Conditions: Heart Failure With Preserved Ejection Fraction (HFpEF)
Keywords: Phase 2, Double-Blind, Placebo and Active Control, Verinurad, Allopurinol, HFpEF, Heart Failure
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 159
Healthy volunteers: no

Brief summary:
International, Multicenter, Double-Blind, Placebo and Active Control Efficacy and Safety Study to Evaluate Verinurad combined with Allopurinol in Heart Failure with Preserved Ejection Fraction

Detailed description:
Evidence shows independent associations between hyperuricaemia and the risk of cardio-renal conditions, including heart failure (HF). Serum uric acid (sUA) is also a strong prognostic factor and correlates with other markers of poor prognosis in HF patients with preserved ejection fraction (HFpEF), and an estimated 1/2-2/3 of HFpEF patients have hyperuricaemia. HFpEF is a microvascular disease likely partly driven by endothelial dysfunction and inflammation in coronary vessel walls. Uric acid crystals have been identified in coronary vessel walls in some hyperuricaemic patients.

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 and lowering of uric acid in the blood. Verinurad is a novel URAT1 inhibitor in Phase 2 development for chronic kidney disease (CKD) and HF. 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 approximately 80%.

The primary objective of this Phase 2 study is to assess the effect of a combination of verinurad and allopurinol on exercise capacity in patients with HFpEF.

The secondary objectives are to assess effect of combination of verinurad and allopurinol in comparison to allopurinol monotheraphy on excercise capacity dwhich will be measured in peak VO2 as well as effect of verinurad and allopurinol compared to placebo and to allopurinol monotheraphy on Kansas City cardiomyopathy questionnaire (KCCQ)-total symptom score (TSS). A sub-study aims to investigate the relationship between UA crystals and inflammation.

Arms:
arm 1: Dose \[mg\] verinurad/allopurinol:

Step 1 - titration\_3/100 Step 2 - titration\_7.5/200 Step 3 - target dose 12/300 arm 2: Dose \[mg\] verinurad/allopurinol:

Step 1 - titration\_0/100 Step 2 - titration\_0/200 Step 3 - target dose 0/300 arm 3: 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: The treatment will be titrated in 3 steps for target low dose (3 mg), intermediate dose (7.5 mg) and high dose (12mg) of verinurad.

Drug: Allopurinol The treatment will be titrated in 3 steps. Low dose (100mg), intermediate (200mg) and high dose (300mg) of allopurinol. intervention 2: Study treatments will be titrated in 3 steps: Low dose (100mg), intermediate (200mg) and high dose (300mg) of allopurinol intervention 3: Matching Capsule intervention 4: Matching tablet

Protocol document:
Prot_000.pdf: 
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Clinical Study Protocol
Drug Substance
Verinurad / RDEA3170 
Study Code
D5496C00005
Version
4.0
Date
20 September 2021
A Phase 2, Multicentre, Double-Blind, Placebo and Active Control 
Efficacy and Safety Study to Evaluate Verinurad combined with 
Allopurinol in Heart Failure with Preserved Ejection Fraction 
(AMETHYST)
Sponsor: AstraZeneca AB, 151-85 Södertälje, Sweden
Regulatory Agency Identifying Number(s): USIND 146049, EudraCT 2019-004862-16


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VERSION HISTORY
Version 4, 20 September 2021
Version 4 is a substantial amendment to the Clinical Study Protocol (CSP). The purpose of 
the substantial amendment is to inform of a decision to hold further study recruitment, 
remove the interim analysis, and remove a treatment arm (24 mg verinurad in combination 
with allopurinol) that was previously planned to be included (CSP version 3). There was a 
decision taken to hold recruitment at the original number of patients targeted for the interim 
analysis, i.e. reducing the sample size from n=435 to approximately 150 patients. This 
smaller sample size is considered to be enough for the evaluation of the primary efficacy 
objective, and the interim analysis is no longer needed. The reduction of the sample size and 
the removal of the treatment arm were not based on safety concerns, and the safety profile 
remains unchanged. Should results indicate a need for a larger study, as was originally 
planned, the CSP may be amended to restart recruitment, understanding the potential 
limitations of the added data.
The substantial changes and all other changes in this amendment are summarised below.
Changes summarised below:
Section 1.1, Schedule of Activities
!
!
Removed references to DECT and PET/CT from table and footnotes due to substudy 
cancellation.
!
Clarified that progression to Visit 2 can be performed before HLA-B results are 
available.
Section 1.2, Synopsis
!
 
.
!
Removed text relating to 24 mg verinurad + allopurinol treatment arm and timing of 
Protocol Version 3.0 implementation.
!
Updated estimated date of the last visit of the last patient, number of patients that will
be randomised/enrolled, and estimated screen-failure rate.
!
Removed dosing schedule (Table 1) relating to 24 mg verinurad + allopurinol treatment 
arm.
!
Removed text relating to planned analysis of pooled data from 24 mg verinurad + 
allopurinol treatment arm.
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Section 1.3, Study Schema
!
Updated labelling of Figure 1 study schema.
!
Removed study schema labelled as Part (B) for 24 mg verinurad + allopurinol treatment 
arm.
Section 2.3, Benefit/Risk Assessment
!
Removed reference to previous study of 24 mg verinurad dose (ER8 formulation) in 
healthy subjects.
!
Updated total number of treatment arms to reflect removal of 24 mg verinurad + 
allopurinol treatment arm.
!
 
