of contraception 
(Table 5) from the time of Screening throughout the total duration of the drug treatment 
and the drug washout period (4 weeks) after the last dose of study treatment.  Cessation of 
birth control after this point should be discussed with a responsible physician.  Periodic 
abstinence, the rhythm method, and the withdrawal method are not acceptable methods of 
contraception.  Female patients should refrain from breastfeeding throughout this period. 
2 
Male patients are not required to use contraception 
Please note, females of childbearing potential are defined as those who are not surgically 
sterile (ie, bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) or 
post-menopausal. 
Women will be considered post-menopausal if they have been amenorrhoeic for 12 months 
without an alternative medical cause.  The following age-specific requirements apply:  
• 
Women <50 years of age would be considered post-menopausal if they have been 
amenorrhoeic for 12 months or more following cessation of exogenous hormonal 
treatments and if they have luteinizing hormone and follicle-stimulating hormone levels 
in the post-menopausal range for the institution. 
• 
Women ≥50 years of age would be considered post-menopausal if they have been 
amenorrhoeic for 12 months or more following cessation of all exogenous hormonal 
treatments, had radiation-induced menopause with last menses >1 year ago, or had 
chemotherapy-induced menopause with last menses >1 year ago. 
• 
Women who are surgically sterile (ie, bilateral salpingectomy, bilateral oophorectomy, or 
complete hysterectomy) are eligible. 
 


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Table 5 
Acceptable methods of contraception (<1% failure rate) 
Barrier/intrauterine methods 
Hormonal methods 
• 
Copper T intrauterine device 
• 
Levonorgestrel-releasing intrauterine system 
(eg, Mirena®)a 
 
• 
Implants: Etonogestrel-releasing implants (eg, 
Implanon® or Norplant®) 
• 
Intravaginal Devices: 
Ethinylestradiol/etonogestrel-releasing 
intravaginal devices (eg, NuvaRing®)  
• 
Injection: Medroxyprogesterone injection (eg, 
Depo-Provera®) 
• 
Combined Pill: Normal and low dose 
combined oral contraceptive pill 
• 
Patch: Norelgestromin/ethinylestradiol-
releasing transdermal system (eg, Ortho 
Evra®) 
• 
Minipill: Progesterone based oral contraceptive 
pill using desogestrel: Cerazette® is currently 
the only highly efficacious progesterone based 
pill  
a 
This is also considered a hormonal treatment 
 
5.3.2 
Alcohol intake 
Investigational product should not be taken within an hour of ingesting alcohol.  There are no 
restrictions on combining IP intake with caffeine or nicotine intake, but it is recommended to 
take the IP with food. 
5.3.3 
MRI procedures: 
Patients will be instructed to drink at least 250 mL water within 1 hour before the scan. 
5.4 
Pre-screen and screen failures 
The study will include a two-step screening procedure: 
• 
Pre-screening (Visit 1): Patients with sUA <6.0 mg/dL, eGFR <25 mL/min/1.73 m2 or 
UACR <30 mg/g will be classified as pre-screen failures.  A single repeat test is permitted 
if initial sUA, eGFR or UACR results are not in the eligible range. 
− 
Patients are eligible to pre-screen up to 2 times.  There are no time restrictions 
between the two pre-screening visits. 
− 
The visit at which the pre-screening criteria are met should be within Weeks -6 to -1. 
− 
Once patients have met the criteria set in pre-screening, patients are eligible for 
screening. 
− 
If a patient passes pre-screening but does not yet satisfy the inclusion/exclusion 
criteria, the subject may wait to screen at the discretion of the investigator. 
• 
Screening (Visit 2):  Patients who do not meet all eligibility criteria based on the full 
Visit 2 assessment will be classified as Screen Failures. 


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− 
A single repeat of an out-of-eligibility range assessment is permitted. 
− 
Patients can undergo screening up to 2 times. 
− 
The same IXRS ecode should be used for the re(pre)screened patient. 
 
Screen failures are defined as patients who signed the ICF to participate in the clinical study 
but are not subsequently randomly assigned to study treatment.  A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure patients to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities.  Minimal information includes demography, 
screen failure details, eligibility criteria, and any SAE. 
These patients should have the reason for study withdrawal recorded in the electronic case 
report form (eCRF). 
6 
STUDY TREATMENTS 
Study treatment is defined as any IP (including marketed product comparator and placebo) or 
medical device(s) intended to be administered to a study participant according to the study 
protocol.  Study treatment in this study refers to verinurad, allopurinol or placebo. 
Study treatment is to be administered in the morning and will be generally better tolerated if 
taken in association with food.  Patients should be advised to maintain adequate hydration. 
6.1 
Treatments administered 
6.1.1 
Investigational products 
Table 6 
Study treatments (prior to Protocol Version 5.0) 
 
IP 1 
IP 2  
Study treatment name: 
Verinurad or matching placebo 
Allopurinol or matching placebo 
Dosage formulation: 
Capsule 
Tablet 
Route of administration  
Oral 
Oral 
Dosing instructions: 
3, 7.5, or 12 mg to be taken, one time 
a day 
100, 200, or 300 mg to be taken, one 
time a day 
Packaging and labelling 
Verinurad capsules will be packaged 
in bottles. Each bottle will be labelled 
in accordance with Good 
Manufacturing Practice (GMP) 
Annex 13 and per country regulatory 
requirement 
Allopurinol tablets will be packaged 
in bottles. Each bottle will be 
labelled in accordance with Good 
Manufacturing Practice (GMP) 
Annex 13 and per country regulatory 
requirement 
Provider 
AstraZeneca  
AstraZeneca 
IP  Investigational product 
 


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At the time of implementation of Protocol Version 5.0, a new dosing regimen will be 
introduced to assess the higher dose of 24 mg verinurad.  Patients in the 3 mg verinurad cohort 
who will have Visit 9 after the amendment implementation in the prospective country/site and 
who have signed ICF for the new dosing regimen will be switched to 24 mg dose at Visit 9.  
Patients who do not consent should be discontinued from the study at a subsequent visit.  To 
introduce the new 24 mg dose, a new dosing regimen across treatment arms will be initiated to 
maintain blinding in all study cohorts.  All patients in the new dosing regimen will receive 2 
capsules, as patients switched from 3 mg to 24 mg dose will receive two 12-mg verinurad 
capsules, and the bottles differentiated by colour, will be administered to all other patients.  
Patients on 24 mg verinurad need to take two 12-mg verinurad capsules.  To match, patients in 
the other arms must take 2 capsules for blinding purposes.  Patients will be instructed to take 
one capsule out of two different bottles every day.  Allopurinol dosing will remain the same. 
Table 7 
Study treatments (after implementation of Protocol Version 5.0) 
 
IP 1 
IP 2  
Study treatment name: 
Verinurad or matching placebo 
Allopurinol or matching placebo 
Dosage formulation: 
Capsule 
Tablet 
Route of administration  
Oral 
Oral 
Dosing instructions: 
3*, 7.5, or 12 mg to be taken, one time a 
day from two differently coloured bottles 
Patients from 3 mg dose who will be 
switched to 24 mg will receive 24 mg as 
two 12-mg capsules**  
100, 200, or 300 mg to be taken, one 
time a day 
Packaging and labelling 
Verinurad capsules will be packaged in 
bottles. Each bottle will be labelled in 
accordance with Good Manufacturing 
Practice (GMP) Annex 13 and per 
country regulatory requirement 
Allopurinol tablets will be packaged 
in bottles. Each bottle will be 
labelled in accordance with Good 
Manufacturing Practice (GMP) 
Annex 13 and per country regulatory 
requirement 
Provider 
AstraZeneca  
AstraZeneca 
IP  Investigational product 
*3 mg verinurad capsules will only be used for down-titration for patients on the new dosing regimen as of 
Protocol Version 5.0. 
**Patients on 24 mg verinurad need to take two 12-mg verinurad capsules.  To match, patients in the other 
treatment arms must take 2 capsules to maintain the blind.  Patients will be given two different bottles with 
differently coloured labels.  Patients will be instructed to take one capsule from each of two different bottles 
every day.  Patients who do not tolerate the new dosing regimen will be down-titrated to the initial dosing 
regimen (ie, patients on 24 mg will be down-titrated to 3 mg, and patients in other cohorts will not be dispensed 
the matching placebo capsule). 
 
The verinurad capsules release verinurad over 8 h, hence the formulation is referred to as ER8 
(Extended Release over 8 h). 


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Study treatments will be titrated in discrete steps as shown in Table 8.  Titration steps will be 
spaced at 4-week (±1 week) intervals to minimise the risk of skin reactions to allopurinol.  
Patients unable to tolerate the stepped dosage may be down-titrated only by reversing the 
assigned steps within treatment group, and verinurad and allopurinol dosages cannot be 
unpaired from the titration schedule.  Patients who cannot tolerate the step-1 dose will be 
discontinued from IP and be followed for the remainder of the study. 
At Visit 5 (approximately 8 weeks after randomisation) through Visit 9, titration to step-3 
target dose will only be allowed if the patient’s eGFR was ≥30 mL/min/1.73m2 at Visits 3 and 
4. 
When the new dosing regimen is introduced under Protocol Version 5.0, patients who were 
down-titrated due to intolerance in the initial dosing regimen will not switch treatment to the 
new dosing regimen.  These patients will instead remain on the same treatment after Visit 9.  
Patients who do not tolerate the new dosing regimen will be down-titrated to the initial dosing 
regimen (ie, patients on 24 mg will be down-titrated to 3 mg, and patients in other cohorts will 
not be dispensed the matching placebo capsule). 
Patients will only be allowed to switch to the new dosing regimen introduced under Protocol 
Version 5.0 if the patient’s eGFR was ≥30 mL/min/1.73m2 at Visit 8.  Management of patients 
with eGFR <30 mL/min/1.73m2 at Visit 9 should be discussed with the medical monitor. 
In case patient down-titration was done in error, the patient can be up-titrated only after 
consultation with the medical monitor. 
Table 8 
Titration schedule 
 
Step 1 - titration 
(verinurad/allopurinol) 
Step 2 - titration 
(verinurad/allopurinol) 
Step 3 - target dose 
(verinurad/allopurinol) 
High Dose (mg) 
3/100 
7.5/200 
12/300 
Intermediate Dose (mg) 
3/100 
7.5/200 
7.5/300 
Low Dose (mg) 
3/100 
3/200 
3/300 
Allopurinol alone (mg) 
0/100 
0/200 
0/300 
Placebo (mg) 
0/0 
0/0 
0/0 
 
6.2 
Preparation/handling/storage/accountability 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported 
and resolved before use of the study treatment. 


Cli nical St u d y Pr ot oc ol - 5. 0  
Astra Ze neca  
Veri n ura d / R D E A 3 1 7 0  - D 5 4 9 5 C 0 0 0 0 2  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
5 7  of 1 2 2  
 
O nl y patie nts e nr olle d i n t he st u d y ma y recei ve st u d y treat me nt a n d o nl y a ut h orise d site staff 
ma y s u p pl y or a d mi nister st u d y treat me nt.  All st u d y treat me nts m ust be st ore d i n a sec ure, 
e n vir o n me ntall y c o ntr olle d, a n d m o nit ore d ( ma n u al or a ut o mate d) area i n acc or da n ce wit h t he 
la belle d st ora ge c o n diti o ns wit h access li mite d t o t he i n vesti gat or a n d a ut h orise d site staff. 
A f or mal s yste m f or dr u g acc o u nta bilit y will be i m ple me nte d.  T he i n vesti gat or, i nstit uti o n, or 
t he hea d of t he m e dical i nstit uti o n ( w here a p plica ble) is res p o nsi ble f or st u d y treat me nt 
acc o u nta bilit y, rec o nciliati o n, a n d rec or d m ai nte na nce (ie, recei pt, rec o n ciliati o n, a n d fi nal 
dis p ositi o n rec or ds). 
6. 3  
Me as ures t o mi ni mise bi as: r a n d o mis ati o n a n d bli n di n g  
All patie nts will be ce ntr all y assi g ne d t o ra n d o mise d st u d y trea t me nt usi n g a n I V R S/I W R S.  
Bef ore t he st u d y is i nitiate d, t he tele p h o ne n u m b er a n d call-i n directi o ns f or t he I V R S a n d/ or 
t he l o g-i n i nf or m ati o n a n d directi o ns f or t he I W R S will be pr o vi de d t o eac h site. 
Patie nts w h o meet t he eli gi bilit y criteria will be r a n d o mise d i n a 1: 1: 1: 1: 1 rati o t o hi g h, 
i nter me diate or l o w d ose of veri n ura d pl us all o p uri n ol, all o p uri n ol or place b o. 
 
 
 
 
La b orat or y re p orts f or s U A a n d U A C R will be mas ke d t o g uar d a gai nst re veali n g gr o u p 
differe n ces i n treat me nt e n d p oi nts e x ce pt d uri n g pre- scree ni n g a n d scree ni n g.  T he ce ntral 
la b orat or y will iss ue n otificati o ns t o st u d y sites if s U A or U A C R val ues i n dicate p ote ntial 
healt h c o ncer ns. 
If a patie nt wit h dr a ws fr o m t he st u d y, t he n his/ her e nr ol me nt/ra n d o misati o n c o de ca n n ot be 
re use d.  Wit h dra w n patie nts will n ot be re place d. 
T he I V R S/I W R S will pr o vi de t o t he i n vesti gat or(s) or p har macists t he kit i de ntificati o n 
n u m ber t o be all ocat e d t o t he patie nt at t he dis pe nsi n g visit.  R o uti nes f or t his will be 
descri be d i n t he I V R S/I W R S user ma n ual t hat will be pr o vi de d t o eac h ce ntre.  F or p atie nts 
w h o nee d d o w n titrati o n, t he i n vesti gat or will nee d t o use t he I V R S/I W R S f or all ocati o n of 
ne w st u d y dr u g kits f or t he l o wer d ose. 
T he ra n d o misati o n c o de s h o ul d n ot be br o ke n e x ce pt i n me dical e mer ge nci es w he n t he 
a p pr o priate m a na ge me nt of t he patie nt re q uires k n o wle d ge of t he treat me nt ra n d o misati o n.  
T he i n vesti gat or d oc u me nts a n d re p orts t he acti o n t o Astra Ze neca, wit h o ut re veali n g t he 
treat me nt gi ve n t o patie nt t o t he Astra Ze neca staff. 
C CI


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AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an IP and that potentially require expedited reporting to 
regulatory authorities.  Randomisation codes will not be broken for the planned analyses of 
data until all decisions on the evaluability of the data from each individual patient have been 
made and documented. 
The IVRS/IWRS will be programmed with blind-breaking instructions.  The blind may be 
broken if, in the opinion of the investigator, it is in the patient’s best interest for the 
investigator to know the study treatment assignment.  The sponsor must be notified before the 
blind is broken unless identification of the study treatment is required for a medical 
emergency in which the knowledge of the specific blinded study treatment will affect the 
immediate management of the patient’s condition (eg, antidote available).  In this case, the 
Sponsor must be notified within 24 h after breaking the blind.  The date and reason that the 
blind was broken must be recorded in the source documentation and case report form (CRF) 
(electronic or paper), as applicable. 
Study unblinding should not occur until database lock and all decisions on the evaluability of 
the data from each individual patient have been made and documented. 
Individual treatment codes, indicating the treatment randomisation for each randomised 
patient, will be available to the personnel analysing the PK samples. 
Provisions for interim analysis are described in Section 9.5. 
6.4 
Treatment compliance 
Any change from the dosing schedule, dose interruptions, dose reductions, or dose 
discontinuations should be recorded in the eCRF. 
The investigator is responsible for management of the IP from receipt by the study site until 
the destruction or return of all unused IP.  The investigator(s) is responsible for ensuring that 
the patient has returned all unused IP.  For the new dosing regimen, following Protocol 
Version 5.0 implementation, patients will be instructed thoroughly and receive new dosing 
card instructions at Visit 9.  They will be instructed to take 1 tablet daily from one bottle of 
allopurinol/matching placebo and 1 capsule daily from each of two verinurad/matching 
placebo bottles that will be differentiated by the label colour. 
Treatment compliance:  The patient will be asked about compliance at each study visit starting 
from Visit 4 onwards.  When study medication is returned, compliance will be assessed based 
upon patient’s interview and a count of the tablets returned.  Compliance should be between 
≥80% and ≤100% of that prescribed.  If the patient is not compliant with recording study drug 
doses during the study, then the period of non-compliance should be noted as a protocol 
deviation and the sponsor should be notified.  Patients judged to be non-compliant may 


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continue in the study, but should be counselled on the importance of taking their study 
medication and applicable ancillary medications as prescribed.  The investigator (or designee) 
will record the amounts of study medication dispensed and returned at each visit as described 
in Table 1 and Table 2, as well as document reasons for non-compliance in the source 
document.  The dates of all study medication dosing, including interruptions, missed doses, or 
overdose, must be recorded on the eCRF.  The administration of all study medications 
(including IPs) should be recorded in the appropriate sections of the eCRF. 
6.5 
Concomitant therapy 
Any medication or vaccine including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements that the patient is receiving at the time of enrolment or receives 
during the study must be recorded along with: 
• 
Reason for use 
• 
Dates of administration including start and end dates 
• 
Dosage information including dose and frequency 
 
An increased risk of hypersensitivity has been reported when allopurinol is given with 
ampicillin, amoxicillin, ACE inhibitors, or diuretics, in particular thiazides, especially in renal 
impairment.  It is recommended that in patients receiving allopurinol an alternative therapy is 
used where available. 
Table 9 
Restricted medications 
Medication/class of drug: 
Usage (including limits for duration permitted and 
special situations in which it is allowed): 
Treatments known to lower albuminuria should be 
stable (consistent dosing for at least 4 weeks), eg, 
ACEi, ARBs, mineralocorticoid receptor 
antagonists, or sodium-glucose linked transporter-2 
inhibitors. 
Proteinuria-lowering therapies must not be started, and 
doses not changed, between screening and the end of the 
treatment period of the study unless required for patient 
safety.  Patients on stable doses at study entry should 
continue on the same doses. 
Any medication restricted by the allopurinol 
package insert; eg, vidarabine, uricosuric drugs 
such as probenicid and large doses of salicylate, 
chlorpropamide, warfarin, coumarin anticoagulants, 
phenytoin, theophylline, amoxicillin, ampicillin, 
cytostatics such cyclophosphamide, doxorubicin, 
bleomycin, procarbazine and alkyl halogenides, 
ciclosporin, didanosine, furosemide and other 
thiazide diuretics, ACEi, aluminium hydroxide. 
Use in accordance with the allopurinol package insert.  
Case reports suggest concomitant ACEi therapy (eg, 
captopril and enalapril) enhance the risk of allopurinol-
related hypersensitivity reactions.  Hypersensitivity 
reactions can occur in the absence of ACEi therapy as in 
the presence of diuretics and renal dysfunction. 
ACEi  Angiotensin-converting enzyme inhibitor; ARBs  Angiotensin receptor blockers 
 






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6.7 
Treatment after the end of the study 
After the end of the study patients can be treated with uric acid lowering therapy and/or other 
therapies for CKD or other conditions requiring treatment at the responsible physician’s 
discretion. 
7 
DISCONTINUATION OF TREATMENT AND PATIENT 
WITHDRAWAL  
7.1 
Discontinuation of study treatment  
Patients may be discontinued from IP in the following situations.  Note that discontinuation 
from study treatment is NOT the same as a complete withdrawal from the study. 
• 
Patient decision.  The patient is at any time free to discontinue treatment, without 
prejudice to further treatment 
• 
Adverse event 
• 
Severe non-compliance with the Clinical Study Protocol  
• 
Skin reactions and hypersensitivity 
− 
Study drug should be discontinued immediately at the first sign of a skin rash or other 
signs which may indicate an allergic reaction.  Skin rash is a commonly-reported AE 
in patients taking allopurinol.  Skin reactions may be severe and can be fatal. 
− 
Extra vigilance for the signs of hypersensitivity syndrome or Stevens-Johnson 
syndrome / toxic epidermal necrolysis is required and the patient should be informed 
of the need to stop treatment immediately and permanently at the first appearance of 
symptoms. 
• 
Development of signs/symptoms of nephrolithiasis or potential renal injury 
− 
Guidelines for assessing possible renal injury or kidney stone and altering treatment 
are in Appendix F 
• 
Development of AST or ALT ≥3xULN together with total bilirubin ≥2xULN as described 
in Section 8.3.8 and Appendix E  
• 
If a patient becomes pregnant during the course of the study, the IP should be 
discontinued immediately and an AstraZeneca representative notified. 
 
Patients who discontinue IP will be recommended to continue on the study and follow the 
original visit schedule without taking IP. 
See the SoA for data to be collected at the time of treatment discontinuation and follow-up 
and for any further evaluations that need to be completed. 