Section 4.1.1, Overview
!
Removed reference to 24 mg verinurad + allopurinol treatment arm and timing of 
Protocol Version 3.0 implementation, and reverted to 1:1:1 randomisation ratio.
!
Related to the 24 mg verinurad + allopurinol treatment arm, removed the number of 
patients that would have been randomised/enrolled and the estimated screen-failure 
rate.
Section 4.1.2.2, Week -2 to -1 (Visit 2), Only if Eligibility Criteria Met as Assessed in 
Visit 1
!
Clarified that patients can progress to Visit 2 before HLA-B results are available.
Section 4.1.2.3, Week 0 (Visit 3)
!
!
Removed references to DECT and PET/CT due to substudy cancellation.
Section 4.1.2.5, Week 8 (Visit 5)
!
Removed reference to 24 mg verinurad + allopurinol treatment arm in final (titration 
step 3).
Section 4.1.2.6, Week 12 (Visit 6)
!
!
Removed reference to 24 mg verinurad + allopurinol treatment arm in final (titration 
step 3).
Section 4.1.2.7, Week 22 (Visit 7)
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!
Removed reference to 24 mg verinurad + allopurinol treatment arm in final (titration 
step 3).
Section 4.1.2.8, Week 32 (Visit 8)
!
!
Removed references to DECT and PET/CT due to substudy cancellation.
Section 4.1.2.9, Week 36 (Visit 9)
!
Section 4.1.2.10, Premature Treatment Discontinuation Visit
!
!
Removed references to DECT and PET/CT due to substudy cancellation
Section 4.3, Justification for Dose
!
Removed clarification that 12-mg verinurad was the initially targeted dose and 
justification that doubling the initially targeted dose to 24 mg would occur at the last 
up-titration visit (Visit 5).
Section 5.2, Exclusion Criteria
!
Removed exclusion criteria #26 due to substudy cancellation.
Section 5.3.1, Pregnancy
!
Rearranged text for clarification.
Section 6.1.1, Investigational Products
!
Removed text regarding dispensing of verinurad doses in separate treatment arms at 
study visit (24 mg and 12 mg).
!
Removed clarification regarding how study treatments have changed and measures 
taken to ensure blinding in patients randomised after implementation of Protocol 
Version 3.
!
Updated title of Table 4 and deleted Table 5.
!
Removed clarification regarding implementation of Protocol Version 3.0 only when 
investigational products with updated labels are available and only at study sites where 
all necessary approvals are in place.
Section 6.3, Measures to Minimise Bias: Randomisation and Blinding
!
Removed reference to 24 mg verinurad + allopurinol treatment arm and reverted to 
1:1:1 randomisation ratio.
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Section 8.1.3.9, Dual –emission Computed Tomography and PET Substudy
!
Section deleted due to substudy cancellation.
Section 8.6.1, Assessment of HLA-B Genotype
!
Clarified ethnic groups with higher B*5801 allele frequency.
Section 8.7, Biomarkers
!
Changed cross reference to biomarker section.
!
Clarified that participation in future research is optional and contingent upon local 
regulations.
Section 9.2, Sample Size Determination
!
Removed reference to 24 mg verinurad + allopurinol treatment arm and 1:1:1:1 
randomisation ratio.
!
Relating to 24 mg verinurad + allopurinol treatment arm, removed the number of 
patients that would have been randomised/enrolled and statistical power.
Section 9.4, Statistical Analysis
!
Replaced reference to interim analysis with final data base lock.
Section 9.4.1.1, Analysis of the Primary Objective
!
Removed references to planned analysis to include pooled data from the 24 mg 
verinurad + allopurinol and 12 mg verinurad + allopurinol treatment arms.
!
Removed reference to new planned sensitivity analyses of the primary analysis with 
respect to the updated study design in Protocol Version 3.0.
Section 9.4.1.2, Analysis of the Secondary Objectives
!
Removed reference to new planned analysis of pooled data from the 24 mg verinurad + 
allopurinol and 12 mg verinurad + allopurinol treatment arms.
Section 9.4.2, Safety Analyses
!
Removed reference to new planned analysis of pooled data from the 24 mg verinurad + 
allopurinol and 12 mg verinurad + allopurinol treatment arms.
 
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Section 9.5, Interim Analysis
!
Removed section. Interim analysis replaced by final data base lock.
Section 10, References
!
Removed references relating to cancelled DECT/PET substudy.
Version 3, 03 February 2021
Changes summarised below:
Clinical Study Protocol Title
!
Updated title to remove text specifying a “3-arm” study because patients randomised 
after implementation of Protocol Version 3.0 are assigned to one of 4 treatment arms as 
part of modified study design.
Section 1.1, Schedule of Activities
!
Updated timings when Patient Dosing Cards are given to patient (additionally at 
Visits 3, 6 and 7) and inserted cross-reference to new appendix describing Patient 
Dosing Cards.
!
Updated to include additional ECG assessment at Visit 6.
!
Clarified that, for patients who prematurely discontinued treatment, DECT should be 
performed only at the premature treatment discontinuation visit.
!
 