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7.1.1 
Temporary interruption of study treatment 
Patients may temporarily interrupt IP administration, for instance based on criteria for 
Appendix F.  Temporary interruption of IP does not mean discontinuation of follow-up or 
termination of study participation.  Study assessments should continue.  When the IP is 
resumed, last dose taken should be administered again.  If temporary interruption of IP 
occurred during titration step, the patient should resume titration with the last tolerable dose 
given.  In the event of an interruption exceeding 1 month the administration of IP can be 
re-titrated to avoid allopurinol induced hypersensitivity reactions, after communication with 
the sponsor or sponsor’s representative. 
7.1.2 
Study termination 
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. 
The study may be stopped if, in the judgment of AstraZeneca, trial patients are placed at 
undue risk because of clinically significant findings that: 
• 
Meet individual stopping criteria or are otherwise considered significant 
• 
Are assessed as causally related to study drug 
• 
Are not considered to be consistent with continuation of the study 
 
Regardless of the reason for termination, all data available for the patient at the time of 
discontinuation of follow-up must be recorded in the CRF. 
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the patients’ interest. 
7.1.3 
Procedures for early discontinuation of study treatment 
The investigator should instruct the patient to contact the site before or at the time if study 
treatment is stopped.  A patient who decides to discontinue study treatment will always be 
asked about the reason(s) and the presence of any AEs.  The date of last intake of study 
treatment should be documented in the CRF (electronic or paper).  All study treatment should 
be returned by the patient at their next on-site study visit or unscheduled visit.  Patients 
permanently discontinuing study treatment should be given locally available standard of care 
therapy, at the discretion of the investigator. 
Patients who discontinue study treatment will attend the end of treatment visit as soon as 
possible after treatment discontinuation.  Discontinuation of study treatment, for any reason, 
does not impact on the patient´s participation in the study.  The patient should continue 
attending subsequent study visits and data collection should continue according to the study 
protocol (including a follow-up visit, but no need to do another end of treatment visit).  If the 


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patient does not agree to continue in-person study visits, a modified follow-up must be 
arranged to ensure the collection of endpoints and safety information.  This could be a 
telephone contact with the patient, a contact with a relative or treating physician, or 
information from medical records.  The approach taken should be recorded in the medical 
records.  A patient who agrees to modified follow-up is not considered to have withdrawn 
consent or to have withdrawn from the study. 
If a patient becomes pregnant during the course of the study, IP should be discontinued 
immediately and an AstraZeneca representative notified. 
7.2 
Lost to follow-up 
A patient will be considered potentially lost to follow-up if he or she fails to return for 
scheduled visits and is unable to be contacted by the study site.   
The following actions must be taken if a patient fails to return to the clinic for a required study 
visit: 
• 
The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible and counsel the patient on the importance of maintaining the assigned visit 
schedule. 
• 
Before a patient is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the patient or next of kin by, eg, repeat telephone calls, 
certified letter to the patient´s last known mailing address or local equivalent methods.  
These contact attempts should be documented in the patient’s medical record. 
• 
Efforts to reach the patient should continue until the end of the study.  Should the patient 
be unreachable at the end of the study, the patient should be considered to be lost to 
follow-up with unknown vital status at end of study. 
 
7.3 
Withdrawal from the study 
A patient may withdraw from the study (eg, withdraw consent), at any time (IP and 
assessments) at his/her own request, without prejudice to further treatment. 
A patient who considers withdrawing from the study must be informed by the investigator 
about modified follow-up options (eg, telephone contact, a contact with a relative or treating 
physician, or information from medical records).  Circumstances of withdrawal will be 
documented either in writing by patient (ICF re-signature) or investigator. 
If the patient withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
If a patient withdraws from the study, he/she may request destruction of any samples taken, 
and the investigator must document this in the site study records. 


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A patient who withdraws consent will always be asked about the reason(s) and the presence of 
any AE.  The investigator will follow up patients as medically indicated. 
Patients who fail to meet the eligibility criteria must not, under any circumstances, be 
randomised or receive IP.  There can be no exceptions to this rule. 
Where a patient does not meet all the eligibility criteria but is randomised in error, or 
incorrectly started on treatment, the investigator should inform the AstraZeneca study 
physician or representative immediately, and a discussion should occur between the 
AstraZeneca study physician and the investigator regarding whether to continue or discontinue 
the subject from treatment.  The AstraZeneca study physician or representative must ensure all 
decisions are appropriately documented. 
In those cases where continuation of study therapy is judged not to present a concern related 
to safety and disease management, the rationale for continuing study therapy must be clearly 
documented.  The patient should continue follow-up in accordance with defined study 
procedures. 
See SoA, Table 1 for data to be collected at the time of study discontinuation and follow-up 
and for any further evaluations that need to be completed.  All study treatment should be 
returned by the patient. 
8 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarised in the SoA. 
The investigator ensures the accuracy, completeness, legibility, and timeliness of the data 
recorded and of the provision of answers to data queries according to the Clinical Study 
Agreement.  The investigator will sign the completed eCRFs.  A copy of the completed eCRFs 
will be archived at the study site. 
Immediate safety concerns should be discussed with the sponsor upon occurrence or 
awareness to determine if the patient should continue or discontinue study treatment. 
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential patients 
meet all eligibility criteria.  The investigator will maintain a screening log to record details of 
all patients screened and to confirm eligibility or record reasons for screening failure, as 
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T he ma xi m u m a m o u nt of bl o o d c ollecte d fr o m eac h patie nt o ver t he d urati o n of t he st u d y, 
i ncl u di n g a n y e xtra assess me nts t hat ma y be re q uired, will n ot e x cee d 4 0 0 m L.  Re peat or 
u nsc he d ule d sa m ples ma y be t a ke n f or safet y reas o ns or f or tec h ni cal iss ues wit h t he sa m ples. 
8. 1  
Effic ac y assess me nts  
La b orat or y efficac y assess me nts are s h o w n i n  Ta bl e 1 1. 
T a ble  1 1  
L a b or at or y effic ac y v ari a bles  
U A C R  
Cli nic al c he mistr y (ser u m or pl as m a)  
U- Al b u mi n ( m g/ d L) a 
U- Creati ni ne ( g/ d L) a 
S- Uric Aci d ( m g/ d L) b 
S- Creati ni ne ( m g/ d L) b 
S- C ystati n C ( m g/ L) b 
S/ P -N T -pr o B N P  
a 
F or deri vati o n of U A C R ( pri mar y o utc o me varia ble)  
b 
Sec o n dar y o utc o me varia bles  
N T -pr o B N P  N -ter mi nal pr o-brai n natri uretic pe pti de  
 
Uri ne sa m ples will be gat here d as 3 c o nsec uti ve dail y m or ni n g v oi d s a m ples of uri ne f or eac h 
visit.  
8. 1. 1  
Pri m ar y o u tc o me - U A C R 
T he rati o of uri n ar y al b u mi n t o uri nar y creati ni ne ( milli gra ms of al b u mi n p er gra ms of 
creati ni ne) will be assess e d  b y a ce ntral la b orat or y.  T he mea n rati o will be re p orte d f or eac h 
ti me p oi nt base d o n all sa m ples c ollecte d ( F M V sa m ple 1, 2, a n d 3 ). 
First m or ni n g v oi d uri n e sa m ples will be use d f or assess me nt of U A C R.  Patie nts will recei ve 
a uri ne sa m ple c ollecti o n kit all o wi n g t he m t o c ollect t he first m or ni n g v oi d uri ne o n 3 
c o nsec uti ve da ys.  C ollecte d sa m ples will be refri gerate d u ntil t h e y ca n be br o u g ht t o t he 
st u d y site f or f urt her pr ocessi n g i n acc or d a nce wit h t he la b orat or y ma n u al.  I d eall y t he uri ne 
sa m ples s h o ul d be c ollecte d 2 da ys bef ore, t he da y bef ore a n d o n t he da y of a st u d y visit t o 
mi ni mise st ora ge a n d tra ns p ortati o n of c ollecte d s a m ples.  
If a patie nt h as f or g otte n t o c ollect o ne or m ore of t he sa m ples bef ore a visit, t he n t he sa m ples 
s h o ul d be c ollecte d o n t h e u p-t o- 3 c o ns ec uti ve da ys f oll o wi n g t he visit i nstea d ( wit h e x ce pti o n 
f or t he ra n d o misati o n visit uri ne sa m ples, w hich m ust be c ollecte d bef ore treat me nt is starte d).  
I n t he a bse n ce of res ults fr o m 3 a nal yse d s a m ples, t he U A C R f or a ti me p oi nt will be 
calc ulate d b ase d o n t he a vaila ble res ults.  
Uri ne sa m ples c ollecte d f or assess me nt of U A C R 
 m ust n ot be 
c o nf use d wit h uri nal ysis sa m ples c ollecte d at st u d y site d uri n g visits f or assess me nt of safet y 
para meters a n d pr e g na n c y testi n g.  
C CI


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8. 1. 2  
Sec o n d ar y o utc o mes 
Sec o n dar y o utc o me m eas ures of r e nal f u ncti o n i ncl u de: 
•  
e G F R calc ulate d usi n g t h e C K D -E PI f or m ula as pre vi o usl y p u blis he d ( Le ve y et al 2 0 0 9 ).  
Details of t he met h o d ar e prese nte d i n  A p p e n di x F 
•  
Ser u m c yst ati n C  
•  
Ser u m creati ni ne  
 
Sec o n dar y o utc o me m eas ures f or ge neral meta b olic effects i ncl u de:  
•  
s U A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI


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See Table 14 for the list of clinical safety laboratory tests to be performed and to the SoA for 
the timing and frequency.  All protocol-required laboratory assessments, as defined in the 
table, must be conducted in accordance with the laboratory manual and the SoA.   
The investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities.  The laboratory results should be signed and dated and retained at the 
centre as source data for laboratory variables. 
For information on how AEs based on laboratory tests should be recorded and reported, see 
Section 8.3.7. 
Additional safety samples may be collected and analysed by a central laboratory if clinically 
indicated at the discretion of the investigator.  The date of collection will be recorded on the 
appropriate CRF. 
Table 14 
Laboratory safety variables 
Haematology/Haemostasis (whole blood) 
Clinical Chemistry (serum or plasma) 
B-Haemoglobin (Hb) 
S/P-Bilirubin, total 
B-Leukocyte count 
S/P-Alkaline phosphatase (ALP) 
B-Leukocyte differential count (absolute count) 
S/P-Aspartate transaminase (AST) 
B-Platelet count 
S/P-Alanine transaminase (ALT) 
B-Haematocrit 
S/P-Albumin 
B-Haemoglobin A1c 
S/P-Potassium 
B-Red blood cell count (RBC) 
S/P-Calcium, total 
B-Mean corpuscular hemoglobin (MCH) 
S/P-Sodium 
B- Mean corpuscular hemoglobin concentration 
(MCHC) 
S/P-Creatine kinase (CK) 
B-Red blood cell morphology 
S/P-Bicarbonate 
B-Mean corpuscular volume (MCV) 
S/P-Blood Urea Nitrogen 
 
S/P-Phosphate 
Urinalysis (dipstick) 
S/P-Creatinine 
U-Hb/Erythrocytes/Blood 
 
U-Glucose 
 
Note: If a patient shows an AST or ALT ≥3xULN together with total bilirubin ≥2xULN, refer to Appendix E 
‘Actions required in cases of increases in liver biochemistry and evaluation of Hy’s Law’, for further 
instructions. 
If a patient shows a creatinine value outside the normal range, refer to Appendix F ‘Actions required in cases of a 
renal-related or kidney stone treatment-emergent adverse event or a serum creatinine elevation’ for further 
instructions.  
 


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8.2.2 
Physical examinations 
Physical examination will be performed at timelines as specified in the SoA.  Full physical 
examinations will include an assessment of the following: general appearance, respiratory, 
CV, abdomen, and musculoskeletal (including spine and extremities) systems, and the skin.  
Brief physical examinations are to be utilised by the investigator based on clinical 
observations and symptomatology, but must include an assessment of the patients’ skin.  
Investigators should pay special attention to clinical signs related to previous serious illnesses; 
new or worsening abnormalities may qualify as AEs, see Section 8.3.7 for details. 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE unless unequivocally 
related to the disease under study. 
8.2.3 
Vital signs 
Temperature, pulse rate, and blood pressure will be assessed. 
Blood pressure and pulse measurements will be assessed with a completely automated device 
with the patient in a seated position.  Manual techniques will be used only if an automated 
device is not available. 
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for 
the patient in a quiet setting without distractions (eg, television, cell phones). 
Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse and 
3 blood pressure measurements (3 consecutive blood pressure readings will be recorded at 
intervals of at least 1 minute).  The average of the 3 blood pressure readings will be recorded 
on the CRF. 
8.2.4 
Electrocardiograms 
A 12-lead ECG will be performed after the patient has been lying down for 5 minutes at the 
times indicated in the SoA.  The ECG assessment (normal, abnormal but not clinically 
significant, or abnormal and clinically significant; and QT interval, QTcF) will be recorded in 
the CRF.  Any clinically significant findings should be reported as AEs or in the Medical 
History, as appropriate. 
8.3 
Collection of adverse events 
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section 
The definitions of an AE or SAE can be found in Appendix B. 


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An AE will be reported by the patient (or, when appropriate, by a caregiver, surrogate, or the 
patient's legally authorised representative).   
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE.  For information on how to follow up on 
AEs, see Section 8.3.3.   
8.3.1 
Method of detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended and 
non-leading verbal questioning of the patient is the preferred method to inquire about 
AE occurrences.   
8.3.2 
Time period and frequency for collecting AE and SAE information  
Serious adverse events will be collected from the time of signature of the ICF, throughout the 
treatment period and including the follow-up period and last contact.  Adverse events will be 
collected from the time of the first dose of IP.  Changes in medical history between the time of 
signature of the ICF and the first dose of IP will be reported as medical history. 
All SAEs will be recorded and reported to the sponsor or designee within 24 h, as indicated in 
Appendix B.  The investigator will submit any updated SAE data to the sponsor within 24 h of 
it being available. 
Investigators are not obligated to actively seek AE or SAE in former study patients.  However, 
if the investigator learns of any SAE, including a death, at any time after a patient’s last visit 
and he/she considers the event to be reasonably related to the study treatment or study 
participation, the investigator may notify the sponsor. 
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Appendix B. 
8.3.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each patient 
at subsequent visits/contacts.  All AEs will be followed until resolution, stabilisation, the 
event is otherwise explained, or the patient is lost to follow-up  
Any AEs that are unresolved at the patient’s last AE assessment in the study are followed up 
by the investigator for as long as medically indicated, but without further recording in the 
CRF.  AstraZeneca retains the right to request additional information for any patient with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 


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8.3.4 
Adverse event data collection 
'The following variables will be collected for each AE; 
• 
AE (verbatim) 
• 
The dates when the AE started and stopped 
• 
Maximum intensity 
• 
Whether the AE is serious or not 
• 
Investigator causality rating against the IP(s) (yes or no) 
• 
Action taken with regard to IP(s) 
• 
Select the appropriate as required: AE caused patient’s withdrawal from study (yes or no) 
• 
Outcome. 
 
In addition, the following variables will be collected for SAEs: 
• 
Date AE met criteria for serious AE 
• 
Date investigator became aware of serious AE 
• 
AE is serious due to 
• 
Date of hospitalisation 
• 
Date of discharge 
• 
Probable cause of death 
• 
Date of death 
• 
Autopsy performed 
• 
Causality assessment in relation to study procedure(s) 
• 
Causality assessment to other medication' 
 
8.3.5 
Causality collection 
The investigator will assess causal relationship between IP 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 and study procedures.  
Note that for SAEs that could be associated with any study procedure, the causal relationship 
is implied as ‘yes’. 
A guide to the interpretation of the causality question is found in Appendix B to this Clinical 
Study Protocol. 


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8.3.6 
Adverse events based on signs and symptoms 
All AEs spontaneously reported by the patient or reported in response to the open question 
from the study site staff: ‘Have you had any health problems since the previous visit?’, or 
revealed by observation will be collected and recorded in the CRF.  When collecting AEs, the 
recording of diagnoses is preferred (when possible) to recording a list of signs and symptoms.  
However, if a diagnosis is known and there are other signs or symptoms that are not generally 
part of the diagnosis, the diagnosis and each sign or symptom will be recorded separately. 
8.3.7 
Adverse events based on examinations and tests 
The results from the Clinical Study Protocol mandated laboratory tests and vital signs will be 
summarised in the Clinical Study Report (CSR).  Deterioration as compared to baseline in 
protocol-mandated laboratory values or vital signs should therefore only be reported as AEs if 
they fulfil any of the SAE criteria, are the reason for discontinuation of treatment with the IP, 
or qualify as AEs of interest. 
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information.  Wherever possible, the reporting investigator 
uses the clinical, rather than the laboratory term (eg, anaemia versus low haemoglobin value).  
In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-
mandated parameters should be reported as AE(s). 
8.3.8 
Hy’s Law 
Cases where a patient shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥3xULN together with total bilirubin ≥2xULN may need to 
be reported as SAEs.  Please refer to Appendix E for further instruction on cases of increases 
in liver biochemistry and evaluation of Hy’s Law 
8.3.9 
Adverse events of special interest 
AEs of major CV events and acute changes in serum creatinine values which are clinically 
significant will be included as AEs of special interest in this study.  To ensure that data on 
increased serum creatinine values are collected systematically, data will be recorded in the 
eCRF. 
8.4 
Safety reporting and medical management 
8.4.1 
Reporting of serious adverse events 
All SAEs must be reported, whether or not considered causally related to the IP, or to the 
study procedure(s).  All SAEs will be recorded in the CRF. 


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If any SAE occurs in the course of the study, then investigators or other site personnel inform 
the appropriate AstraZeneca representatives within 1 day; ie, immediately, but no later than 
24 h of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar 
days of initial receipt for all other SAEs. 
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately.  Investigators or other site personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within 1 calendar day; ie, immediately, but no later than 24 h of when he or she becomes 
aware of it. 
Once the investigators or other site personnel indicate an AE is serious in the electronic data 
capture (EDC) system, an automated email alert is sent to the designated AstraZeneca 
representative. 
If the EDC system is not available, then the investigator or other study site staff reports an 
SAE to the appropriate AstraZeneca representative by telephone. 
The AstraZeneca representative will advise the investigator/study site staff how to proceed.   
Investigators or other site personnel send relevant CRF modules by fax to the designated 
AstraZeneca representative. 
For further guidance on the definition of an SAE, see Appendix B of this Clinical Study 
Protocol. 
8.4.2 
Pregnancy 
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except for: 
• 
If the pregnancy is discovered before the study patient has received any study drug 
• 
Pregnancy in a partner to the study subject 
 
If a pregnancy is reported, the investigator should inform the sponsor within 24 h of learning 
of the pregnancy. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, foetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 


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8.4.2.1 
Maternal exposure 
If a patient becomes pregnant during the course of the study, all study drugs should be 
discontinued immediately. 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study 
may have interfered with the effectiveness of a contraceptive medication.  Congenital 
abnormalities/birth defects and spontaneous miscarriages should be reported and handled as 
SAEs.  Elective abortions without complications should not be handled as AEs.  The outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth or congenital abnormality) should be followed up and documented even if the patient 
was discontinued from the study. 
If any pregnancy occurs in the course of the study, then the investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1 day; ie, immediately but no 
later than 24 h of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for SAEs (see Section 8.4.1) and within 30 days for all other pregnancies. 
The same timelines apply when outcome information is available. 
The PREGREP module in the CRF is used to report the pregnancy and the PREGOUT module 
is used to report the outcome of the pregnancy. 
8.4.3 
Overdose 
For this study, any dose of verinurad or allopurinol greater than those specified in this 
protocol within the same day will be considered an overdose.  If an overdose is suspected, the 
patient should be closely monitored, and treatment should consist of observation and general 
support measures, including adequate hydration.  If considered necessary, haemodialysis may 
be used for allopurinol. 
• 
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the CRF and on the Overdose CRF module. 
• 
An overdose without associated symptoms is only reported on the Overdose CRF module 
 
If an overdose on an AstraZeneca study drug occurs in the course of the study, then the 
investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, or no later than 24 h of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site. 


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• 
For overdoses associated with an SAE, the standard reporting timelines apply, see Section 
8.3.2.  For other overdoses, reporting must occur within 30 days. 
 
8.4.4 
Medication error 
If a medication error occurs in the course of the study, then the investigator or other site 
personnel informs the appropriate Covance representatives within 1 day; ie, immediately but 
no later than 24 h of when he or she becomes aware of it. 
The designated Covance representative works with the investigator to ensure that all relevant 
information is completed within 1 (Initial Fatal/Life-Threatening or follow up Fatal/Life-
Threatening) or 5 (other serious initial and follow-up) calendar days if there is an SAE 
associated with the medication error (see Section 8.3.2) and within 30 days for all other 
medication errors. 
The definition of a Medication Error can be found in Appendix B. 
8.4.5 
Management of IP-related toxicities 
Study drug should be discontinued immediately at the first sign of a skin rash or other signs 
which may indicate an allergic reaction, and patients should be maintained in the study for 
safety surveillance.  In cases of intolerance (gastrointestinal, headache, or other mild AEs) 
from the combination IP, dosage will be down-titrated as described in Section 6.1. 
Patients developing renal-related or kidney stone AEs, or creatinine elevations during 
treatment should be managed in accordance with Appendix F. 
Patients developing elevated liver transaminase tests should be managed in accordance with 
Appendix E. 
8.4.6 
Data monitoring committee (DMC) 
An independent DMC will be appointed and will report to AstraZeneca and the CRO.  The 
DMC will be responsible for ensuring patient safety by assessing the safety of the IP during 
the study, and for reviewing the overall conduct of the study.  The DMC will have access to 
the individual treatment codes and be able to merge these with the collected study data while 
the study is ongoing.  
A DMC charter will be prepared to detail precise roles and responsibilities and procedures to 
ensure maintenance of the blinding and integrity of the study in the review of accumulating 
data and interactions with AstraZeneca and the CRO. 


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8.4.7 
 Clinical event adjudication committee  
The role of the clinical event adjudication committee (CEA) is to independently review, 
interpret and adjudicate potential CV events that are experienced by the patients.  CV events 
will be identified preliminarily by the investigators, and also by AZ personnel, CRO personnel 
or in the CEA process as specified in the CEA charter.  The CEA member/s will not have 
access to individual treatment codes for any patient or clinical efficacy endpoint and safety 
event. 
The Investigator’s Manual or other investigator material will specify the information to be 
collected for potential CV events. 
8.5 
Pharmacokinetics 
Whole blood samples will be collected for measurement of plasma concentrations of 
verinurad, allopurinol and oxypurinol (active metabolite of allopurinol) as specified in the 
SoA.  Instructions for the collection and handling of biological samples will be provided by 
the sponsor or analytical test site.  The actual date and time (24-hour clock time) of each 
sample and date and time (24-hour clock time) of previous dose taken will be recorded in the 
CRF (an electronic bottle cap or another method may be used to assist in capturing the 
information). 
The PK blood samples will be taken at 5 different visits: 
• 
 (Visit 6) Week 12: pre-dose; ie, visit must take place in the morning and the patient must 
take the study medication at the clinic after pre-dose PK has been taken. 
− 
A subset of at least 95 patients (19 patients per arm, considering some patients may 
terminate the study before Visit 6) will have samples taken pre-dose followed by 
post-dose blood samples within 3 to 4, 4 to 5, 5 to 6, and 8 to 9 h windows (sample 
taken at each time window). 
• 
 (Visit 7) Week 20: study medication taken at home, PK blood sample during the visit. 
• 
 (Visit 8) Week 34: study medication taken at home, PK blood sample during the visit. 
• 
 (Visit 9) Week 47: study medication taken at home, PK blood sample during the visit. 
• 
  (Visit 10) Week 60: study medication taken at home, regardless of dosing regimen, PK 
blood sample will be collected post dose during the visit. 
 
8.5.1 
Determination of drug concentration 
Samples for determination of drug concentration will be analysed by analytical test sites on 
behalf of AstraZeneca, using an appropriate bioanalytical method.  Full details of the 
analytical method used will be described in a separate bioanalytical report. 


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I n c urr e d sa m ple r e pr o d u ci bilit y a nal ysis, if a n y, will be perf or me d al o n gsi de t he bi oa nal ysis 
of t he test sa m ples.  T he res ults fr o m t he e val u ati o n will n ot be re p orte d i n t he C S R b ut 
se parat el y i n a Bi oa n al yti cal Re p ort. 
8. 5. 2  
St or a ge a n d dest r ucti o n of p h ar m ac o ki neti c s a m ples 
P har mac o ki netic ( P K) s a m ples will be dis p ose d of after t he Bi oa n al ytical Re p ort fi nalisati o n 
or si x m o nt hs after iss ua nce of t he draft Bi oa nal ytical Re p ort ( w hic h e ver is earlier), u nless 
re q ueste d f or f ut ur e a nal ys es.  Left-o v er P K sa m ples ma y b e use d f or a nal ysis of safet y, 
efficac y or bi o mar ker la b orat or y para meters if sa m ples dra w n f or t h at p ur p ose at t he sa me 
ti me p oi nt were i ns uffici e nt f or t he a n al ys es nee d e d.  
P har mac o ki netic sa m ples ma y b e dis p ose d of or d estr o ye d a n d a n o n y mise d b y p o oli n g.  
A d diti o nal a nal ys es ma y be c o n d ucte d o n t h e a n o n y mise d, p o ole d p har mac o ki netic sa m ples t o 
f urt her e v al uate a n d vali date t he a n al ytical met h o d.  A n y res ults fr o m s uc h a nal ys es ma y be 
re p orte d se p ar atel y fr o m t he C S R. 
8. 6  
P h ar m ac o d y n a mics  
N o f urt her p h ar mac o d y n a mic sa m ples, a part fr o m t h ose  descri be d a b o ve a n d i n Secti o n 8. 8 , 
will be ta ke n d uri n g t he st u d y. 
8. 7  
Ge netics  
8. 7. 1  
Assess me nt of H L A- B ge n ot y pe 
S ki n reacti o ns are t h e m ost c o m m o n reacti o ns f or all o p uri n ol, a n d rarel y m a y i n cl u de t he dr u g 
h y perse nsiti vit y s y n dr o m e, Ste ve ns –J o h ns o n s y n dr o me, a n d t o xic e pi der mal necr ol ysis.  
H L A -B * 5 8 0 1 allele is a n i m p orta nt ge n etic ris k fact or f or t h es e life-t hreate ni n g c o n diti o ns.  
H L A – B * 5 8 0 1 allele fr e q ue nc y is hi g h i n K orea n ( 1 2 %) a n d H a n C hi nese or T hai ( 6 % t o 8 %) 
c o m pare d wit h Ca u casia n ( 2 %) patie nts.  I n t his st u d y, H L A- B * 5 8 0 1 allele testi n g is 
ma n dat or y i n all patie nts pri or t o ra n d o misati o n .  If H L A- B * 5 8 0 1 allele is p ositi ve, t he patie nt 
s h o ul d n ot be i ncl u de d i n t he st u d y. 
 
 
 
 
 
 
 
 
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8. 8  
Bi o m ar kers  
Ma n dat or y c ollecti o n of sa m ples f or ot her bi o mar ker res earc h is als o part of t his st u d y.  T he 
f oll o wi n g sa m ples f or bi o mar ker r esearc h are re q uire d a n d will be c ollecte d fr o m all patie nts 
i n t his st u d y as s p ecifie d i n t he S o A a n d s h o w n i n Ta ble  1 5. 
T a ble  1 5  
Bi o m ar ker c ollecti o ns  
Uri n al ysis  
Cli nic al c he mistr y ( pl as m a)  
Pr otei n  
Uri nar y e pi der mal gr o wt h fact or  
U A  
Uri ne c reati ni ne 
Ki d ne y i nj ur y mar kers s uc h as: uri nar y ki d ne y i nj ur y 
pr otei n 1, Ne utr o p hil gelati nas e -ass ociate d li p ocali n, 
etc 
He m o d y na mics s uc h as: al d oster o ne,  
C H F bi o mar kers s uc h as: N T -pr o B N P  
I nfla m mati o n bi o mar kers s uc h as: i nterleu ki n 1 8, 
m o n oc yte c he m otactic pr otei n 1, hs C R P, etc.  
E n d ot helial f u ncti o n s uc h as: as y m metrical 
di met h ylar gi ni ne, s y m metrical di met h ylar gi ni ne, 
L- ar gi ni ne, etc  
C K D pr o gressi o n mar ker s uc h as: s ol u ble ur o ki nase -
t y pe plas mi n o ge n acti vat or rece pt or 
Ot hers s uc h as: fi br o blast gr o wt h fact or 2 3, etc  
C H F  c o n gesti ve heart fai l ure; C K D  c hr o nic ki d ne y disease; h s C R P Hi g h-se nsiti vit y C-reacti ve pr otei n; N T -
pr o B N P  N- ter mi nal pr o-brai n natri uretic pe pti de ; U A  uric a ci d   
 
Uri ne a n d bl o o d sa m ples ( plas ma) will be c ollecte d, ali q u ote d a n d a nal yse d or st ore d i n a 
bi o ba n k f or a ma xi mu m of 1 5 years fr o m t he date of t he Last Patie nt’s Last Visit, after w hic h 
t he y will be d estr o ye d.  S o me of t he pla n ne d bi o m ar ker a nal yses ma y b e perf or me d o nl y if t he 
st u d y pr o vi des e vi de nce of efficac y a n d ma y be p erf or me d i n a sta g gere d fas hi o n t o mi ni m ise 
res o urces s pe n d.  Res ults of bi o mar ker a nal yses will be iss ue d se paratel y fr o m t he C S R . 
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8.8.1 
Storage, re-use and destruction of biomarker samples 
Samples will be stored for a maximum of 15 years from the date of the Last Patient’s Last 
Visit, after which they will be destroyed.  The results of this biomarker research will be 
reported either in the CSR itself or as an addendum, or separately in a scientific report or 
publication. The results of this biomarker research may be pooled with biomarker data from 
other studies with the study drug to generate hypotheses to be tested in future research. 
8.9 
Medical resource utilisation and health economics 
Medical resource utilisation and health economics parameters are not evaluated in this study. 
8.10 
Guidelines, study assessments, and procedures during COVID-19 
pandemic 
In view of the ongoing and emerging novel coronavirus (COVID-19) pandemic spreading 
worldwide, the safety and well-being of our study participants is of primary importance.  To 
protect the safety and well-being of study participants, this section will provide guidelines on 
study assessments and procedures during this period. 
1 
Every effort should be made to follow the clinical study protocol (CSP).  Participant 
safety is paramount, and the investigator should continue to reassess the risk/benefit of 
continued study involvement for each study participant. 
2 
Investigational study sites must comply with local public health rules. 
3 
If a study participant is diagnosed with COVID-19 or is suspected to have COVID-19, 
they should follow the local area treatment and quarantine guidance. 
(a) Please accurately document all diagnoses, procedures, assessments, dosing 
interruptions, and sequelae in the eCRFs.  All AEs/SAEs should be reported in line 
with instructions for safety reporting documented in the CSP. 
(b) If a COVID-19 AE/SAE is reported, the investigator should determine whether the 
participant’s investigational product should continue, be interrupted, or stopped in 
accordance with the CSP. 
(c) Patients with confirmed or suspected COVID-19 infection with moderate to severe 
symptoms may be at risk of dehydration or hypoxia.  In case of such events the PI 
should consider IP interruption until symptoms improve. 
4 
If a study participant is unable to attend clinic visits, and/or receive study intervention, the 
site staff should keep in close contact with the study participant(s), preferably through 
telephone calls, to maintain awareness of their status. 
5 
If a patient cannot be seen on site, please consider the following options: 
(a) Conducting the visits in the patient’s home by study personnel or other trained 
professionals.  In addition, third party vendor personnel may be utilised to conduct 
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(b) Conducting the visit by phone, with urine samples, investigational product and urine 
sample collection containers shipped or otherwise transported between site and 
patient.  The collection and analysis of safety blood samples at an alternative 
healthcare facility should be considered.  Local lab results will not be collected or 
stored in the study database but will help the investigator to assess patient safety. 
(c) If labs collected for safety assessments cannot be collected for more than two 
consecutive visits between Visit 3 and Visit 7 including Visit 7 or for more than one 
visit between Visit 7 and Visit 14, the IP should be temporarily interrupted.  With the 
absence of safety labs as described in the above case, IP will not be dispensed.  
However, if it is interrupted for greater than one month, the investigator should 
discuss with the medical monitor how to re-start treatment and titrate the IP to 
maintenance treatment.  IP could be re-started during the unscheduled visits and then 
study participant should return to regular visits as per the study protocol. 
References: 
https://www.fda.gov/media/136238/download 
https://www.ema.europa.eu/en/implications-coronavirus-disease-covid-19-methodological-
aspects-ongoing-clinical-trials 
https://www.ema.europa.eu/en/news/guidance-sponsors-how-manage-clinical-trials-during-
covid-19-pandemic 
9 
STATISTICAL CONSIDERATIONS  
9.1 
Statistical hypotheses 
Three hypotheses will be included in confirmatory testing for the primary objective.  See 
Section 9.4.4 for a description of multiplicity control.  The following hypotheses will be tested 
sequentially at two-sided alpha = 0.1 (treatments refer to initial dosing regimen prior to 
Protocol Version 5.0): 
• 
Null hypothesis: No difference between high dose verinurad plus allopurinol compared to 
placebo on UACR at 6 months  
• 
Alternative hypothesis: There is a difference between high dose verinurad plus allopurinol 
compared to placebo on UACR at 6 months 
 
• 
Null hypothesis: No difference between high and intermediate dose verinurad combined 
plus allopurinol compared to allopurinol alone on UACR at 6 months  
• 
Alternative hypothesis: There is a difference between high and intermediate dose 
verinurad combined plus allopurinol compared to allopurinol alone on UACR at 6 months 
 


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• 
Null hypothesis: No difference between allopurinol alone compared to placebo on UACR 
at 6 months  
• 
Alternative hypothesis: There is a difference between allopurinol alone compared to 
placebo on UACR at 6 months 
 
No other comparisons between treatment groups for the primary and secondary objectives will 
be adjusted for multiplicity. 
9.2 
Sample size determination 
The estimated sample size of 145 patients per arm (initial dosing regimen) will yield 80% 
power to detect a 25% reduction in UACR for the high dose of verinurad + allopurinol 
compared to placebo (treatment difference of approximately -0.29 on the natural log scale) at 
the two-sided alpha level of 0.1, assuming a standard deviation of 1.0 on the natural log-scale.  
A total of 725 patients (145 patients per arm [initial dosing regimen]) must be randomised.  
The standard deviation estimate is based on the results of Study D5495C00007. 
For the MRI substudy, a sample size of 30 in each arm (initial dosing regimen) will have at 
least 80% power to detect a difference (high dose verinurad + allopurinol vs. placebo) in 
means of 0.05 in renal arterial resistive index assuming that the common standard deviation is 
0.05 with a 0.05 two-sided significance level.  The standard deviation of 0.05 is based on data 
published by Leoncini et al 2002. 
9.3 
Populations for analyses 
For purposes of analysis, the following populations are defined in Table 16: 
Table 16 
Analysis populations 
Population 
Description 
Enrolled  
All patients who sign the main ICF 
Randomised set 
All patients who are randomised 
Full Analysis Set 
All randomised patients 
PPS 
The per-protocol analysis set is a subset of the Full Analysis Set consisting 
of all patients who do not violate the terms of the protocol in a way that may 
affect the primary efficacy endpoint significantly.  All decisions to exclude 
patients from the per-protocol analysis set will be made prior to the un-
blinding of the study. 
Efficacy analysis set 
Full analysis set 
Safety analysis set 
All patients  who had at least 1 dose of IP. 
PK set 
All patients who received allopurinol and verinurad treatment and have at 
least one post-dose plasma concentration measurement of verinurad at a 
scheduled time point 
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treatment discontinuation.  In other words, post-discontinuation data will be collected and 
included in the primary analysis.  Details on how to handle missing data will be provided in 
the SAP. 
In addition to analysis of the hypotheses in Section 9.1, the primary efficacy variable will be 
analysed comparing (initial dosing regimen): 
• 
Intermediate dose verinurad plus allopurinol with placebo 
• 
Low dose verinurad plus allopurinol with placebo 
• 
High dose verinurad plus allopurinol with allopurinol alone 
• 
Intermediate dose verinurad plus allopurinol with allopurinol alone 
• 
Low dose verinurad plus allopurinol with allopurinol alone 
 
The analysis of change in UACR from baseline to Week 34 will be conducted on the natural 
log-transformed UACR values using a repeated measures mixed model. 
The analysis model will include the fixed categorical effects of treatment, week, DM status 
yes or no, microalbuminuria or macroalbuminuria, NT-proBNP < or ≥360 pg/mL, use of 
SGLT2 yes or no, and treatment-by-week interaction as well as the continuous fixed 
covariates of baseline log(UACR) and baseline log(UACR) by-week interaction.  An 
unstructured matrix for the within patient error variance-covariance will be used.  The 
denominator degrees of freedom will be calculated according to the Kenward-Roger method.  
A number of back-up models will be defined in the SAP in case of non-convergence of the 
preferred model or other issues. 
The least squared mean change from baseline to 6 months in the log-transformed UACR will 
be calculated by treatment with its 95% confidence intervals.  The least squared mean 
difference between the treatments will be calculated with its 95% confidence interval.  
P-values of the treatment differences between active treatment group and placebo/comparator 
will also be calculated. 
The above least squared mean change from baseline (and the 95% confidence interval) for 
each treatment will be exponentiated to yield the geometric mean ratio from baseline for each 
treatment with its 95% confidence interval at the original scale of UACR.  The least squared 
mean difference between the active treatments and placebo/comparator (and its 95% 
confidence interval) will also be exponentiated to yield the geometric mean ratio between the 
2 treatments at each visit and its 95% confidence interval at the original scale of UACR.  
Percent change from baseline will be derived from the geometric estimated mean ratio by 
([geometric mean ratio] - 1) × 100%. 


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9. 4. 2. 2  
Sec o n d ar y effic ac y a n al yses 
F or t he sec o n dar y varia bl es at 6 m o nt hs, t he f oll o wi n g c o m p aris o ns will be ma de  (i nitial 
d osi n g re gi me n): 
•  
Hi g h d ose v eri n ur a d pl us all o p uri n ol wit h place b o 
•  
I nter me diate d os e veri n ura d pl us all o p uri n ol wit h place b o 
•  
L o w d os e veri n ur a d pl us all o p uri n ol wit h place b o 
•  
Hi g h d ose v eri n ur a d pl us all o p uri n ol wit h all o p uri n ol al o ne 
•  
I nter me diate d os e veri n ura d pl us all o p uri n ol wit h all o p uri n ol al o ne 
•  
L o w d os e veri n ur a d pl us all o p uri n ol wit h all o p uri n ol al o ne 
•  
All o p uri n ol wit h place b o 
 
F or t he sec o n dar y varia bl es at 1 2 m o nt hs, t he c o m paris o n " 2 4 m g ( d o u bl e d ose)" v ers us 
" Place b o ( d o u ble d ose)" will be ma de.  If t he m o d el will n ot pr o vi de relia ble res ults (e g, d u e 
t o n o c o n ver ge n ce), d escri pti ve statistics o nl y will be c o nsi dere d s ufficie nt. 
All sec o n dar y v aria bles will be l o g -tra nsf or me d b ef ore a nal ysis. 
A nal ysis of s ec o n dar y varia bles at 6 a n d 1 2 m o nt hs will be perf or me d usi n g a m o del si milar 
t o t hat use d f or t he pri mar y efficac y v aria ble.  C ha n ge fr o m baseli ne a n d treat me nt 
c o m paris o ns will als o be esti mate d si milarl y.  
T he d ose res p o ns e of veri n ura d pl us all o p uri n ol o n U A C R a n d s U A will be e val uat e d usi n g 
m o delli n g, a n d t he d etails will be pr o vi de d i n t he S A P.  
 
9. 4. 2. 4  
S u b gr o u p a n al yses 
S u b gr o u p a n al ys es f or t h e pri mar y e n d p oi nt will b e perf or me d f or t h e f oll o wi n g s u b gr o u ps: 
•  
dia betics a n d n o n- dia b etics at baseli ne  
•  
C K D 1, C K D 2, a n d C K D 3 + C K D 4 at baseli ne  
•  
Micr oal b u mi n uria a n d m acr oal b u mi n uria at baseli ne  
•  
< Me dia n bas eli ne s U A a n d ≥ me dia n baseli ne s U A  
•  
Baseli ne N T - pr o B N P < 3 6 0 p g/ m L a n d N T-pr o B N P ≥3 6 0  p g/ m L  
•  
Baseli ne e G F R ≤6 0  m L/ mi n/ 1. 7 3 m2 vs > 6 0  m L/ mi n/ 1. 7 3 m2 
•  
Race of Blac k or Africa n A merica n,  W hite, Asia n, Ot her 
•  
A ge < 6 5, a n d ≥6 5 years  
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• 
Gender of male, female 
• 
Geographic region 
 
The primary analysis model will be repeated for each subgroup adding factors for subgroup 
and treatment by subgroup interaction. 
These analyses will be conducted only to the extent the results are considered reliable, eg, the 
analyses should converge. 
9.4.3 
Safety analyses 
All safety analyses will be performed on the Safety Population. 
The assessment of safety will be based on the analyses of AEs, vital signs, ECGs and 
laboratory evaluations. 
All safety data will be summarised by treatment group based on the treatment received. 
The number and percent of patients with at least one AE will be summarised for each 
treatment group, including summaries of AEs, SAEs, and AEs leading to discontinuation.  
Summaries will include the number of subjects with events by system organ class and 
preferred term.  The incidence of laboratory abnormalities, to be defined in the SAP, will be 
summarised for each treatment group.  Values and changes from baseline at each scheduled 
time point for clinical laboratory parameters and vital signs, including blood pressure and 
heart rate, will be summarised by treatment group using descriptive statistics.  Additional 
analyses of creatinine will be specified in the SAP.  The normality/abnormality of ECG 
tracings, as determined by the investigator, will be summarised by shift tables overall and by 
ECG tracing at baseline.  
9.4.4 
Methods for multiplicity control 
The experiment-wise Type I error will be controlled at 10% by hierarchical testing of the 
hypotheses in Section 9.1.  No other comparisons will be adjusted for multiplicity.  
9.5 
Interim analyses  
Two interim analyses will be performed to support internal decisions of the programme 
development.  No multiplicity adjustment is planned for the interim analyses because there is 
no provision to stop the trial early at the interim analyses to claim efficacy. 
These interim analyses will be conducted by an independent team who are not involved in the 
conduct of the study.  A communication plan will be developed to explain who will review the 
results from interim analyses.  All necessary steps will be taken to ensure the integrity of the 
trial by keeping the study team blinded throughout the study. 


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The first interim analysis will be performed no later than when 90% of subjects have 
completed 12 weeks of treatment after titration (Visit 7).  The second interim analysis will be 
conducted after all subjects complete 26 weeks of treatment after titration (Visit 8).  The scope 
of data analysis will be specified in a SAP.  


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10 
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Borstad et al 2004 
Borstad GC1, Bryant LR, Abel MP, Scroggie DA, Harris MD, Alloway JA. Colchicine for 
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Choi et al 2005 
Choi HK, Mount DB, Reginato AM. Pathogenesis of gout. Ann. Intern Med 2005;143(7):499-
516. 
Fleischmann et al 2018a 
Fleischmann R, Winkle P, Miner JN, Yan X, Hicks L, Valdez S, et al. Pharmacodynamic and 
pharmacokinetic effects and safety of verinurad in combination with allopurinol in adults with 
gout: a phase IIa, open-label study. RMD Open 2018 Feb 8;4(1):e000584. doi: 
10.1136/rmdopen-2017-000584. eCollection 2018. 
Fleischmann et al 2018b 
Fleischmann R, Winkle P, Hall J, Valdez S, Liu S, Yan X, et al. Pharmacodynamic and 
pharmacokinetic effects and safety of verinurad in combination with febuxostat in adults with 
gout: a phase IIa, open-label study. RMD Open. 2018 Apr 9;4(1):e000647. doi: 
10.1136/rmdopen-2018-000647. eCollection 2018. 
Grayson et al 2011 
Grayson PC, Kim SY, LaValley M, Choi HK. Hyperuricemia and incident hypertension: a 
systematic review and meta-analysis. Arthritis Care Res (Hoboken) 2011;63(1):102-10. 
Hall et al 2018 
Hall J, Gillen M, Liu S, Miner JN, Valdez S, Shen Z, et al. Pharmacokinetics, 
pharmacodynamics, and tolerability of verinurad, a selective uric acid reabsorption inhibitor, 
in healthy Japanese and non-Asian male subjects. Drug Des Devel Ther 2018 Jun 20;12:1799-
807. 
Hyndman et al 2016 
Hyndman D, Liu S, Miner JN. Urate handling in the human body. Curr Rheumatol Rep 
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Ioachimescu AG, Brennan DM, Hoar BM, Hazen SL, Hoogwerf BJ. Serum uric acid is an 
independent predictor of all-cause mortality in patients at high risk of cardiovascular disease: 
a preventive cardiology information system (PreCIS) database cohort study. Arthritis Rheum 
2008;58(2):623-30. 
Jankowska et al 2007 
Jankowska EA, Ponikowska B, Majda J, Zymlinski R, Trzaska M, Reczuch K, et al. 
Hyperuricaemia predicts poor outcome in patients with mild to moderate chronic heart failure. 
Int J Cardiol 2007;115(2):151-5. 
Jordan et al 2007 
Jordan KM, Cameron JS, Snaith M, Zhang, W, Doherty M, Secki J, et al. British Society for 
Rheumatology and British Health Professionals in Rheumatology guideline for the 
management of gout. Rheumatology (Oxford) 2007;46(8):1372-4. 
Khanna et al 2012 
Khanna D1, Fitzgerald JD, Khanna PP, Bae S, Singh MK, Neogi T, et al. 2012 American 
College of Rheumatology guidelines for management of gout.  Part 1: systematic 
nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care 
Res (Hoboken). 2012 Oct;64(10):1431-46. 
Kim et al 2008 
Kim SY, De Vera MA, Choi HK. Gout and mortality. Clin Exp Rheumatol 2008;26(5)(suppl 
51):S115-9. 
Kodama et al 2009 
Kodama S, Saito K, Yachi Y, Asumi M, Sugawara A, Totsuka K, et al. Association between 
serum uric acid and development of type 2 diabetes. Diabetes Care 2009;32(9):1737-42. 
Leoncini et al 2002 
Leoncini G, Martinoli C, Viazzi F, Ravera M, Parodi D, Ratto E, et al. Changes in renal 
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treatment with lisinopril or nifedipine GITS. Nephron. 2002 Feb;90(2):169-73. 
Levey et al 2009 
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, et al. A new 
equation to estimate glomerular filtration rate. Ann Intern Med 2009;150(9):604-12. 
Leyva et al 1998 
Leyva F, Anker SD, Godsland IF, Teixeira M, Hellewell PG, Kox WJ, et al. Uric acid in 
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Nakagawa et al 2006 
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11 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
Appendix A Regulatory, ethical and study oversight considerations 
A 1 
Regulatory and ethical considerations 
This study will be conducted in accordance with the protocol and with the following: 
• 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organisations of Medical Sciences 
(CIOMS) International Ethical Guidelines 
• 
Applicable International Conference of Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines 
• 
Applicable laws and regulations 
 
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant documents 
(eg, advertisements) must be submitted to an Institutional Review Board/Institutional Ethics 
Committee (IRB/IEC) by the investigator and reviewed and approved by the IRB/IEC before 
the study is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study patients. 
The investigator will be responsible for the following: 
• 
Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC 
• 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
• 
Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
studies (if applicable), and all other applicable local regulations 
 
The study will be performed in accordance with the AstraZeneca policy on Bioethics and 
Human Biological Samples. 
A 2 
Financial disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities.  Investigators 


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are r es p o nsi ble f or pr o vi di n g i nf or mati o n o n fi na ncial i nterests d uri n g t he c o urse of t he st u d y 
a n d f or 1 year after c o m pleti o n of t he st u d y. 
A 3  
I nf or me d c o nse nt pr ocess 
T he i n vesti gat or or his/ her re prese nt ati ve will e x plai n t he nat ure of t h e st u d y t o t he patie nt or 
his/ her le gall y a ut h orise d re pres e ntati ve a n d a ns w er all q uesti o ns re gar di n g t he st u d y.   
Patie nts m ust be i nf or me d t hat t heir partici pati o n is v ol u ntar y.  Patie nts or t heir le gall y 
a ut h orise d re prese ntati ve  will be re q uire d t o si g n a state me nt of i nf or me d c o nse nt t hat meets 
t he re q uire m e nts of 2 1 C F R 5 0, l ocal re g ul ati o ns, I C H g ui deli nes, Healt h I ns ura nce P ort a bilit y 
a n d Acc o u nt a bilit y Act ( HI P A A) r e q uire me nts, w here a p plica ble, a n d t h e I R B/I E C or st u d y 
ce ntre.  
T he me dical r ec or d m ust i ncl u de a state me nt t hat writte n i nf or me d c o ns e nt was o btai ne d 
bef ore t h e patie nt was e nr olle d i n t he st u d y a n d t h e date  t he writte n c o nse nt was o btai ne d.  
T he a ut h orise d pers o n o btai ni n g t he i nf or m e d c o nse nt m ust als o si g n t he I C F. 
Patie nts m u st be re-c o nse nte d t o t he m ost c urre nt versi o n of t he I C F(s) d uri n g t heir 
partici pati o n i n t he st u d y.  
A c o p y of t he I C F(s) m ust be pr o vi de d t o t he pati e nt or t he patie nt’s le gall y a ut h oris e d 
re pres e ntati ve. 
If a p plica bl e, a se p arate i nf or me d c o ns e nt will be s u b mitte d t o t he Et hical C o m mittee f or 
pr oce d ur es c o ncer ni n g t h e M RI test p ers o ns t hat are sca n n e d t o e ns ure t he c orrect 
i m ple me ntati o n of i ma gi n g met h o ds. 
 
 
Patie nts w h o are r e - pr escree ne d ar e re q uire d t o si g n a ne w brief I C F.  T he brief I C F is use d t o 
o btai n patie nt c o nse nt f or s U A, e G F R, a n d U A C R assess me nts.  Patie nts w h o are rescree n e d 
are r e q uired t o si g n a n e w f ull I C F.  T he f ull I C F is t he master I C F f or t he st u d y.  
 
 
 
 
 
 
C CI
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A 4  
D at a pr otecti o n  
Eac h patie nt will be assi g ne d a u ni q ue i de ntifier b y t he s p o ns or.  A n y patie nt rec or ds or d ata 
sets tra nsferre d t o t he s p o ns or will c o ntai n o nl y t he i de ntifier; patie nt na mes or a n y 
i nf or mati o n w hic h w o ul d ma ke t he patie nt i de ntifi a ble will n ot be tra nsferre d. 
T he patie nt m ust be i nf or me d t hat his/ her pers o nal st u d y- relate d dat a will be use d b y t he 
s p o ns or i n acc or d a nce wit h l ocal data pr otecti o n la w.  T he le vel of discl os ure m ust als o be 
e x plai ne d t o t he patie nt. 
T he patie nt m ust be i nf or me d t hat his/ her me dical rec or ds ma y b e e x a mi ne d b y Cli nical 
Q ualit y Ass ur a nce a u dit ors or ot her a ut h orise d pers o n nel a p p oi nte d b y t h e s p o ns or, b y 
a p pr o priate I R B/I E C me m bers, a n d b y i ns pect ors fr o m re g ulat or y a ut h orities. 
A 5  
C o m mittees str uct ure  
T he safet y of all Astra Ze neca cli nical st u dies is cl osel y m o nit ore d o n a n o n -g oi n g basis b y 
Astra Ze neca re pr ese ntati ves i n c o ns ultati o n wit h Patie nt Safet y.  Iss u es i de ntifie d will be 
a d dresse d; f or i nsta nce , t his c o ul d i n v ol ve a me n d me nts t o t he Cli nical St u d y Pr ot oc ol a n d 
letters t o i n vesti gat ors. 
D at a m o nit ori n g c o m mittee ( D M C)  
A n i n de pe n de nt D M C will be a p p oi nte d a n d will re p ort t o Astra Ze n eca a n d t he C R O.  T he 
D M C will be res p o nsi ble f or e ns uri n g patie nt safet y b y ass essi n g t he s afet y of t he I P d uri n g 
t he st u d y, a n d f or r e vie wi n g t he o verall c o n d uct of t he st u d y.  T h e D M C will ha ve access t o 
t he i n di vi d ual treat me nt c o des a n d be a ble t o mer ge t h ese wit h t he c ollecte d st u d y data w hile 
t he st u d y is o n g oi n g.  
A D M C c harter will be pre par e d t o detail precise r oles a n d res p o nsi bilities a n d pr oce d ures t o 
e ns ure mai nte n a nce of t he bli n di n g a n d i nte grit y of t he st u d y i n t he re vie w of acc u m ulati n g 
data a n d i nter acti o ns wit h Astra Ze neca a n d t he C R O.  
Cli nic al e ve nt a dj u dic ati o n ( C E A)  
T he r ole of t he C E A is t o i n de pe n de ntl y re vie w, i nter pret a n d a dj u dicate p ot e ntial C V e ve nts 
t hat are e x perie n ce d b y t he patie nts. C V e ve nts will be i de ntifie d preli mi naril y b y t he 
i n vesti gat ors, a n d als o b y A Z p ers o n nel, C R O pers o n nel or i n t he C E A pr ocess as s pecifie d i n 
t he C E A c harter. T he C E A me m ber/s will n ot ha ve access t o i n di vi d ual treat me nt c o des f or 
a n y p atie nt or cli nical efficac y e n d p oi nt a n d s afet y e ve nt. T he precise res p o nsi bilities a n d 
pr oce d ur es a p plica bl e f or C E A will be detaile d i n t he C E A c hart er.  
C CI


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A 6 
Dissemination of clinical study data 
A description of this clinical trial will be available on http://astrazenecaclinicaltrials.com and 
http://www.clinicaltrials.gov as will the summary of the study results when they are available.  
The clinical trial and/or summary of study results may also be available on other websites 
according to the regulations of the countries in which the study is conducted. 
A 7 
Data quality assurance 
All patient data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data).  The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.   
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.   
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
The sponsor or designee is responsible for the data management of this study including quality 
checking of the data. 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorised site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of patients are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period.  No records may be destroyed during 
the retention period without the written approval of the sponsor.  No records may be 
transferred to another location or party without written notification to the sponsor. 
A 8 
Source documents 
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected.  Source documents are filed at the investigator’s site. 
Data reported on the CRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained.  The investigator may need to 
request previous medical records or transfer records, depending on the study.  Also, current 
medical records must be available. 


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All information in original records and certified copies of original records of clinical findings, 
observations, or other activities in a clinical study necessary for the reconstruction and 
evaluation of the study are defined as source documents.  Source data are contained in source 
documents (original records or certified copies). 
A 9 
Study and site start and closure 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first site deemed “ready to enrol” and will be the study start 
date. 
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
• Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of participants by the investigator 
• Discontinuation of further study intervention development 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participants and should ensure 
appropriate participant therapy and/or follow-up. 
Participants from terminated sites will have the opportunity to be transferred to another site to 
continue the study. 
A 10 
Publication policy 
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor before 


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submission.  This allows the sponsor to protect proprietary information and to provide 
comments. 
The sponsor will comply with the requirements for publication of study results.  In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 
multicentre studies only in their entirety and not as individual site data.  In this case, a 
coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements. 


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Appendix B Adverse event definitions and additional safety information 
B 1 
Definition of adverse events 
An AE is the development of any untoward medical occurrence in a patient or clinical study 
patient 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 (eg, nausea, chest pain), or disease 
temporally associated with the use of a medicinal product, whether or not considered related 
to the medicinal product. 
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence.  An AE may occur at any time, including 
run-in or washout periods, even if no Study treatment has been administered. 
B 2 
Definitions of serious adverse event 
An SAE is an AE occurring during any study phase (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.   
• 
Is a congenital abnormality or birth defect 
• 
Is an important medical event that may jeopardise the patient or may require medical 
treatment to prevent one of the outcomes listed above. 
 
Adverse events for malignant tumours reported during a study should generally be assessed 
as Serious AEs.  If no other seriousness criteria apply, the ‘Important Medical Event’ criterion 
should be used.  In certain situations, however, medical judgement 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 in adults include Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer 
removed via cone biopsy. 


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B 3 
Life threatening 
‘Life-threatening’ means that the patient 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 patient’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). 
B 4 
Hospitalisation 
Outpatient treatment in an emergency room is not in itself a serious AE, 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 patient was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study. 
B 5 
Important medical event or medical treatment 
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardize the patient or may require 
medical treatment to prevent one or more outcomes listed in the definition of serious.  These 
should usually be considered as serious. 
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used. 
• 
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment 
• 
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine 
• 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
• 
Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation 
• 
Development of drug dependency or drug abuse 
 
B 6 
Intensity rating scale: 
1 
mild (awareness of sign or symptom, but easily tolerated) 
2 
moderate (discomfort sufficient to cause interference with normal activities) 
3 
severe (incapacitating, with inability to perform normal activities) 
 
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix B 2.  An AE of severe 


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intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Appendix B 2.  On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Appendix B 2. 
B 7 
A Guide to Interpreting the Causality Question 
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug. 
• 
Time Course.  Exposure to suspect drug.  Has the patient 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? 
• 
De-challenge experience.  Did the AE resolve or improve on stopping or reducing the 
dose of the suspect drug? 
• 
No alternative cause.  The AE cannot be reasonably explained by another aetiology such 
as the underlying disease, other drugs, other host or environmental factors. 
• 
Re-challenge experience.  Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped? AstraZeneca would not normally recommend or support a re-
challenge. 
• 
Laboratory tests.  A specific laboratory investigation (if performed) has confirmed the 
relationship. 
 
In difficult cases, other factors could be considered such as: 
• 
Is this a 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. 
B 8 
Medication Error 
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study drug that either causes harm to the participant 
or has the potential to cause harm to the participant.   
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant. 
Medication error includes situations where an error: 
• 
occurred 
• 
was identified and intercepted before the participant received the drug 
• 
did not occur, but circumstances were recognise that could have led to an error 
 
Examples of events to be reported in clinical studies as medication errors: 
• 
Drug name confusion 
• 
Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the participant 
• 
Drug not administered as indicated, for example, wrong route or wrong site of 
administration 
• 
Drug not taken as indicated eg, tablet dissolved in water when it should be taken as a 
solid tablet  
• 
Drug not stored as instructed eg, kept in the fridge when it should be at room temperature  
• 
Wrong participant received the medication (excluding IVRS/IWRS errors) 
• 
Wrong drug administered to participant (excluding IVRS/IWRS errors) 
 
Examples of events that do not require reporting as medication errors in clinical studies: 
• 
Errors related to or resulting from IVRS/IWRS - including those which lead to one of the 
above listed events that would otherwise have been a medication error  
• 
Participant accidentally missed drug dose(s) eg, forgot to take medication 
• 
Accidental overdose (will be captured as an overdose) 
• 
Participant failed to return unused medication or empty packaging 
• 
Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AZ product 
 


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Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error. 


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


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AstraZeneca ensures the organisations holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed and the action 
documented and returned to the study site. 
C 3 
International Airline Transportation Association (IATA) 6.2 
Guidance Document 
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES 
International Airline Transportation Association (IATA) classifies biohazardous agents into 3 
categories 
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.htm).  For 
transport purposes the classification of infectious substances according to risk groups was 
removed from the Dangerous Goods Regulations in the 46th edition (2005).  Infectious 
substances are now classified either as Category A, Category B or Exempt.  There is no direct 
relationship between Risk Groups and Categories A and B. 
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.  Category A pathogens are eg, Ebola, Lassa fever virus: 
• 
are to be packed and shipped in accordance with IATA Instruction 602. 
 
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A.  Category B pathogens are eg, Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus types 1 and 2.  They are assigned the following UN number 
and proper shipping name: 
• 
UN 3373 – Biological Substance, Category B 
• 
are to be packed in accordance with UN3373 and IATA 650 
Exempt - all other materials with minimal risk of containing pathogens 
• 
Clinical trial samples will fall into Category B or exempt under IATA regulations 
• 
Clinical trial samples will routinely be packed and transported at ambient 
• 
temperature in IATA 650 compliant packaging 
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.htm) 
• 
Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content 
• 
IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as applicable 
• 
Samples routinely transported by road or rail are patient 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 


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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 E Actions required in cases of increases in liver biochemistry 
and evaluation of Hy’s Law 
E 1 
Introduction 
This Appendix describes the process to be followed in order to identify and appropriately 
report Potential Hy’s Law (PHL) cases and Hy’s Law (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 patient meets 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 TBL from 
a local laboratory. 
The investigator will also review Adverse Event 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 IP. 
The investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting Serious Adverse Events (SAEs) and Adverse Events (AEs) according to the 
outcome of the review and assessment in line with standard safety reporting processes. 
E 2 
Definitions 
Potential Hy’s Law (PHL) 
Aspartate transaminase (AST) or alanine transaminase (ALT) ≥3× upper limit of normal 
(ULN) together with total bilirubin (TBL) ≥2×ULN at any point during the study following 
the start of study medication irrespective of an increase in alkaline phosphatase (ALP). 
Hy’s Law (HL) 
AST or ALT ≥3 × ULN together with TBL ≥2 ×ULN, where no other reason, other than the 
IP, 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 time frame within which the 
elevations in transaminases and TBL must occur. 
E 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 patient who meets any of the following identification criteria in 
isolation or in combination: 
• 
ALT ≥3 × ULN 
• 
AST ≥3 × ULN 
• 
TBL ≥2 × ULN 
 
Central laboratories being used: 
When a patient meets any of the PHL identification criteria, in isolation or in combination, the 
central laboratory will immediately send an alert to the investigator (and also to the 
AstraZeneca representative). 
The investigator will also remain vigilant for any local laboratory reports where the PHL 
identification criteria are met, where this is the case the investigator will: 
• 
Notify the AstraZeneca representative 
• 
Request a repeat of the test (new blood draw) by the central laboratory without delay 
• 
Complete the appropriate unscheduled CRF module(s) with the original local laboratory 
test result 
 
When the identification criteria are met from central or local laboratory results the investigator 
will without delay: 
• 
Determine whether the patient meets PHL criteria (see Appendix E 2 for definition) by 
reviewing laboratory reports from all previous visits (including both central and local 
laboratory results) 
 
Local laboratories being used: 
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 patient meets PHL criteria (see Appendix E 2 for definition) by 
reviewing laboratory reports from all previous visits 


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• 
Promptly enter the laboratory data into the laboratory CRF 
 
E 4 
Follow-up 
E 4.1 
Potential Hy’s Law criteria not met 
If the patient does not meet PHL criteria the investigator will: 
• 
Perform follow-up on subsequent laboratory results according to the guidance provided in 
the Clinical Study Protocol. 
 
E 4.2 
Potential Hy’s Law criteria met 
If the patient does meet PHL criteria the investigator will: 
• 
Determine whether PHL criteria were met at any study visit prior to starting study 
treatment (See Section E 6) 
• 
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 
Potential Hy’s Law; serious criteria ‘Important medical event’ and causality assessment 
‘yes/related’ according to CSP process for SAE reporting. 
• 
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 patients’ follow-up and the continuous review of data. 
• 
Subsequent to this contact the investigator will: 
− 
Monitor the patient until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated.  Complete the follow-up SAE Form as required. 
− 
Investigate the aetiology of the event and perform diagnostic investigations as 
discussed with the Study Physician.  This includes deciding which the tests available 
in the Hy’s law lab kit should be used.  
− 
Complete the three Liver CRF Modules as information becomes available  
 
E 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 IP, 
to ensure timely analysis and reporting to health authorities within 15 calendar days from the 


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date 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 patient 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 ALT or AST and TBL elevations, 
a determination of whether the alternative explanation is an AE will be made and 
subsequently whether the AE meets the criteria for a SAE: 
• 
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF 
• 
If the alternative explanation is an AE/SAE: update the previously submitted Potential 
Hy's Law SAE and AE CRFs accordingly with the new information (reassessing event 
term; causality and seriousness criteria) following the AZ standard processes. 
 
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IP: 
• 
Send an updated SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes.   
− 
The ‘Medically Important’ serious criterion should be used if no other serious criteria 
apply 
− 
As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned. 
 
If there is an unavoidable delay of over 15 calendar days in obtaining the information 
necessary to assess whether or not the case meets the criteria for HL, then it is assumed that 
there is no alternative explanation until such time as an informed decision can be made: 
• 
Provide any further update to the previously submitted SAE of Potential Hy's Law, 
(report term now 'Hy's Law case') ensuring causality assessment is related to IP and 
seriousness criteria 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 the CSP process for SAE reporting, according to the outcome of the review 
amending, the reported term if an alternative explanation for the liver biochemistry 
elevations is determined. 
 


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E 6 
Actions required for repeat episodes of potential Hy’s Law 
This section is applicable when a patient meets PHL criteria on study treatment, and has 
already met PHL criteria at a previous on study treatment visit. 
The requirement to conduct follow-up, review, and assessment of a repeat occurrence(s) of 
PHL is based on the nature of the alternative cause identified for the previous occurrence.   
The investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question: 
Was the alternative cause for the previous occurrence of PHL criteria being met found to be 
the disease under study (eg, chronic or progressing malignant disease, severe infection or 
liver disease)? 
If No: Follow the process described in Appendix E 4.2 for reporting PHL as an SAE 
If Yes: Determine if there has been a significant# change in the patient’s condition compared 
with when PHL criteria were previously met. 
• 
If there is no significant change, no action is required. 
• 
If there is a significant change, follow the process described in Appendix E 4.2 for 
reporting PHL as an SAE 
 
# A ‘significant’ change in the patient’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. 
E 7 
Laboratory tests 
The list below represents the standard, comprehensive list of follow-up tests which are 
recommended when using a central laboratory. 
Some of the tests may also be considered for use with local laboratories that have respective 
testing capabilities. Any test results need to be recorded in the CRF 
Hy’s Law lab kit for central laboratories 
Additional standard chemistry and coagulation 
tests 
GGT 
LDH 
Prothrombin time 
INR 


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Viral hepatitis 
IgM anti-HAV  
IgM and IgG anti-HBc 
HBsAg 
HBV DNA 
IgG anti-HCV 
HCV RNA 
IgM anti-HEV 
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 
 
REFERENCES 
Aithal et al 2011 
Aithal GP, Watkins PB, Andrade RJ, Larrey D, Molokhia M, Takikawa H et al. Case 
definition and phenotype standardization in drug-induced liver injury. Clinical Pharmacology 
and Therapeutics. 2011;89(6):806-815. 
FDA 2009 
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’ 


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Appendix F Actions required in cases of a renal-related or kidney stone 
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.  
F 1 
Signs and symptoms suggestive of renal injury or kidney stone 
After initiation of study medication, if a patient 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 MRI) 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 the CRF. 
If a patient develops a urinary tract calculus (as confirmed and documented by imaging or 
passage of a stone) at any time during the study, the patient 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. 
F 2 
Deterioration of renal function 
This study will have at least 2 pre-dose serum creatinine measurements.  The (higher) of all 
creatinine measurements collected before randomisation will be considered the baseline serum 
creatinine for renal safety monitoring.  
This study enrols patients with chronic kidney disease (CKD).  These patients may have 
changes in serum creatinine and estimated glomerular filtration rate (eGFR) that may be due 
to various causes such as: deterioration of renal function due to the underlying cause of CKD, 
volume depletion, hypotension, intercurrent medical conditions such as worsening heart 
failure, concomitant drugs that alter renal tubular creatinine secretion or reabsorption, or 
change in glomerular filtration rate via haemodynamic effects. 
The investigator should assess each patient carefully to determine the most likely cause for the 
deterioration of renal function.  Following a thorough assessment, the patient 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. 


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Patients on ACEi/ARB medication (CKD, heart failure) or on mineralocorticoid receptor 
antagonists or beta-blockers (heart failure) should not have these treatments reduced in dose or 
discontinued unless all other measures fail to improve the patient’s situation. 
F 2.1 
Patients with baseline eGFR ≥40 mL/min/1.73 m2 
F 2.1.1 
Serum creatinine increase to ≥1.5-fold from baseline 
• 
Assess the patient to identify and manage any potential contributing factor.  Correct any 
dehydration and ensure the patient is well hydrated prior to next renal safety monitoring 
visit. 
• 
At the investigator’s discretion, the patient may continue with study treatment, and retest 
of serum creatinine should be performed the following week.  If the underlying cause (eg, 
dehydration) is still present at the next evaluation, the investigator should carefully 
consider if the retesting should be postponed for another week. 
• 
Patient should attend the following week for repeat serum creatinine measurement.  If an 
underlying potentially treatable cause (eg, dehydration) is still present, the investigator 
should treat this appropriately and postpone testing for up to a week.  
• 
Subsequent management will depend on the repeat measurement(s): 
− 
If serum creatinine <1.5-fold of baseline value for two successive measurements, the 
patient may restart/continue with study treatment and the original study visit 
schedule. 
− 
If repeat serum creatinine is between ≥1.5 to <2.0-fold of baseline value, the patient 
should be evaluated every 1 to 2 weeks.  During this evaluation period, the 
randomised treatment can be temporarily interrupted at the investigator’s discretion.  
If serum creatinine is <1.5-fold of baseline value during the evaluation period, study 
treatment may be restarted/continued on the original study visit schedule. 
− 
If serum creatinine ≥2.0-fold of baseline value for 2 successive measurements 
(including the original high value if applicable), randomised treatment should be 
permanently discontinued and the patient should be followed up as per study 
schedule. 
 
F 2.2 
Patients with baseline eGFR <40 mL/min/1.73 m2 
The CKD-EPI formula (Michels et al 2010) should be used to estimate GFR for enrolment 
criteria, baseline value and subsequent on-study measurements. 
More intense renal monitoring and discontinuation are based on % drop from the baseline 
value. 


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F 2.2.1 
If eGFR drops to <75% of the baseline value 
• 
Assess the patient to identify and manage any potential contributing factor.  Correct any 
dehydration and ensure the patient is well hydrated prior any future evaluation. 
• 
At the investigator’s discretion, the patient may continue with study treatment and retest 
of serum creatinine should be performed within 7 days.  If the underlying cause (eg, 
dehydration) is still present at the next evaluation, the investigator should carefully 
consider if the retesting should be postponed for another week. 
• 
Subsequent management will depend on the repeat measurement(s): 
− 
If eGFR is >75% of the baseline value on 2 successive measurements, the patient 
may restart/ continue with study treatment on the original study visit schedule. 
− 
If the repeat eGFR value is between 60% and 75% of the baseline value, the patient 
should be evaluated every 1 to 2 weeks for serum creatinine measurements/ GFR 
estimation.  During this evaluation period, the randomised treatment can be 
temporarily interrupted at the investigator’s discretion.  If eGFR returns to >75% of 
baseline value during the evaluation period, study treatment may be restarted/ 
continued on the original study visit schedule. 
− 
If eGFR is <60% of the baseline value on 2 successive measurements, randomised 
treatment should be permanently discontinued, and the patient should be followed up 
as per study schedule. 
 
Examples of eGFR changes and triggered actions 
Baseline eGFR 
(mL/min/1.73 m2) 
Intense renal monitoring 
 ± temporary interruption of treatment 
eGFR (mL/min/1.73 m2) 
Permanently discontinue 
randomised treatment 
eGFR (mL/min/1.73 m2) 
39 
23 to 29  
<23 
36 
21 to 27 
<21 
32 
19 to 24 
<19 
28 
17 to 21 
<17 
25 
15 to 19 
<15 
REFERENCE 
Michels et al 2010 
Michels WM1, Grootendorst DC, Verduijn M, Elliott EG, Dekker FW, Krediet RT. 
Performance of the Cockcroft-Gault, MDRD, and new CKD-EPI formulas in relation to GFR, 
age, and body size. Clin J Am Soc Nephrol. 2010 Jun;5(6):1003-9. 


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Appendix G Abbreviations  
Abbreviation or special 
term 
Explanation 
ACEi 
angiotensin-converting enzyme inhibitor 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase 
ARB 
angiotensin receptor blocker 
AST 
aspartate transaminase 
CKD 
chronic kidney disease 
CRF 
case report form (electronic/paper) 
CRO 
contract research organisation 
CSR 
clinical study report 
DMC 
data monitoring committee 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
GCP 
Good Clinical Practice 
hsCRP 
high-sensitivity C-reactive protein 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IP 
investigational product 
IRB 
Institutional Review Board 
IVRS 
interactive voice response system 
IWRS 
interactive web response system 
NSAID 
non-steroidal anti-inflammatory drug 
NT-proBNP 
N-terminal natriuretic peptide 
OATP 
organic anion transporting polypeptide 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PWV 
pulse wave velocity 
SAE 
serious adverse event  
SAP 
statistical analysis plan 
SGLT2 
sodium-glucose transport protein 
sUA 
serum uric acid 
uUA 
urinary uric acid 
UACR 
urinary albumin to creatinine ratio 


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Abbreviation or special 
term 
Explanation 
UA 
uric acid 
ULN 
upper limit of normal 
URAT1 
uric acid transporter 1 
XOI 
xanthine oxidase inhibitor 
 


SI G N A T U R E P A G E
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electr o nic ally a n d t his p a ge is t he m a nifest ati o n of t he electr o nic si g n at ure
D oc u me nt N a me: d 5 4 9 5c 0 0 0 0 2-cs p- v 5
D oc u me nt Title:
D 5 4 9 5 C 0 0 0 0 2 Cli nical St u d y Pr ot oc ol versi o n 5
D oc u me nt I D:
D oc I D- 0 0 4 4 2 5 7 3 4
Versi o n L a bel:
1. 0 C U R R E N T L A T E S T A P P R O V E D
Ser ver D ate
( d d- M M M- y y y y H H: m m ‘ U T C’ Z)
Si g ne d b y
Me a ni n g of Si g n at ure
C o nte nt A p pr o val
C o nte nt A p pr o val
Ma na ge me nt A p pr o val
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N otes: ( 1) D oc u me nt details as st ore d i n A N G E L, a n Astra Ze neca d oc u me nt ma na ge me nt s yste m.
P P D
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SAP_001.pdf: 
Statistical Analysis Plan 
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Statistical Analysis Plan
Study Code
D5495C00002
Edition Number
3.0
Date
16 July 2021
A Phase 2b, Multicentre, Randomised, Double-blind, Placebo-
controlled Study of Verinurad and Allopurinol in Patients with 
Chronic Kidney Disease and Hyperuricaemia






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Sec o n dar y  e n d p oi nts at 1 2 m o nt hs ( V 1 0)..........................................................5 3
6. 9
[ Re mo ve d] ........................................................................................................5 4
6. 1 0
e G F R sl o pe at V9 a n d at e n d -of -treat me nt ( E O T) .............................................5 4
7
A P P E N DI X ......................................................................................................5 5
7. 1
Refere nces ........................................................................................................5 5
LI S T O F T A B L E S
LI S T O F FI G U R E S
N o ta bl e of fi g ures e ntries f o u n d.
C CI


Statistical A nal ysis Pla n 
Astra Ze neca
D 5 4 9 5 C 0 0 0 0 2 - 3. 0
1 6 J ul 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
5 of 5 5
LI S T O F A B B R E VI A TI O N S
A b bre vi ati o n or s peci al 
ter m
E x pl a n ati o n
A 1c
a glyc ate d f or m of h ae m o gl o bi n A 1
A C Ei
a n gi ote nsi n c o n verti n g e nz y me i n hi bit or
A E
a d verse e ve nt
A E o SI
a d verse e ve nt of s pecial i nterest
AI
a u g me ntati o n i n de x
A L P
al kali ne p h os p hatase
A L T
ala ni ne tra nsa mi nase
A N C O V A
a nal ysis of c o varia nce (st atistic al m o del)
A R B
a n gi ote nsi n rece pt or bl oc ker
A S T
a s partate tra nsa mi nase
A T C
a nat o mical t hera pe utic c he mical
A Z
Astra Ze neca
CI
co nfi de nce i nter val
C K
creati ni ne ki nase
C K D
chr o nic ki d ne y disease
C O VI D - 1 9
c or o na vir us disease 2 0 1 9
C S R
cli nical st u d y re p ort
C S R H L D
cli nical st u d y re p ort or hi g her le vel d oc u me nt
C V
car di o vasc ular
C V
c oefficie nt of variati o n
D A E
disc o nti n uati o n of st u d y dr u g d ue t o a n a d verse e ve nt
D B L
data base l oc k
D B P
diast olic bl o o d press ure
D M
d ia betes mellit us
e C R F
electr o nic case re p ort f or m
e G F R
esti mate d gl o mer ular filtrati o n rate
E C G
electr ocar di o gra m
E O S
e n d of st u d y
E O T
en d of treat me nt
e x p
e x p o ne ntial (f u ncti o n)
C CI
C CI
C CI


Statistical A nal ysis Pla n 
Astra Ze neca
D 5 4 9 5 C 0 0 0 0 2 - 3. 0
1 6 J ul 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
6 of 5 5
A b bre vi ati o n or s peci al 
ter m
E x pl a n ati o n
F A S
full a nal y sis set
G 1, G 2, G 3, G 3a, G 3 b, 
G 4 , G 5
K DI G O 2 0 1 2 G F R cate g ories 1 , 2 , 3, 3a, 3 b, 4, 5 , see K DI G O 2 0 1 3
G F R
gl o mer ular filtrati o n rate
g C V
ge o metric c oefficie nt of variati o n
g mea n
ge o metric mea n
g S D
ge o metric sta n dar d -de viati o n
H b
hae m o gl o bi n
H L R
hi g h -le vel res ults
I C H
I nter nati o nal C o u ncil f or Har m o nisati o n of Tec h nical Re q uire me nts f or
P har mace uticals f or H u ma n Use
I P
i n vesti gati o nal pr o d uct
I P D
im p orta nt pr ot oc ol de viati o n
K DI G O
Ki d ne y  Disease: I m pr o vi n g Gl o bal O utc o mes
L L O Q
l o wer li mit of q ua ntificati o n
l o g
l o garit h m(ic)
L S Mea n
least s q uares mea n
M A C E
maj or car di o vasc ular e ve n
M A R
missi n g at ra n d o m
M C H
mea n c or p usc ular hae m o gl o bi n
M C H C
mea n c or p usc ular hae m o gl o bi n c o nce ntrati o n
M C V
mea n c or p usc ular v ol u me
Me d D R A
Me dical Dicti o nar y f or Re g ulat or y Acti vities
M M R M
mi xe d m o del (f or) re peate d meas ure( me nt)s (st atistic al m o del)
M N A R
missi n g n ot at ra n d o m
N C
n ot calc ula ble
N Q
bel o w  L L OQ
N R
n ot re p orte d
N S
n o sa m ple
N T -pr o B N P
N- ter mi nal pr o h or m o ne of brai n natri uretic pe pti de
P A 5
pr ot oc ol a me n d me nt 5 (s a me as pr ot oc ol versi o n 5. 0)
P D
p har mac o d y na mic(s)
P K
p har mac o ki netic(s)
P T
Me d D R A pr eferre d ter m
C CI


Statistical A nal ysis Pla n 
Astra Ze neca
D 5 4 9 5 C 0 0 0 0 2 - 3. 0
1 6 J ul 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
7 of 5 5
A b bre vi ati o n or s peci al 
ter m
E x pl a n ati o n
Q Tc F
Q T i nterv al c orrecte d f or he art r ate acc or di n g t o Fr i dericia
R 1, R 2, R 2 *
s pecifiers t o s o me ki d ney e n d p oi nts
R B C
re d bl o o d cell c o u nt
S A E
seri o us a d verse e ve nt
S A P
statistical a nal ysis pla n
S B P
s yst olic bl o o d press ure
S G L T 2
s o di u m/ gl uc ose c otra ns p orter 2
S G L T 2i
s o di u m/ gl uc ose c otra ns p orter 2 i n hi bit or
S M Q
sta n dar dise d Me d D R A q uer y
S O C
Me d D R A s yste m or ga n class
s qrt
s q uare r o ot (f u ncti o n)
s U A
ser u m uric aci d
TI A
tra nsie nt isc hae mic attac k
U A C R
uri nar y  al b u mi n t o creati ni ne rati o
U A
uric aci d
U L N
u p per li mit of n or mal
U L N A L T
u p per li mit of n or mal f or A L T
U L N A S T
u p per li mit of n or mal f or A S T
U L N t otal bilir u bi n
u p per li mit of n or mal f or t otal bilir u bi n
U L O Q
u p per li mit of q ua ntificati o n
v
versi o n
V 1, V 2, …, V 1 4
visit 1, visit 2, …, visit 1 4
V x
visit x, a pl ace h ol der f or a ny n u m bere d visit
W H O
W orl d Healt h Or ga nizati o n
W H O D D
W H O Dr u g Dicti o nar y
S a m ple m atrices
B-
bl o o d
P-
plas ma
S-
ser u m
S/ P -
ser u m or plas ma ( u n deci de d)
U-
uri n e
C CI
C CI


















Statistical A nal ysis Pla n 
Astra Ze neca
D 5 4 9 5 C 0 0 0 0 2 - 3. 0
1 6 J ul 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
1 6 of 5 5
1
S T U D Y D E T AI L S
1. 1
St u d y o bjecti ves
Acc or di n g t o t he pr ot oc ol , t he o bject i ves are:
Pri m ar y o bjecti ve
1.
T o assess t he effects of treat me nt wit h veri n ura d a n d all o p uri n o l, allo p uri n ol  alo n e, 
a n d place b o o n U A C R at 6 m o nt hs.
Sec o n d ar y o bjecti ves
2.
T o assess t he effects of treat me nt wit h veri n ura d a n d all o p uri n o l, allo p uri n ol alo n e, 
a n d place b o o n U A C R at 1 2 m o nt hs.
3.
T o assess t he effects of veri n ura d a n d all o p uri n o l, allo p uri n ol  alo n e, a n d place b o o n 
s U A.
4.
T o esti mate t he d ose -res p o nse relati ons hi p a m o n g 3 d oses of veri n ura d a n d all o p uri n o l 
a n d place b o o n U A C R a n d s U A.
5.
T o asses s t he effects of veri n ura d a n d all o p uri n ol vers us place b o o n ki d ne y  fu nct i on.
 
 
 
 
 
 
 
S afet y o bjecti ve
1 3. T o assess t he safet y a n d t olera bilit y of i nte nsi ve U A l o weri n g t hera p y  wit h veri n ura d 
a n d all o p uri n o l.
C CI


Statistical A nal ysis Pla n 
Astra Ze neca
D 5 4 9 5 C 0 0 0 0 2 - 3. 0
1 6 J ul 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
1 7 of 5 5
1. 2
St u d y desi g n
T his is a ra n d omise d , d o u ble- bli n d, pl ace b o -c o ntr olle d, parallel, gl o bal, d ose -fi n di n g, 
p hase 2 b st u d y  t o assess t he efficac y a n d safety of  veri n ura d a n d all o p uri n ol i n s u bjects wit h 
c hr o nic ki d ne y disease a n d h y per uricae mia. S u bject s w h o meet t he eli gi bility cri t eria will be 
ra n d omise d 1: 1: 1: 1: 1 t o , res pecti vel y,

h i g h d ose of veri n ura d pl us all o p u rin o l (“ H i g h”),

i nter me diate d ose of veri n ura d pl us all o p uri n o l ( “I nt er me diate”) ,

l ow d ose of veri n ura d pl us all o p uri n o l (“ L o w”),

all o p uri n o l o nl y (“ Allo p uri n ol  alo n e”) , or

pl ace b o (“ Place b o”).
T w o s u b-st u dies, t he o ne o n ma g net ic res o na nce i ma gi n g ( M RI) a n d t he ot her o n 
p har mac o ki net ics ( P K), are pla n ne d t hat t o get her will f or m f o ur strata acc or di n g t o a s u bject’s 
parti ci pat i on i n t he s u b-st u dies. T he f o ur strata are: Partici pati on ( 1) i n n o ne of t he s u b-
st u dies, ( 2) i n M RI o nl y , ( 3) i n P K o nl y, a n d ( 4) in b ot h M RI a n d P K. F or eac h s u bject, 
parti ci pat i on is o pti o nal. Ra n d o mizat i on will  be stratifie d t o e ns ure a p pr o xi mate bala nce 
bet wee n treat me nt gr o u ps wit hi n eac h s u b-st u dy.
 
 
F or f urt her details, please see t he pr ot oc ol.
1. 3
N u m ber of s u bjects
Wit h 1 4 5 ra n d omise d s u bjects i n eac h ar m a n d a bet wee n-s u bject sta n dar d-de viati o n of 1. 0 o n 
l og- scale ( nat ural l o garit h m), a relati ve tr e at me nt differe nce of – 2 5 % bet wee n hi g h -d ose a n d 
pl ace b o i n ge o metri c-mea n rati o of U A C R at 6 m o nt hs o ver baseli ne will be detecte d wit h
close u p t o 8 0 % p o wer, base d o n a t w o -si de d t-test wit h si g nifica nce le vel 0.1. Ass u mi n g t he 
sa me n u m ber i n all ar ms, 5 × 1 4 5 = 7 2 5 s u bjects m ust be ra n d o mise d i n t otal. T h e esti mate d 
val ue of 1. 0 f or t he sta n dar d de viat i on o n l o g -scale is deri ve d fr om t he res ults fr o m t he 
Astra Ze neca cli nical-st u d y D 5 4 9 5 C 0 0 0 0 7.
 
 
C CI
C CI


Statistical A nal ysis Pla n 
Astra Ze neca
D 5 4 9 5 C 0 0 0 0 2 - 3. 0
1 6 J ul 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
1 8 of 5 5
 
1. 4
T his st atistic al a n al ysis pl a n
T his st atistical a nal ysis pla n (S A P ) c o vers v 5. 0 of  t he pr ot oc ol.
2
A N A L Y SI S S E T S
2. 1
Defi niti o n of a n al ysis sets
F ull a n al ysis set ( F A S): A ll ra n d omise d s u bjects. S u bjects will be a nal yse d b y ra n d o mise d
treat me nt.
S afet y a n al ysis set : All s u bjects w h o ha d at least o ne d ose of i n vesti gati onal pr o d uct . A 
s u bject will be a nal yse d b y his/ her ra n d omise d treat me nt , u nless t he s ubject (err o ne o usl y) was 
gi ve n a n ot her s pecific i n vesti gati onal treat me nt f or t he wh ole d ur ati o n of t he st u dy, i n w hic h 
case t he s u bject will be a nal yse d b y t hat ot her treat me nt i nstea d.
P K ( a n al ysis) set: All s u bjects w h o recei ve d i n vesti gati onal all o p uri n o l or veri n ura d a n d ha ve 
at least o ne p ost -baseli ne c o nce ntrati o n meas ure me nt of veri n ura d, all o p ur i n ol, or o x yp uri n o l 
at a sc he d ule d ti me p o i nt.
T he pr ot oc ol als o me nt i ons t he per- p r ot oc ol a n al ysis set , t he e nr olle d ( a n al ysis set) , t he 
r a n d o mise d ( a n al ysis) set , a n d t he effic ac y a n al ysis set . N o ne of t hese f our a nal ysis sets will 
be use d i n t his S A P.
2. 2
Vi ol ati o ns a n d de vi ati o ns
T he i de nt ifie d t y pes of im p orta nt pr ot oc ol de viati o ns (I P D) as well as n o n-i m p orta nt pr ot oc ol 
de viat i ons are f o u n d i n t he pr ot oc ol -de viat i on list acc o m pa n yi n g t he c urre nt versi on of t he 
Pr ot oc ol  De viati on Pl a n. F or t he di s pla y, please see S u bsect i on 4. 2. 7. 7 .
2. 3
S witc hi n g t o t w o -c a ps ule re gi me n
As per versi o n 5. 0 of t he pr ot oc ol ( pr ot oc ol a me n d me nt 5, P A 5), t he last pla n ne d, n u m bere d 
visit will be V 1 0. M ost of t h ose s u bjects t hat ha ve reac he d V 9 ha ve bee n as ke d t o s witc h t o 
t wo- ca ps ule re gi me n fr o m t he pre vi o us o ne -ca ps ule re gi me n, b ut s o me ha ve decli ne d a n d 
t heref ore c o nti n ue d o n o ne -ca ps ule re gi me n u ntil V 1 0 a n d disc o nt i n ue d st u d y t here. Ot her 
s u bjects ma y ha ve passe d V 1 0 w he n versi o n 5 of  t he pr ot oc ol t o o k effect; t hese s u bjects will 
st a y o n o ne-ca ps ule treat me nt u ntil ne xt pla n ne d, n u m bere d visit a n d disc o nt i n ue st u d y t here.
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With respect to “switching status”, we thus need to identify these subsets of subjects:
1. PA5 consenters: All randomised subject who have signed the informed consent at V9 
according to PA5.
2. Non-PA5-consenters: All randomised subjects who are not PA5 consenters.
3. All: All randomized subjects.
The basic principle is that, in an analysis (table, figure, formal statistical analysis) where

at least one of the involved visits
o
is strictly beyond V9 or
o
is the EOT visit or the follow-up visit, or

at least one of the involved study periods
o
partly or in total falls strictly beyond V9, like V3V10 or V3 (whole study), or
o
involves the EOT visit or the follow-up visits, like V3EOT,
the presented “switching status” groups should be PA5-consenters, Non-PA5-consenters. If –
on the other hand – all involved visits of analysis and all involved study periods neither go 
beyond V9, nor involve the EOT visit or the follow-up visit, then the appropriate group is All. 
An exception is summaries and displays of baseline data, where all three groups should be 
considered.
Subject dispositions (see Subsection 4.2.7.2) must take switching into double-capsule regimen 
into account. Listings must also be adjusted to meet the “switching status”
In output where the group of PA5-consenter (or non-PA5-consenters) is taken into account, it 
could be wise to clearly indicate – in one way or another, e.g. in the treatment label – that the 
“Low” arm does not necessarily takes its label from the lowest planned dose of verinurad, 
3 mg, but could very well connote the very highest planned dose of verinurad, 24 mg, this to 
avoid grave misreading with ensuing misinterpretation.
3
PRIMARY AND SECONDARY VARIABLES
3.1
Baseline. On treatment. In study
For all longitudinal series of measurements of the same kind, the baseline is derived – if not 
otherwise specified – as the latest non-missing value with a date on, or prior to, the date of the 
randomization visit. If no such value exists, the baseline assessment will be set to missing. For 
baseline S-creatinine used for determining S-creatinine elevations, in particular, another rule 
applies, see Subsection 4.2.6.3.
A subject is on treatment from the first dosing day until five (5) whole days after last dosing 
day (both end-days included).


Statistical A nal ysis Pla n 
Astra Ze neca
D 5 4 9 5 C 0 0 0 0 2 - 3. 0
1 6 J ul 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
2 0 of 5 5
A s u bject i s i n st u dy fr o m t he d a y  of V 3 u ntil t he da y of last atte n de d sc he d ule d visit , i.e. o ne 
of  t he visits V 3, V 4, …, V 1 4 ( or be y o n d) , t he e n d-of -treat me nt ( E O T ) visit , a n d t he f oll o w - u p 
visit .
3. 2
Missi n g v al ues
N o missi n g val ues will be i m p ute d u nless ot her wise state d i n S u bsect i on 4. All st atistical 
a nal yses ( parti c ularl y t he for m al statistic al a nal yses of U A C R, s U A, e G F R, S -creat i ni ne, a n d 
S/ P -c ystati n C) are base d o n a treat me nt-p olic y strate g y  for i nterc urre nt e ve nts, s o all i n- st u d y 
val ues f or all s u bjects are vali d, re gar dless of  a n y i nterc urre nt e ve nt.
3. 3
E n d p oi nts
T he f or mal e n d p o i nts, as state d i n t he pr ot oc ol, are liste d bel o w. “ At 6 mo nt hs” is defi ne d as 
V 8. “A t 1 2 mo nt hs” is defi n e d as V 1 0. “ E n d o f treat me nt ” is defi n e d as t he e n d-of -tr e at me nt 
( E O T) visit. “F o ll ow- u p ” is defi ne d as t he f oll o w -u p visit . T hese are t he e n d p o i nts (f or 
S u bsecti o ns 3. 3. 1 , 3. 3. 2 , a n d 3. 3. 3 bel o w , refere nce is S u bsect i on 9. 4. 1 i n v 5 . 0 of t he 
pr ot oc ol ; f or S u bsecti on 3. 3. 4 bel o w it is Ta ble 4 i n Secti o n 3 of  v 5. 0 of t he pr ot oc ol ; f or 
Ta ble 1 bel o w it is Ta ble 1 2 [ m o difie d] i n S u bsecti o n 8. 1. 3. 1 i n v 5. 0 of t he pr ot oc ol ):
3. 3. 1
Pri m ar y e n d p oi nt

C ha n ge fr o m baseli ne i n U A C R at 6 m o nt hs
3. 3. 2
Sec o n d ar y e n d p oi nts

C ha n ge fr o m baseli ne i n U A C R at 6 a n d 1 2 m o nt hs

C ha n ge fr o m baseli ne i n s U A at 6 a n d 1 2 m o nt hs

C ha n ge fr o m baseli ne i n esti mate d gl o mer ular filtrati o n rate at 6 a n d 1 2 m o nt hs

C ha n ge fr o m baseli ne i n creat i ni ne at 6 a n d 1 2 m o nt hs

C ha n ge fr o m baseli ne i n c ystati n -C at 6 a n d 1 2 m o nt hs
 
C CI




Statistical A nal ysis Pla n 
Astra Ze neca
D 5 4 9 5 C 0 0 0 0 2 - 3. 0
1 6 J ul 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
2 2 of 5 5
 
 
 
 
3. 3. 4
S afet y e n d p oi nts

Rat es of A Es a n d S A Es, i ncl u di n g C V e ve nts

C ha n ges i n vital si g ns, p h ysical e xa mi nat i ons † † † † , electr ocar dio gra ms ( E C G), a n d 
cli nical la b orat or y para meters.
T he safet y e nd p oi nt “ p h ysical e xa mi nat i ons” – mar ke d a b o ve wit h f our da g ger s ( † † † †) – will 
n ot be a nal y se d, see S u bsecti on 6. 5 bel o w .
Vi t al si g n assess me nts f or safety are:

B o d y  wei g ht

B o d y  mass i n de x

B o d y  t e mperat ure

P ul se rate

S y st olic blo o d press ur e

Di ast olic blo o d press ure
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Electrocardiogram (ECG) assessments for safety are:

Overall ECG evaluation

QT interval

QTcF interval
Clinical-laboratory assessments for safety are:

Haematology/Haemostasis (whole blood)
o
B-Haemoglobin (Hb)
o
B-Leukocyte count
o
B-Leukocyte differential count (absolute count)
o
B-Platelet count
o
B-Haematocrit
o
B-Haemoglobin A1c
o
B-Red blood cell count (RBC)
o
B-Mean corpuscular haemoglobin (MCH)
o
B-Mean corpuscular haemoglobin concentration (MCHC)
o
B-Red blood cell morphology
o
B-Mean corpuscular volume (MCV)

Urinalysis (dipstick)
o
U-Haemoglobin/Erythrocytes/Blood
o
U-Glucose

Clinical Chemistry (serum or plasma)
o
S/P-Bilirubin, total
o
S/P-Alkaline phosphatase (ALP)
o
S/P-Aspartate transaminase (AST)
o
S/P-Alanine transaminase (ALT)
o
S/P-Albumin
o
S/P-Potassium
o
S/P-Calcium, total
o
S/P-Sodium
o
S/P-Creatinine kinase (CK)
o
S/P-Bicarbonate
o
S/P-Blood Urea Nitrogen
o
S/P-Phosphate
o
S/P-Creatinine
3.4
How to identify the end-of-treatment (EOT) visit and the follow-
up visit
Because V10 for quite many (most?) subjects will – according to updated protocol version 5.0 
– also be the EOT visit, and because the EOT visit therefore will carry the label ‘V10’ rather 


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than ‘EOT’ in the datasets, there must be a rule for identifying the EOT visit when it cannot be 
found. Such a rule could very well be useful in other situations when the EOT visit is missing.
An EOT visit, or rather the requested data for it, is identified like this:
1. If data of the requested kind is collected (missing or non-missing) at a visit termed 
“EOT” then that data will – of course – be identified as the EOT-visit data.
2. Else, if there are strong indications that V10 has coincided with the EOT visit, then the 
V10 data will be identified as the EOT-visit data, if data of the requested kind is 
collected (missing or non-missing) at ‘V10’.
3. Else, if last day of treatment falls within the planned time window of a numbered visit, 
then the data from that numbered visit will be identified as the EOT-visit data, if data 
of the requested kind is collected (missing or non-missing) at that visit, and as long as 
the numbered visit actually occurs after the last treatment day.
4. Else, data obtained on the visit closest to, or on, but not preceding, the last treatment 
day – be this visit scheduled or unscheduled – will be identified as the EOT-visit data, 
if data of the requested kind is collected (missing or non-missing) at that visit.
However, to be eligible, that visit must not fall more than two weeks after last 
treatment day.
5. Else, EOT visit data will be set to missing.
Also we could use a rule to identify the follow-up visit when it cannot be readily found. 
Typically, this would be the case when a subject has permanently discontinued treatment 
early. Requested data for a follow-up visit is identified like this:
1. If data of the requested kind is collected (missing or non-missing) at a visit termed 
“Follow-up”, then that data will – of course – be identified as the follow-up-visit data.
2. Else, if the subject permanently discontinued treatment early, the data will be the data 
for the last scheduled, numbered visit after last treatment day, if data of the requested 
kind is collected (missing or non-missing) at that visit.
3. Else, again if the subject permanently discontinued treatment early, the data will be the 
data for the last visit, scheduled or unscheduled, after last treatment day, if data of the 
requested kind is collected (missing or non-missing) at that visit
4. Else, be it scheduled or unscheduled, closest to four weeks after last treatment day will 
be identified as the follow-up data, if the requested kind of data is collected (missing 
or non-missing) at that visit, and as long as the visit takes place between three and five 
weeks after last treatment day.
5. Else, the follow-up-visit data will be set to missing. 


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A N A L Y SI S M E T H O D S
4. 1
Ge ner al pri nci ples
4. 1. 1
Descri pti ve st atistics
A ll v ari a bles i n t his S A P will be s u m marise d i n ta bles a n d gra p hs, as a p pr o priat e.
I n ta bles, nu mer ical varia bles will be s u m marize d b y  t he n u m ber of o bser vati ons, ari t h metic 
mea n, ( arit h metic) sta n dar d-de viat i on, m e dia n, mi ni m u m, a n d ma xi m u m . H o we ver, if best 
a nal yse d o n l o g scale (li ke U A C R, s U A, e G F R , S- creati ni ne, a n d S/ P -c ystati n C), t he 
varia bles will  be s u m marise d b y nu m ber of o bser vati o ns, ge o metri c mea n ( g mea n) , c oefficie nt 
of  variati on ( C V), me d ia n, mi ni m u m, a n d ma xi m u m. Cate g ori cal varia bles will be 
s u m marize d b y n u m ber of o bser vat i ons, fre q ue nc y c o u nts f or eac h cate g or y, a n d perce nta ges 
f or eac h cate g or y. All v ari a bles will be s u m marise d b y visit a n d b y treat me nt.
N u m erical v aria bles assesse d at se veral visits will, w he n nee de d, be d is pla ye d gra p hicall y  as 
arit h metic-me a n, ge o metric- mea n , or me dia n c ur ves (li ne pl ot) o ver ti me ( visit), b y  tr e at me nt.
N u m erical v ari a bles t hat are deri ve d c ha n ge -fr om- baseli ne varia bles will, w he n nee de d, ha ve
ta bles a n d gra p hs as a b o ve f or b ot h t he ra w val ues a n d t he c ha n ge-fr om- base li ne val ues.
C ha n ge fr o m baseli ne i n cate g orical varia bles will , w he n dee me d nee de d, be s u m marise d i n 
s hift ta bles.
 
 
 
 
 
 
 
Ge o m etric mea ns, 
, ge o metric c oefficie nts of 
variat i on, (esti mate d) ge o metric -mea n rati os, a n d t he u p per a n d l o wer li mit s of  c o nfi de nce 
i nter vals f or (esti mate d) ge o metric- me a n ratios m ust be prese nte d wi t h at least f o ur ( 4) 
sig nifica nt di gi ts.
C CI
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4. 1. 2
H a n dli n g of l a b or at or y v al ues t h at ( 1) are n ot re p ort a ble, ( 2) are 
re p orte d as “ N o s a m ple ” or are ot her wise missi n g, or ( 3) are bel o w
L L O Q
F or a ll la b orat or y v aria bles 
: Val ues re p orte d as ‘ N ot 
Re p orta ble’, or t he li ke, will, if feasi ble, be liste d as N R ( n ot re p orte d), ot her wise as missi n g. 
Missi n g val ues, s o me of t he m per ha ps re p orte d as ‘ N o Sa m ple’ or t he li ke, will i n listi n gs, if 
feasi ble, be prese nte d as N S ( n o sa m ple), ot her wise as missi n g. N u merical val ues bel o w 
L L O Q will i n list i n gs prefera bl y be prese nte d as “ < { L L O Q }”, w here “ { L L O Q }” is re place d 
b y t he n u merical val ue of t he L L O Q i n q uesti o n, e. g., “ < 5 1”, ot her wise as “ < L L O Q”, “ N Q”, 
or t he li ke . If re p orte d as “ < L L O Q” or “ N Q”, t he n t he val ue of L L O Q m ust be state d i n a 
f oot n ote ( or t he li ke) o f t he listi n g. Val ues t hat are n ot re p orta bl e ( N R) or n o n-sa mple ( N S) 
will be c o nsi dere d missi n g i n all statistical a nal yses, b ot h descri pt i ve a n d i nfere ntial. 
N u m erical val ues t hat are belo w L L O Q ( N Q) will i n all statistical a nal yses, b ot h descri pt i ve 
a n d i nfere ntial, be re place d b y a val ue w hic h is half t he val ue of t he L L O Q, i.e., b y LL O Q/ 2; 
t his r ule m ust – w here ver a p plie d – be fla g ge d i n a f o ot n ote ( or t he li ke) i n t he o ut p ut re p ort i n 
q uesti o n , pr efera bl y t o get her wit h t he n u m ber, a n d fracti on, of va l ues bel o w L L O Q.
4. 1. 3
H a n dli n g of l a b or at or y v al ues t h at are a b o ve t he u p per li mit of 
q u a ntific ati o n ( U L O Q)
N u m erical val ues a b o ve t he u p per li mit of q ua ntificati o n ( U L O Q) will prefera bl y be liste d as 
“ > { U L O Q } , w here “ {U L O Q }” is re place d b y t he n u merical val ue of t he U L O Q i n questi o n ., 
e. g., “ > 5 0 0”, ot her wise as “ > U L O Q”. If re p orte d as “ > U L O Q”, t he n t he val ue o f U L O Q 
m ust be state d i n a f o ot n ote ( or t he li ke) of t he list i n g.
N u m erical val ues t hat are a b o ve U L O Q will i n all statistical a nal yses, b ot h descri pt i ve a n d 
i nfere ntial, be re place d b y t he val ue of t he U L O Q; t his r ule m ust – w here ver a p plie d – be 
fla g ge d i n a f o ot n ote ( or t he li ke) i n t he o ut p ut re p ort i n q uesti on, prefera ble t o get her wit h t he 
n u m ber, a n d fract i on, of s u bjects e xcee di n g U L O Q.
4. 2
A n al ysis met h o ds
4. 2. 1
Pri m ar y e n d p oi nt: C h a n ge fr o m  baseli ne i n U A C R at 6 m o nt hs ( V 8):
“ Hi g h ” vs. “ Pl ace b o ”
4. 2. 1. 1
M ai n
a n al ysis
T he nat ural  lo g -tra nsf or me d U A C R val ues f or V 4, V 5, V 6, V 7, V 8, a n d V 9 (f or t he sec o n d 
i nteri m a nal ysis: V 4, V 5, V 6, V 7, a n d V 8) will be a nal yse d usi n g a re peate d m eas ures mi xe d 
m o d el ( M M R M) w here l o g( U A C R) w o ul d de pe n d o n t he fi xe d cate g orical effects of 
ra n d omise d tr e at me nt, visit , dia betes mellit us ( D M ) stat us ( yes/ n o) at baseli ne, al b u mi n uria 
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status (see Subsection 4.2.11.1) at baseline, NT-proBNP status (see Subsection 4.2.11.6) at 
baseline, use of sodium/glucose cotransporter 2 inhibitor (SGLT2i) (yes/no) at baseline, and 
treatment-by-visit interaction, as well as the continuous fixed covariate of baseline 
log(UACR) and its baseline-log(UACR)-by-visit interaction. An unstructured matrix for the 
within subject error variance-covariance will be used. The denominator degrees of freedom 
will be calculated according to the Kenward-Roger method. If the estimating algorithms will
not converge, the following steps will be taken to simplify the model until convergence is 
achieved:
1. As a first step, try in order these three covariance structures: Toeplitz, the first-order 
autoregressive, and compound symmetry.
2. If step 1 does not work, the baseline-log(UACR)-by-visit interaction will be removed
from the last model in step 1, i.e. from the model with compound symmetry.
3. If step 2 does not work either, then instead the treatment-by-visit interaction will be 
removed from the last model in step 1, i.e. from the model with compound symmetry.
4. If step 3 does not work either, then both the baseline-log(UACR)-by-visit interaction 
and the treatment-by-visit interaction will be removed from the last model in step 1, 
i.e. from the model with compound symmetry.
5. If step 4 did not work either, then (a) NT-proBNP-status factor, (b) the DM-status 
factor, and (c) the albuminuria-status factor will be removed, one at a time, in this 
order, starting with the model in step 4, until convergence.
The least squares mean (LSmean) change from baseline to 6 months (V8) in the log-
transformed UACR will be calculated by treatment (“High” and “Placebo”) with its 95 % 
confidence intervals (CI). The LSMeans difference between the two treatments (“High” vs. 
“Placebo”) will be calculated with its 95 % CI. A p-value for the treatment difference between 
“High” and “Placebo” will also be calculated. The above LSMeans change from baseline (and 
the 95 % CI) for each of the two treatments will be exponentiated to yield the geometric mean 
ratio from baseline for each treatment with its 95 % CI at the original scale of UACR. Percent 
change from baseline with 95 % CI for each of the two treatments will in turn be derived from 
the geometric estimated mean ratio, and CI, by ([geometric mean ratio] – 1) × (100 %). The 
LSMeans difference between “High” and “Placebo” (and its 95 % CI) will also be 
exponentiated to yield the geometric mean ratio between the two treatments at V8 and its 
95 % CI at the original scale of UACR.
All available in-trial UACR values at (V3,), V4, V5, V6, V7, V8, and V9 will be used (for the 
second interim analysis: [V3,] V4, V5, V6, V7, and V8), regardless of any intercurrent events. 
Missing values will not be imputed. In this analysis it is thus assumed that any missing UACR 
values are missing at random (MAR).
Missing explanatory covariates and factors will not be imputed either.


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The analysis set will be the FAS.
4.2.1.2
Sensitivity analysis: Jump to placebo arm
A sensitivity analysis will be conducted, a multiple-imputations analysis with an assumption 
of “unconditional jump to placebo arm” for off-treatment subjects.
All available in-trial values for UACR at (V3,) V4, V5, V6, V7, V8, and V9 (for the second 
interim analysis: [V3,] V4, V5, V6, V7, and V8) will be used in the sensitivity analysis, 
regardless of any intercurrent events.
Missing values of log(UACR) from V4, V5, V6, V7, V8, and V9 (for the second interim 
analysis: V4, V5, V6, V7, and V8) will be imputed recursively by means of simulation, visit 
by visit, starting with the imputations at V4. Missing log(UACR) data at a visit x (Vx) will be 
simulated like this: 
A. Missing off-treatment values will be simulated from an ANCOVA where non-missing
log(UACR) at Vx depends on baseline log(UACR) and on the last post-baseline, non-
missing or previously imputed log(UACR)-value before Vx (if any) as covariates and 
DM status at baseline, albuminuria status at baseline, NT-proBNP status at baseline, 
and use of SGLT2i at baseline as factors. Only subjects in the placebo arm (on or off 
treatment) will contribute to the ANCOVA, and they do it as long as they have non-
missing log(UACR) at Vx and has a full set of explanatory variables.
B. Missing on-treatment values will be simulated form an ANCOVA where non-missing
log(UACR) at Vx depends on baseline log(UACR) and all post-baseline, non-missing 
or previously imputed log(UACR)-values before Vx (if any) as covariates and 
randomised treatment, DM status at baseline, albuminuria status at baseline, NT-
proBNP status at baseline, and use of SGLT2i at baseline as factors and baseline-
log(UACR)-by-treatment as interaction. Only subjects with non-missing, on-treatment 
log(UACR)-value at Vx and with a full set of explanatory variables will contribute to 
the ANCOVA.
A simulated log(UACR) value from one of the ANCOVAs above is its predicted mean-value 
plus the estimated standard-deviation times a random number from a standard-normal 
distribution. We will conduct the simulations in A and B above not just once but multiple 
times (a kind of multiple imputations). In this way, we will simulate 500 independent data-sets 
where all missing log(UACR) values from V4 until V9 (V8 for second interim) have been 
imputed with simulated values.
In case of missing covariates and factors, all of what is laid down above must – for each of the 
500 data-sets – be preceded by one cycle of imputation by chained equations, where the 
missing covariates and factors are imputed, one covariate/factor after the other:


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A. First, the covariate log(UACR) at baseline (V3) will, if missing, be simulated from an 
ANCOVA where log(UACR) at baseline depends on log(UACR) at V4, treatment, and 
treatment-by-log(UACR)-at-V4. All subjects with non-missing log(UACR) at baseline 
and at V4 will contribute to the ANCOVA. The imputed log(UACR) value from the 
ANCOVA is its predicted mean-value plus the estimated standard-deviation times a 
random number from a standard-normal distribution. For those subjects where 
log(UACR) is missing also at V4, log(UACR) at baseline will, if missing, instead be 
imputed as random numbers from a normal distribution with mean and standard-
deviation set to the observed mean and standard-deviation for the non-missing 
log(UACR) values at baseline. Hereafter, the covariate log(UACR) at baseline is 
complete. Please note that by now, we can form change-from-baseline in log(UACR) 
for those subjects where log(UACR) was missing at baseline; this was unfeasible 
before.
B. Next, the factor albuminuria status at baseline will, when missing, be imputed. The 
imputed value will be derived from imputed baseline log(UACR) values, obtained as 
in step A, according to the definition in Subsection 4.2.11.1. Hereafter, also the factor 
albuminuria status at baseline is complete.
C. Next, log(NT-proBNP) at baseline will, when missing, be simulated from an 
ANCOVA where log(NT-proBNP) at baseline depends on log(UACR) at baseline and 
albuminuria status at baseline (both either non-missing or imputed). All subjects with 
non-missing log(NT-proBNP) at baseline at baseline will contribute to the ANCOVA 
model. The imputed log(NT-proBNP) value from the ANCOVA is its predicted mean-
value plus the estimated standard-deviation times a random number from a standard-
normal distribution.
D. Next: Back-transformation of the imputed values of log(NT-proBNP) at baseline in 
step C above, and then categorisation, makes the factor NT-proBNP status (see 
Subsection 4.2.11.6) at baseline complete too.
E. Next, the factor DM status at baseline will, when missing, be simulated from a
logistic-regression model where “yes” (vs. “no) for DM status at baseline depends on 
log(NT-proBNP) at baseline, log(UACR) at baseline, and albuminuria status at 
baseline (all three either non-missing or imputed). All subjects with a non-missing DM 
status at baseline, with a non-missing log(NT-proBNP) at baseline, and a non-missing 
log(UACR) at baseline will contribute to the logistic-regression model. The imputed 
DM status at baseline will be a random outcome from a binomial distribution with the 
probability of DM status at baseline being ‘yes’ is set to the estimated probability of 
DM status at baseline being ‘yes’, given by the logistic-regression model. Hereafter 
the factor DM status at baseline is also complete.
F. Eventually, the factor SGLT2i use at baseline: It is not expected that the value of 
SGLT2i use at baseline be missing, so all covariates and factors are complete by now.


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The 500 datasets will each be analysed with the same MMRM model as for the main analysis 
in Subsection 4.2.1.1. However, before being applied to the 500 datasets, the MMRM must be 
simplified to the same extent as was needed for the main analysis to converge, in terms of the 
simplification steps 1 to 5 in Subsection 4.2.1.1.
The MMRM will leave us with 500 regression results (regression-parameter estimates with 
standard-error). Before back-transformation from log-scale, Rubin’s formulae will be applied
to the 500 results and compile them into one estimate of the log-scale treatment-difference for 
“High” vs. “Placebo”, together with a 95 % CI. Back-transformation from log-scale will then 
give an estimate, with a 95 % CI, of the treatment ratio for “High” vs. “Placebo”. Yet another 
transformation will eventually give an estimate, with 95 % CI, of the relative treatment 
difference for “High” vs “Placebo”, ([treatment ratio] – 1) × (100 %).
No p-value will be provided.
The analysis set will be the FAS.
Since off-treatment subjects without assessment in this analysis are assumed to behave 
basically as placebo subjects, missing UACR values are automatically modelled as missing 
not at random (MNAR), and from that aspect, this analysis challenges the main analysis, 
which assumes MAR. If the result from the main analysis and the ones from the sensitivity 
analysis will not sensibly match, the robustness of the results from the main analysis will be 
questionable.
4.2.1.3
Supplementary subgroup analyses
The following 16 subgroupings will be investigated:

DM status at baseline

Hypertension status at baseline (see Subsection 4.2.11.3)

eGFR status, two categories, (see Subsection 4.2.11.4) at baseline

eGFR status, three categories, (see Subsection 4.2.11.4) at baseline

eGFR status, four categories, (see Subsection 4.2.11.4) at baseline

eGFR status, six categories, (see Subsection 4.2.11.4) at baseline

Albuminuria status (see Subsection 4.2.11.1) at baseline

sUA status, two categories, median-based, (see Subsection 4.2.11.5) at baseline

sUA status, four categories, (see Subsection 4.2.11.5) at baseline

NT-proBNP status (see Subsection 4.2.11.6) at baseline

Race

Age group (< 65 yr; ≥65 yr) at baseline

Sex

Geographic region (see Subsection 4.2.11.2)

SGLT2i use at baseline

Use of angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor 
blockers (ARB) (see Subsection 4.2.11.7) at baseline.


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Each of the 16 subgroup analyses will be carried out exactly as for the main analysis in 
Subsection 4.2.1.1, except
1. that the subgrouping factor itself and the subgrouping-by-treatment interaction both
will be added to the list of explanatory variables of the MMRM (if the subgrouping 
factor is already included, then only the interaction will be added), and
2. that a p-value for the subgrouping-by-treatment interaction will be given, and
3. that measures must be taken in case scarcity in any of the subgroups precludes
convergence (collapsing of subgroups is not advisable, removing small subgroups is 
better), and
4. that measures must be taken in Step 5 in the model-simplification in Subsection 4.2.1.1
to prevent that the current subgrouping’s main factor is not removed, and
5. that the subsequent estimates and CIs all are reported subdivided by current subgroups, 
and
6. that the corresponding p-values related to treatment differences will not be provided.
The CIs in item 5 above will, besides in one or more tables, also be presented in a forest plot.
Those subjects for which the grouping variable is missing will be excluded from the 
corresponding analysis.
The analysis set will be the FAS.
4.2.2
Primary endpoint: Change from baseline in UACR at 6 months (V8): other 
comparisons
The analyses of change from baseline in UACR at 6 months (V8) in this subsection focus on 
the following comparisons:

“High” and “Intermediate” combined vs. “Allopurinol alone” **

“Intermediate” vs. “Placebo”

“Low” vs. “Placebo”

“High” vs. “Allopurinol alone”

“Intermediate” vs. “Allopurinol alone”

“Low” vs. “Allopurinol alone”

“Allopurinol alone” vs. “Placebo” **
Each of these seven (7) analyses will be carried out exactly as the main analysis in
Subsection 4.2.1.1 except that the comparison “High” vs. “Placebo” is replaced by the current 
comparison.
For the comparison “High” and “Intermediate” combined vs. “Placebo”, the two treatment 
categories of “High” and “Intermediate” will be merged, forming one new temporary 
category.


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The double asterisks (**) in the list above indicate where the tests of no treatment difference, 
together with the test of no treatment difference in Subsection 4.2.1.1 (“High” vs. “Placebo”), 
are controlled for multiplicity. See Subsection 4.2.10 below.
4.2.3
Secondary endpoints at 6 months (V8) and 12 months (V10)
4.2.3.1
Secondary endpoints at 6 months (V8)
For the secondary endpoints at 6 months (V8), there are four (4) endpoints, specifically

Change from baseline in sUA at 6 months (V8),

Change from baseline in eGFR at 6 months (V8),

Change from baseline in S-creatinine at 6 months (V8), and

Change from baseline in S/P-cystatin C at 6 months (V8).
and there are seven (7) comparisons requested for each endpoint, namely

“High” vs. “Placebo”,

“Intermediate” vs. “Placebo”,

“Low” vs. “Placebo”,

“High” vs. “Allopurinol alone”,

“Intermediate” vs. “Allopurinol alone”,

“Low” vs. “Allopurinol alone”, and

“Allopurinol alone” vs. “Placebo”.
Thus, in this subsection, 28 analyses are laid down. Each such analysis will be carried out 
exactly as the main analysis in Subsection 4.2.1.1, except that the analyte “UACR” and the 
comparison “High” vs. “Placebo” are replaced by the current analyte and comparison, 
respectively.
The comparison “High” vs. “Placebo” for change from baseline in sUA at 6 months (V8) will 
also be analysed as in Subsection 4.2.1.3.
Please note that the two endpoints change from baseline in UACR at 6 months (V8) and 
change from baseline in sUA at 6 months (V8) also are secondary endpoints in the dose-
response analyses. Instructions for the dose-response analyses are found in Subsection 4.2.9
below.
4.2.3.2
Secondary endpoints at 12 months (V10)
For the secondary endpoints at 12 months (V10), there are five (5) endpoints, specifically

Change from baseline in UACR at 12 months (V10),

Change from baseline in sUA at 12 months (V10),

Change from baseline in eGFR at 12 months (V10),

Change from baseline in S-creatinine at 12 months (V10), and

Change from baseline in S/P-cystatin C at 12 months (V10),








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4.2.6
Safety assessments
All safety endpoints (see Subsection 3.3.4) will be analysed descriptively only. The analysis 
set will be the safety analysis set, unless otherwise specified.
4.2.6.1
Adverse events (AE)
A. All serious adverse events (SAE) occurring before day of randomisation visit (V3) will 
be displayed in listings. This will be done for all subjects, not just for the subjects in 
the safety analysis set.
B. All in-study AEs will be listed. The analysis set will be the safety analysis set.
C. All in-study AEs will be summarised, by allocated treatment (see Subsections 2.1
above [safety analysis set] and 6.4 below). This will be summarised:
1. all AEs,
2. all AEs, by system organ class (SOC)/preferred term (PT),
3. all AEs, most common (> 5 %), by SOC/PT,
4. all AEs, most common (> 5 %), by PT,
5. all AEs, by PT and maximum reported intensity,
6. all AEs, by PT and relationship to investigational product (IP)
7. all SAEs, by SOC/PT,
8. all AEs with outcome death, by SOC/PT,
9. all AEs leading to permanent discontinuation of IP, by SOC/PT, and
10. all non-serious AEs, most common (> 5 %)
Presented will be the number and percentage of subjects with at least one AE of the 
type in question. The number that the percentage relates to (“the denominator”) will
always be the total number of subjects allocated to the treatment in question. For 
items 1, 2, 7, and 10 above, the number of events of the type in question will also be 
presented.
For items 3 and 4 above, the PTs should be sorted, first after descending frequency, 
and then (i.e. when there is a tie) alphabetically.
When the AEs are to be summarised by SOC/PT of the Medical Dictionary for 
Regulatory Activities (MedDRA), then the latest version of the MedDRA dictionary 
must be used for the coding of the AEs.
The analysis set will be the safety analysis set.
D. All in-study AEs will also be summarised in a separate overview table, by study period 
(see Subsection 4.2.11.8 below), and allocated treatment (see Subsections 2.1 above
[safety analysis set] and 6.4 below). These categories of AEs will be summarised:
1. all AEs, 
2. all SAEs,
3. all AEs with outcome death,
4. all AEs leading to permanent discontinuation of IP, and


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5. all AEs with dose reduction.
Presented will be the number and percentage of subjects with at least one AE of the 
type in question. The number that the percentage relates to (“the denominator”) will 
always be the total number of subjects allocated to the treatment in question. Presented 
will also be the number of events of the type in question, except for items 3 (death) 
and 4 (IP discontinuation) above. The analysis set will be the safety analysis set.
E. In the same way as for the in-study AEs in item D above, all on-treatment AEs will be 
summarised, by study period and allocated treatment. The analysis set will be the 
safety analysis set.
F. Key subject information will be provided for all in-study
1. AEs with outcome death,
2. SAEs, and
3. AEs leading to permanent discontinuation of IP.
The analysis set will be the safety analysis set.
4.2.6.2
Adjudicated events
A. All adjudication-confirmed events occurring before day of randomisation visit (V3)
will be listed. This will be done for all subjects, not just for the subjects in the safety 
analysis set.
B. All in-study adjudication-confirmed events will be listed. The analysis set will be the 
safety analysis set.
C. All in-study CV events sent for adjudication will be summarised by type of CV events, 
by allocated treatment (see Subsections 2.1 above [safety analysis set] and 6.4 below),
and by time period (see Subsection 4.2.11.8 below). Types of events sent for 
adjudication that are not AEs, include thromboembolic events and all planned cardiac 
surgery (modules ‘PROCCA’, ‘PROCNCVI’, ‘CERVENT’, ‘CIEVENT’). Presented 
will be the number and percentage of subjects with at least one event. The number that 
the percentage relates to (“the denominator”) should always be the total number of 
subjects allocated to the treatment in question. Presented will also be the number of 
events. The analysis set will be the safety analysis set.
D. All in-study adjudication-confirmed events will also be summarised by allocated 
treatment (see Subsections 2.1 above [safety analysis set] and 6.4 below) and time 
period (see Subsection 4.2.11.8 below). These categories of adjudicated events will be 
summarised:
1. all adjudication-confirmed events, by reported categories of adjudication-
confirmed events,
2. all adjudication-confirmed major CV events (MACE), by reported categories 
of MACEs,
3. all adjudication-confirmed deaths (any type), by reported type of death,
4. all adjudication-confirmed CV deaths, by reported type of CV death,


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5. all adjudication-confirmed non-CV deaths, by reported type of non-CV death.
Presented will be the number and percentage of subjects with at least one event of the 
kind in question. The number that the percentage relates to (“the denominator”) should 
always be the total number of subjects allocated to the treatment in question. Presented 
will also be the number of events of the type in question. The analysis set will be the 
safety analysis set.
E. In the same way as for the in-study events in items C and D above, all on-treatment
adjudicated events will be summarised. The analysis set will be the safety analysis set.
4.2.6.3
S-creatinine elevations
In-study S-creatinine elevations will be summarised, by visit, with number and percentage of 
subjects in each category of S-creatinine elevations. The categories of S-creatinine elevations 
are:

1.5 × baseline ≤S-creatinine

1.5 × baseline ≤S-creatinine < 2.0 × baseline

2.0 × baseline ≤S-creatinine < 3.0 × baseline, or S-creatinine ≥3.0 mg/dL

S-creatinine ≥3. 0 × baseline, or S-creatinine > 4.0 mg/dL
Here, ‘baseline’ refers to a baseline S-creatinine defined as the maximum non-missing 
S-creatinine value observed within 14 days prior to the first dose of randomized study 
medication; if no S-creatinine values exist in that time period, baseline S-creatinine will be set 
to missing. Please note that the four categories above are not mutually exclusive. The 
elevations will be both listed and summarised for the time periods in Subsection 4.2.11.8
below. S-creatinine elevations will also be listed.
Analysis set will be safety analysis set.
4.2.6.4
Potential Hy’s law
Elevated hepatic biochemistry could be identified by means of potential Hy’s law: 
AST ≥3 × ULNAST or ALT ≥ 3 × ULNALT, together with 
{total bilirubin} ≥2 × ULNTotal bilirubin. The ULN values will be provided by the laboratory.
Cases of in-study potential Hy’s law will be both listed and summarised. Plots will also be 
provided: each plot is a log-log scatter plot of maximum in-study (until V8 or V10) total 
bilirubin vs. maximum in-study (until V8 or V10) ALT, both in multiples of upper limit of 
normal (ULN), with horizontal and vertical lines indicating potential Hy’s law thresholds, i.e. 
ALT = 3 × ULNALT and {total bilirubin} = 2 × ULNtotal bilirubin. There will be provided five 
such plots, one per treatment arm, arranged in a panel if feasible, and there will be one such 
panel for V8 and one for V10. All the plots must have same size and axis ranges, for 
comparability.


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The analysis set will be the safety analysis set.
4.2.6.5
The COVID-19 pandemic
The AZ Corporate Pandemic CSRHLD Table and Listing Templates will be followed.
Firstly, COVID-19 pandemic will be given as a reason for not randomized, for not treated 
once randomized, for treatment discontinuation, and for study discontinuation in the subject 
disposition, see Subsection 4.2.7.2 below. As for the subject-disposition summary-table in 
general, the analysis set will be the FAS.
Secondly, important protocol deviations (IPD) related to COVID-19 pandemic will be part of 
the IPD summary in Subsection 4.2.7.7 below. As for the IDP summary-table in general, the 
analysis set will be the FAS.
Thirdly, summary of COVID-19 disruptions will be provided, please cf. template 
‘COVID summary3’ in the AZ Corporate Pandemic CSRHLD Table and Listing Templates.
A COVID-19-related study-disruption is any change in the study conduct or data collection 
due to the COVID-19 pandemic. Examples of COVID-19 related study disruptions include 

the introduction of alternative monitoring approaches,

changes to visit schedules, missed visits, changes to study procedures, and

discontinuation of IP or distribution of IP to patients.
The analysis set will be the FAS.
Fourthly, subjects affected by the COVID-19 pandemic will be listed, cf. template 
‘APL-COVID1’ in the AZ Corporate Pandemic CSRHLD Table and Listing Templates. The 
analysis set will be the FAS.
Fifthly, subjects with reported issues in the Clinical Trial Management System due to the 
COVID-19 pandemic will also be listed, cf. template ‘APL-COVID2’ in the AZ Corporate 
Pandemic CSRHLD Table and Listing Templates. The analysis set will be the FAS.
4.2.6.6
Patient narratives
Programmed patient narratives will be produced for the following AEs and other events, 
irrespective of the events occurred before randomization, on treatment, or off treatment:

all deaths,

all other SAEs,

all AEs leading to permanent discontinuation of IP,

all AEs specifically targeted in the study and/or project (to be decided after DBL),

all S-creatinine elevations (see Subsection 4.2.6.3),

all cases of Hy’s law,

all cases of potential Hy’s law (see Subsection 4.2.6.4),


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
all cases of hypersensitivity (MedDRA SMQ Hypersensitivity broad),

all cases of renal failure (MedDRA SMQ Acute renal failure broad) and

all cases of down-titration.
The narratives are to be presented ‘by patient’, not ‘by event’. More guidance can be found in 
the AZ global guideline LDMS_001_00071172 Patient safety narratives.
4.2.6.7
Overdoses
Overdoses will be listed. The analysis set will be the FAS.
4.2.6.8
Vital signs, electrocariogram (ECG), haematology, clinical chemistry, and 
urinalysis
Vital signs, ECG, haematology, clinichal chemistry, and urianlysis data will be listed.
For tables, the following is minimum for vital signs, ECG, haematology, clinical chemistry, 
and urinalysis:
1. Vital signs over time (in-study). 
2. ECG variables over time (in-study).
3. ECG evaluation over time (in-study).
4. ECG evaluation, last observation (not beyond V9) vs. baseline, shift tables (on-treatment).
5. ECG: QTcF and QTcF intervals, increase from baseline to last timepoint (not beyond V9) 
(on-treatment); not for 2nd interim analysis.
6. Haematology variables over time (in-study).
7. Clinical-chemistry variables over time (in-study).
8. Urinalysis variables over time (in-study).
9. Urinalysis, increase from baseline, not beyond V9 (on-treatement); for 2nd interim analysis 
only; item 10 below is for the CSR.
10. Urinalysis, maximum value vs. baseline, shift tables (on-treatment); for the CSR only; 
item 9 above is for 2nd interim analysis.
11. Haematology, changes outside predefined criteria – key subject information 
(on-treatment).
12. Haematology, changes vs. baseline, w r t extended reference limits – summary 
(on-treatment).
13. Clinical chemistry, changes outside predefined criteria – key subject information 
(on-treatment).
14. Clinical chemistry, changes vs. baseline, w r t extended reference limits – summary 
(on-treatment).
15. Urinalysis, changes outside  predefined criteria – key subject information (on-treatment).
16. Urinalysis, changes vs. baseline, w r t extended reference limits – summary 
(on-treatment).
Suitable graphs will also be produced.


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Analysis set will be the safety analysis set.
4.2.7
Other analyses
4.2.7.1
Demographics and baseline characteristics
This should be presented in the summary by randomised treatment (and total) of 
demographics and baseline characteristics:

Age (yr)

Age group (<65 yr, and ≥65 yr)

Sex

Ethnicity (Hispanic or Latino, Not Hispanic or Latino)

Race

Country

Geographic region (see Subsection 4.2.11.2)

Height (cm) at baseline

Weight (kg) at baseline

Body mass index (kg/m2) at baseline

Use of SGLT2i at baseline

Use of ACEi and ARB (see Subsection 4.2.11.7) at baseline

DM status at baseline

Hypertension at baseline (see Subsection 4.2.11.3)

UACR at baseline

Albuminuria status (see Subsection 4.2.11.1) at baseline

NT-proBNP at baseline

NT-proBNP status (see Subsection 4.2.11.6) at baseline

eGFR at baseline

eGFR status, two categories, (see Subsection 4.2.11.4) at baseline

eGFR status, three categories, (see Subsection 4.2.11.4) at baseline

eGFR status, four categories, (see Subsection 4.2.11.4) at baseline

eGFR status, six categories, (see Subsection 4.2.11.4) at baseline

sUA at baseline

sUA status, two categories, median based,(see Subsection 4.2.11.5) at baseline

sUA status, four categories, (see Subsection 4.2.11.5) at baseline

S-creatinine at baseline

S/P-cystatin C at baseline

Sub-study participation (stratifying sub-studies only; not the vascular-reactivity sub-
study), four categories: No sub-study, Only MRI, Only PK, Both MRI and PK.
The analysis set will be the FAS.
4.2.7.2
Subject disposition
The subject disposition will include at least the following.

Pre-screened


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
Screened (defined as signed the screening informed consent)

Randomised

Not randomised and reasons for not randomised, including COVID-19 pandemic

Randomised and treated 

Randomised and not treated and reasons for not treated, including COVID-19 pandemic

Completed treatment

Discontinued treatment and reasons for discontinuation, including COVID-19 pandemic

Completed study

Discontinued study and reasons for discontinuation, including COVID-19 pandemic

Status w r t double-capsule regimen in PA5
Subject disposition (all subjects) will be given in a table, with number of subjects and 
percentage. For the interim analyses (Section 5), it must also be accounted for subjects still in 
the trial.
Regarding the COVID-19 related reasons for not randomised, for not treated once 
randomised, for treatment discontinuation, and for study discontinuation in the list above, 
please cf. template ‘COVID-summary1’ in the AZ Corporate Pandemic CSRHLD Table and 
Listing Templates.
4.2.7.3
Prior medications and concomitant medications
All medication will be coded with latest version of the WHO Drug Dictionary (WHO DD) 
code. Prior medication and concomitant medication will be summarised in tables (number and 
percentage of subjects), by treatment, anatomical-therapeutic-chemical (ATC) code, and 
generic name.
Partially missing medication start and stop dates will be imputed:

If the year is present but the month and day are missing, then 01JAN will be imputed 
for the start date and 31DEC for the stop date.

If the year and month are present but the day is missing, then 01 will be imputed for 
the start date and the last day of the month (28, 29, 30, or 31) for the stop date.
Medication start-dates and stop-dates with other missing-patterns will not be imputed and are 
deemed missing.

If the medication start-date is missing or, else, falls strictly before the day of 
randomisation visit, then the medication in question is prior.

Again, if the start-date is missing or, else, falls strictly before the day of randomisation 
visit, then the medication in question is concomitant if the stop-date is missing or, else, 
falls on the day of the randomisation visit or thereafter.


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
If, on the other hand, the start-value is not missing and falls on the day of 
randomisation visit, on the last day on study, or between, then the medication in 
question is concomitant.

A medication can thus be both prior and concomitant.
Concomitant medication (not prior medication) will be separated into two tables, allowed 
concomitant medications and disallowed/prohibited concomitant medications. 
Disallowed/prohibited medications are found in Table 10 of the protocol, v 5.0.
Analysis set will be the FAS.
4.2.7.4
Medical history and comorbid conditions
All medical conditions will be coded with latest version of the MedDRA code. Medical 
history and comorbid conditions will be summarised (number and percentage of subjects), by 
treatment, MedDRA system organ class (SOC), and MedDRA preferred term (PT).
Partial start-dates and stop-dates will be imputed as in 4.2.7.3
Analysis set will be the FAS.
4.2.7.5
Compliance
Compliance rate for verinurad (allopurinol) for a subject will be obtained by summing up the 
estimated number of capsules (tablets) taken by the subject during the study and dividing it by 
the number of capsules (tablests) planned to be administered to the subject (expressed as a 
percentage), where the number to be administered is calculated over the subject’s actual 
duration in the study and not the planned duration. A subject’s actual duration is adjusted for
potential dose reductions/interruptions and early treatment stopping.
Compliance rate will be summarised in table(s), by treatment.
The analysis set will be the safety analysis set
4.2.7.6
Exposure
Exposure for a subject will be derived as last dose date minus first dose date plus one day. It
will be summarised in table(s), by treatment. The analysis set will be the safety analysis set.
4.2.7.7
Important protocol deviations
IPDs will be summarised in a table, specified in template AZTSP06 in the AstraZeneca Study-
population table-templates (1 April 2021). Entries shall be adapted to match the COVID-19 
entries in the ‘COVID-summary2’ template of the AZ Corporate Pandemic CSRHLD Table 
and Listing Templates.


Statistical A nal ysis Pla n 
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Besi des n u m ber a n d pr o p orti o n of s u bjects e x perie nci n g at least o ne I P D ( of vari o us ki n ds), 
t he n u m ber of I P D s h o ul d als o be gi ve n.
T he a nal ysis set will be t he F A S .
4. 2. 7. 8
C h a n ge fr o m b aseli ne i n U A C R vs. b aseli ne s U A
Scatter pl ots will be pr o vi d e d at vi sits V 4 t hr o u g h V 1 0, w here c ha n ge fr o m baseli ne U A C R is 
pl otte d a gai nst baseli ne s U A , for eac h treat m e nt ar m at a ti me . C orrelat i on c oefficie nts will be 
gi ve n, b ut n o i nfere nce relate d t o t he m. F or V 8, t he a nal yses will be s u b- gr o u pe d b y t he 
f oll owi n g s u b gr o u pi n g varia bles:

D M stat us at baseli ne,

e G F R stat us, f o ur cate g ories, (see S u bsec tio n 4. 2. 1 1. 4 ) at baseli ne,

s U A stat us, f o ur cate g ories, (see S u bsect i on 4. 2. 1 1. 5 ) at baseli ne,

Al b u mi n uria stat us (see S u bsecti on 4. 2. 1 1. 1 ) at baseli ne.
A nal ysis set will be t he F A S.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI




Statistical A nal ysis Pla n 
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4 6 of 5 5
 
 
 
 
 
 
 
 
4. 2. 9
D ose -res p o nse a n al ysis
T he d ose -res p o nse relati ons hi p will be a nal yse d o nl y  descri pt i vel y. T he descri pti ve statistics 
will i ncl u de, e. g., a mea n pl ot (as a li ne pl ot) of  o bser ve d res p o nse vs. d ose, wit h 
s u peri m p ose d b o x pl ots of t he res p o nse varia ble at eac h d ose le vel. T he d ose varia ble is d ose 
( u nit: 1 m g) of veri n ura d o n t o p of 3 0 0 m g all o p uri n o l. T h us, f o ur ( 4) d ose le vels of veri n ura d 
are i n sc o pe here, na mel y 0 m g, 3 m g, 7. 5 m g, a n d 1 2 m g. Here, t he zer o d ose, i.e. 0 m g of 
veri n ura d, will be re prese nte d b y  t he 3 0 0 m g all o p uri n ol -m o n ot hera p y  ar m. T he place b o ar m 
will n ot c o ntri b ute t o t his pl ot, b ut a b o x pl ot of t he o bser ve d res p o nse s i n t he place b o ar m 
c o uld b e j u xta p ose d t o t he pl ot, relat i n g t o t he sa me res p o nse a xis as t he pl ot, f or refere nce.
T he t w o e n d p oi nts t o be i n vesti gate d i n t he afore me nt i one d d ose -res p o nse a nal ysis are c ha n ge 
fr om baseli ne i n l o g( U A C R ) at 6 m o nt hs ( V 8) a n d c ha n ge fr o m baseli ne i n l o g( s U A) at 6
m o nt hs (V 8) . B ot h are sec o n dar y e n d p oi nts.
A nal ysis set will be t he F A S.
 
 
4. 2. 1 0
F or m al testi n g a n d m ulti plicit y
As sai d a b o ve, t he f oll owi n g t hree tests will be c o n d ucte d se q ue ntiall y , eac h at si gnifica nce 
le vel 0. 1 (cf. S u bsecti ons  4. 2. 1. 1 a n d 4. 2. 2) , i n t his or der:
C CI
C CI


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
Change from baseline in UACR at 6 months (V8); “High” vs. “Placebo”; test of no 
treatment difference.

Change from baseline in UACR at 6 months (V8); “High” and “Intermediate” 
combined vs. “Allopurinol alone”; test of no treatment difference.

Change from baseline in UACR at 6 months (V8); “Allopurinol alone” vs. ”Placebo”; 
test of no treatment difference.
The test sequence will stop as soon as a null hypothesis in the test sequence was not rejected. 
The first null hypothesis not rejected in the sequence and all null hypotheses not yet tested 
thereafter will be considered not rejected regardless their p-values, whereas all null hypotheses 
before that will be considered rejected. In this way the familywise error rate in the strong 
sense is kept under control, below 0.1. A separate table will display the course of this 
sequence of tests.
Multiplicity will not be controlled for in any other test in this study.
4.2.11
Some definitions
4.2.11.1
Albuminuria status
Albuminuria status is a dichotomous variable, based on the UACR value, with these 
categories:
1. Microalbuminuria: 30 mg/g ≤ UACR < 300 mg/g.
2. Macroalbuminuria: UACR ≥ 300 mg/g.
All randomized subjects should have either microalbuminuria or macroalbuminuria at 
baseline, so in all model-based analyses, the explanatory variable ‘albuminuria status at 
baseline’ should be truly dichotomous. However, for observations of albuminuria status 
outside baseline, a third category may be needed:
3. Normal: UACR < 30 mg/g.
4.2.11.2
Geographic region
There are three (3) geographic regions defined in this study:
Europe: Czech Republic, France, Hungary, Israel, Italy, Poland, Romania, Slovakia, 
Spain.
South Africa: South Africa.
North America: Mexico, USA.
China is not part of the trial anymore.
4.2.11.3
Hypertension status at baseline
The trichotomous variable “Hypertension status at baseline” has these three categories:
1. No hypertension


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2. Hypertension, controlled
3. Hypertension, uncontrolled
(all at baseline).
‘No hypertension’ is when ‘Hypertension’ is not set to ‘Yes’ in ‘SPECHIS’ module.
‘Hypertesnion, controlled’ is when ‘Hypertension’ is set to ‘Yes’ in ‘SPECHIS’ module 
AND SBP@baseline ≤140 mmHg AND DBP@baseline ≤90 mmHg.
‘Hypertension, uncontrolled’ is when ‘Hypertension’ is set to ‘Yes’ in ‘SPECHIS’ module 
AND ( SBP@baseline > 140 mmHg OR DBP@baseline > 90 mmHg ).
We have to ignore that we, in principle, do not know if the hypertension, as assessed in the 
‘SPECHIS’ module, is ongoing or not at baseline. However, it is considered highly unlikely 
that one recovers from hypertension. So, all hypertension assessed as such in the ‘SPECHIS’ 
module will be assumed to be ongoing at baseline.
4.2.11.4
eGFR status
eGFR values can be grouped into four different eGFR-status groupings (see KDIGO 2013 for 
underlying groups G1, G2, G3, G3a, G3b, G4, G5):

eGFR status with two categories:
o
eGFR < 60 mL/min/1.73m2 (G3+G4+G5), 
o
eGFR ≥ 60 mL/min/1.73m2 (G1+G2).

eGFR status with three categories: 
o
eGFR < 60 mL/min/1.73m2 (G3+G4+G5), 
o
60 mL/min/1.73m2 ≤eGFR < 90 mL/min/1.73m2 (G2), 
o
eGFR ≥ 90 mL/min/1.73m2 (G1).

eGFR status with four categories: 
o
eGFR < 30 mL/min/1.73m2 (G4+G5), 
o
30 mL/min/1.73m2 ≤eGFR < 60 mL/min/1.73m2 (G3), 
o
60 mL/min/1.73m2 ≤eGFR < 90 mL/min/1.73m2 (G2), 
o
eGFR ≥ 90 mL/min/1.73m2 (G1).

eGFR status with six categories: 
o
eGFR < 30 mL/min/1.73m2 (G4+G5), 
o
30 mL/min/1.73m2 ≤eGFR < 45 mL/min/1.73m2 (G3b), 
o
45 mL/min/1.73m2 ≤eGFR < 60 mL/min/1.73m2 (G3a), 
o
60 mL/min/1.73m2 ≤eGFR < 75 mL/min/1.73m2 (G2), 
o
75 mL/min/1.73m2 ≤eGFR < 90 mL/min/1.73m2 (G2), 
o
eGFR ≥ 90 mL/min/1.73m2 (G1).


Statistical A nal ysis Pla n 
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4 9 of 5 5
4. 2. 1 1. 5
s U A st at us
s U A val ues ca n be gr o u pe d i nt o t w o differe nt s U A-stat us gr o u pi n gs:

s U A stat us wit h t w o cate g ories, me dia n -base d a n d t h us data -dri ve n :
o
s U A < { me d ia n of baseli ne s U A},
o
s U A ≥ { me dia n of baseli ne s U A } .

s U A stat us wit h f o ur cate g ories:
o
0 m g/ d L ≤s U A < 6 m g/ d L,
o
6 m g/ d L ≤s U A < 8 m g/ d L,
o
8 m g/ d L ≤s U A < 1 0 m g/ d L,
o
s U A ≥1 0 m g/ d L .
4. 2. 1 1. 6
N T -pr o B N P st at us
N T -pr o B N P val ues ca n be g r o u pe d i nto a N T -pr o B N P -stat us gr o u pi n g wi t h t w o cate g ories:
o
N T -pr o B N P < 3 6 0 p g/ m L,
o
N T -pr o B N P ≥ 3 6 0 p g/ m L .
4. 2. 1 1. 7
Use of A C Ei a n d A R B
T he use of a n gi ote nsi n c o n verti n g e nz y me i n hi bit ors ( A C Ei) a n d a n gi ote nsi n rece pt or 
bl o c kers ( A R B) is i n t his S A P t o be i nter prete d as a cate g orical varia ble wit h f our cate g ories:
o
N ei t her A C Ei nor A R B,
o
A C E i b ut n ot A R B ,
o
A R B b ut n ot A C Ei ,
o
B ot h A C Ei a n d A R B at t he sa me ti me .
4. 2. 1 1. 8
St u d y peri o ds
St u d y  p erio ds f or  
 A Es, a dj u dicate d e ve nts, a n d S-creatini ne ele vat i ons are:
1.
V 3 — , i.e. t he w h ole i n-st u d y p erio d f r o m d a y of V 3 (i ncl u de d) a n d o n war d,
2.
V 3 — V 4, i .e. i n-st u d y fr o m d a y of V 3 (i ncl u de d) t o da y of V 4 (e xcl u de d),
3.
V 3 — V 5, i .e. i n-st u d y fr o m d a y of V 3 (i ncl u de d) t o da y of V 5 (e xcl u de d),
4.
V 3 — V 8, i .e. i n-st u d y fr o m d a y of V 3 (i ncl u de d) t o da y of V 8 (e xcl u de d),
5.
V 3 — V 9, i .e. i n-st u d y fr o m d a y of V 3 (i ncl u de d) t o da y of V 9 (e xcl u de d), a n d
6.
V 3 — V 1 0, i .e. i n-st u d y fr o m d a y of V 3 (i ncl u de d) t o da y of V 1 0 (e xcl u de d).
4. 2. 1 2
Al b u mi n uri a st at us o ver ti m e
S hift ta b les f or al b u mi n uria stat us (see S u bsecti o n 4. 2. 1 1. 1 a b o ve) fr o m baseli ne t o visits V 5, 
V 8, V 1 0, a n d E O T visit will be pr o vi de d. Please n ote t hat, at baseli ne, t here s h o ul d be n o 
s u bjects wi t h al b u mi n uria stat us “ N or mal”, b ut at a n y ot her visit, t he stat us c o ul d ver y well b e 
“ N or mal”.
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Analysis set will be the FAS.
4.2.13
High-level results
After the second interim there may come a request for high-level results (HLR), together with 
a specification thereof.
5
INTERIM ANALYSES
Two interim analyses are planned to support internal decisions of the program development. 
These analyses will be unblinding, therefore, an independent team at Covance will conduct 
these analyses. These interim analyses are supposed to have no impact on the conduct of the 
study, and since there is no provision to stop the trial early because of any results from the 
interim analyses, no multiplicity adjustment will be required.
The first interim analysis will be performed no later than when 90 % of the subjects have 
completed 12 weeks of treatment after titration (V7). The second interim analysis will be 
conducted after all subjects complete 26 weeks of treatment after titration (V8). 
The analyses below will be done to the extent there is enough data for a meaningful 
interpretation
5.1
The first interim analysis
The following analyses will be carried out in the first interim analysis.

Demographics and baseline characteristics (Subsection 4.2.7.1), except UACR at baseline 
and cystatin-C at baseline if not in place at the first interim.

Prior medications and concomitant medications (Subsection 4.2.7.3).

Medical history and comorbid conditions (Subsection 4.2.7.4).

Subject disposition (Subsection 4.2.7.2) which will have to account also for subjects who 
are still in the trial at the time for the first interim analysis.

UACR will be analysed as in Subsection 4.2.1.1, except that the evaluation visit will be 
V7 and that the comparisons will be not only “High” vs. “Placebo” (as in 4.2.1.1), but 
also “High” and “Intermediate” combined vs. “Allopurinol alone” (as in 4.2.2) and 
“Allopurinol alone” vs. “Placebo” (also as in 4.2.2).

Subgroup analyses of UACR as in Subsection 4.2.1.3 will be carried out for at least the 
subgrouping variables eGFR category (four categories) at baseline, sUA category (four 
categories) at baseline, DM status at baseline, and albuminuria status at baseline, if 
numerically feasible. Then forest plots could be useful. P-values should be avoided. Other 
subgrouping variables, as well as other comparisons than “High” vs. “Placebo”, may be 
investigated as needed.




Statistical A nal ysis Pla n 
Astra Ze neca
D 5 4 9 5 C 0 0 0 0 2 - 3. 0
1 6 J ul 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
5 2 of 5 5

all a nal yses of a dj u dicat i on- c o nfir me d e ve nts (see ite m D i n S u bsect i on 4. 2. 6. 2 ), u nless 
alrea d y pr o vide d t o t he first i nteri m a nal ysis,

k e y -s u bject-i nf or mati on f or S A Es (see it e m F. 2 i n S u bsecti o n 4. 2. 6. 1 ) a n d f or A Es 
lea di n g t o per ma ne nt disc o nti n uati on of I P (see ite m F. 3 i n S u bsecti on 4. 2. 6. 1 ).

all o n- tre at me nt a nal yses of A Es (it e m E i n S u bsecti o n 4. 2. 6. 1 ) a n d a dju dicate d e ve n ts 
(it e m E i n S u bsecti on 4. 2. 6. 2 ),

all a nal yses of I P Ds (see Su bsecti o n 4. 2. 7. 7 ), b ut listi n gs s h o ul d be i ncl u de d,

all patie nt narrati ves (see S u bsect i on 4. 2. 6. 6 ),

all C O VI D -1 9 re p orts (see S u bsect i on 4. 2. 6. 5 ), a n d

t he s u b gr o u pi n g at V 8 i n t he a nal ysis of c ha n ge -fro m -baseli ne U A C R vs baseli ne s U A i n 
S u bsecti o n 4. 2. 7. 8 .
A n y re p orti n g c o ntai n i ng assess me nts/ meas ure me nts be yo n d V 9 s h o ul d be a v oi de d , e xce pt i n 
listi n gs. T he se nsit i vity a nal ysis i n S u bsect i on 4. 2. 1. 2 s h o ul d prefera bl y be part of t he sec o n d 
i nteri m b ut ma y be e xcl u de d fr o m t he sec o n d i nteri m beca use o f its c o mple xi t y. T he n u m ber 
of  ta bles, fi g ures, a n d list i n gs t o be prese nte d at t he i nteri m ma y be re d uce d a d h oc. As f or t he 
first i nteri m a nal ysis, t he s u bject dis p ositi on will ha ve t o acc o u nt als o f or s u bjects w h o are 
still i n t he trial at t he t i me f or t he sec o n d i nteri m a nal ysis.
 
 
6
C H A N G E S O F A N A L Y SI S F R O M P R O T O C O L
6. 1
A n al y sis sets
T he pr ot oc ol me nt i ons t he per- p r ot oc ol a n al ysis set , t he e nr olle d ( a n al ysis set ), t he 
r a n d o mise d ( a n al ysis) set , a n d t he effic ac y a n al ysis set . T hese f o ur a nal ysis sets will n ot be 
use d i n t his S A P.
6. 2
D ose -res p o nse m o delli n g
F or mal d ose -res p o nse m o delli n g will n ot be detaile d i n t his S A P, as s u g geste d i n t he pr ot oc ol, 
b ut i n a se parate a nal ysis -pla n a ut h ore d b y  Astra Ze neca. Astra Ze neca will  be res p o nsi ble f or 
t he f or mal d ose-res p o nse mo delli n g i n t his trial .
6. 3
[ Re m o ve d]
6. 4
Cl arific ati o n re g ar di n g ‘tre at me nt recei ve d’
I n Secti o n 9. 4. 3 of t he pr ot oc ol ( v 4 . 0) it s a ys t hat a ll safety data will be s u m marise d b y 
treat me nt gr o u p base d o n t he treat me nt recei ve d . I n t his S A P, we will let t hat mea n t hat a 
s u bject – f or t he safety a nal yses – will be a ll ocated t o his/ her ra n d o mise d treat me nt, u nless t he 
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subject (erroneously) was given one other specific investigational treatment for the whole 
duration of the study, in which case the subject will be allocated to that other treatment 
instead. For instance, if a subject was randomised to “High” and received “Low”, the subject 
will be allocated to “Low” for the safety analyses if the subject received “Low” for the whole 
duration of the study, otherwise to “High”, the randomised treatment. Consequently, a subject 
that is switched from a treatment A to a treatment B during the trial will always be allocated to 
the randomised treatment for the safety analyses, regardless what treatments A and B may be.
6.5
Change in physical examination
The endpoint “change (deterioration) in physical examination” is an event endpoint and is 
supposed to be reported as an AE on the AE form of the eCRF. However, the AE form does 
not distinguish between physical-examination-related AEs and other AEs. Thus, no analyses 
will be suggested for this endpoint in this SAP.
6.6
Subgrouping variables for the supplementary analyses of the 
primary endpoint
The following assessments have been added to the list of subgrouping variables in 
Subsection 4.2.1.3.

Hypertension status at baseline (see Subsection 4.2.11.3)

eGFR status, four categories, (see Subsection 4.2.11.4) at baseline

eGFR status, six categories, (see Subsection 4.2.11.4) at baseline

sUA status, four categories, (see Subsection 4.2.11.5) at baseline

Use of ACEi and ARB (see Subsection 4.2.11.7) at baseline

SGLT2i use at baseline
The two subgroups eGFR ≤ 60 mL/min/1.73m2 and eGFR > 60 mL/min/1.73m2 for the 
subgrouping variable ‘baseline eGFR ≤ 60 mL/min/1.73m2 vs.
eGFR > 60 mL/min/1.73m2, mentioned in Subsection 9.4.2.4 of the protocol (version 0.3), 
are changed to eGFR < 60 mL/min/1.73m2 (G3+G4+G5) and eGFR ≥ 60 mL/min/1.73m2
(G1+G2), respectively. This new categorisation adapts to the KDIGO 2012 GFR 
categories G1 through G5 (see KDIGO 2013), which the previous one does not.
6.7
Incidence of laboratory abnormalities
Incidence of laboratory abnormalities will not be summarised. 
6.8
Secondary endpoints at 12 months (V10) 
There are five (5) secondary endpoints at 12 month (V10), viz

Change from baseline in UACR at 12 months (V10),

Change from baseline in sUA at 12 months (V10),


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
Change from baseline in eGFR at 12 months (V10),

Change from baseline in S-creatinine at 12 months (V10), and

Change from baseline in S/P-cystatin C at 12 months (V10).
In this SAP, they will all be considered exploratory endpoints, and they will be analysed with 
descriptive statistics only (see Subsection 4.2.3.2).
6.9
[Removed]
6.10
eGFR slope at V9 and at end-of-treatment (EOT)
In this SAP, eGFR slope at V9 has been added as an endpoint. eGFR slope at end-of-treatment 
will not be considered an endpoint anymore, contrary to what is said in the protocol.


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7
APPENDIX
7.1
References
1. Leoncini et al 2002
Leoncini G, Martinoli C, Viazzi F, Ravera M, Parodi D, Ratto E, et al: Changes in 
renal resistive index and urinary albumin excretion in hypertensive patients under 
long-term treatment with lisinopril or nifedipine GITS. – Nephron. 2002; 90(2):169—
173.
2. KDIGO 2013
KDIGO: KDIGO 2012 Clinical Practice Guideline for the Evaluation and 
Management of Chronic Kidney Disease. – Kidney Int., Supplements; 2013, Vol 3, 
Issue 1.