 
Section 1.2, Synopsis, Table – Objectives and Endpoints
!
 
 
Section 1.2, Synopsis
!
Updated to include additional treatment arm (24 mg verinurad in combination with 
allopurinol), timing of Protocol Version 3.0 implementation, estimated date of the last 
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visit of the last patient, number of patients that will be randomised/enrolled and 
estimated screen-failure rate.

Updated dosing schedule (Table 1) in-line with inclusion of additional treatment arm 
(24 mg verinurad in combination with allopurinol).

Updated to include new planned analysis of pooled data from the 24 mg verinurad + 
allopurinol and 12 mg verinurad + allopurinol treatment arms.
Section 1.3, Study Schema

Re-labelled Figure 1 as study schema as Part (A) (prior to implementation of Protocol 
Version 3.0) and corrected designation of KCCQ as secondary endpoint (not key 
secondary endpoint).

Inserted new study schema labelled as Part (B) (after implementation of Protocol
Version 3.0) to include additional treatment arm (24 mg verinurad in combination with 
allopurinol) and corrected designation of KCCQ as secondary endpoint (not key 
secondary endpoint) for consistency with wording throughout the CSP.
Section 2.3, Benefit/Risk Assessment

Provided reference to previous study of 24 mg verinurad dose (ER8 formulation) in 
healthy subjects.

Updated total number of treatment arms to reflect inclusion of additional treatment arm 
(24 mg verinurad in combination with allopurinol).
Section 4.1.1, Overview

Updated to include additional treatment arm (24 mg verinurad in combination with 
allopurinol) and 1:1:1:1 randomisation ratio.

Updated to include additional treatment arm (24 mg verinurad in combination with 
allopurinol), timing of Protocol Version 3.0 implementation, number of patients that 
will be randomised/enrolled and estimated screen-failure rate.
Section 4.1.2.3, Week 0 (Visit 3)

Clarified that study treatment should be taken after blood drawn.

Updated that Patient Dosing Card is given to patient. 
Section 4.1.2.4, Week 4 (Visit 4)

Clarified that patient should take IP from a new bottle at the end of the visit.
Section 4.1.2.5, Week 8 (Visit 5)

Updated that final (titration step 3) verinurad doses will be dispensed in separate 
treatment arms at study visit (24 mg and 12 mg).


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!
Clarified that patient should take IP from a new bottle at the end of the visit.
Section 4.1.2.6, Week 12 (Visit 6)
!
Updated that ECG will be performed at Visit 6.
!
!
Clarified that dose, date and time of study treatment intake should be recorded in 
patient’s medical records.
!
Updated that final (titration step 3) verinurad doses will be dispensed in separate 
treatment arms at study visit (24 mg and 12 mg).
!
Updated that Patient Dosing Card is given to patient.
Section 4.1.2.7, Week 22 (Visit 7)
!
Clarified that dose, date and time of study treatment taken at home should be recorded 
in patient’s medical records.
!
Updated that final (titration step 3) verinurad doses will be dispensed in separate 
treatment arms at study visit (24 mg and 12 mg).
!
Updated that Patient Dosing Card is given to patient.
Section 4.1.2.8, Week 32 (Visit 8)
!
Clarified that, for patients who prematurely discontinued treatment, DECT should be 
performed only at the premature treatment discontinuation visit.
!
Clarified that dose, date and time of study treatment intake should be recorded in 
patient’s medical records.
Section 4.3, Justification for Dose
!
Updated to clarify that 12-mg verinurad was the initially targeted dose and to justify 
doubling the initially targeted dose to 24 mg at the last up-titration visit (Visit 5).
Section 5.2, Exclusion Criteria
!
Corrected text formatting error that grouped 2 separate exclusion criteria from CSP 
Version 1 (#6 [HLA-B*58:01 allele carrier] and #7 [TLS or LNS diagnosis]) into a 
single exclusion criterion in CSP Version 2 (#6). These are now relisted as separate 
criteria.
!
Data collected from patients meeting exclusion criterion in CSP Version 2 (#6) will be 
retrospectively reviewed to confirm the specific exclusion criteria met and to revise 
exclusion criteria numbering (for consistency with that used in CSP Versions 1 and 3), 
which will then be updated in RAVE.
!
Updated and simplified exclusion criterion #17 (long QT syndrome), based on findings 
from recent verinurad thorough QT study.
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Section 6.1.1, Investigational Products

Updated verinurad doses dispensed in separate treatment arms at study visit (24 mg and 
12 mg) and applied throughout the CSP.

Re-labelled Table 4 (Study Treatments) to specify that this is applicable to patients 
randomised prior to implementation of Protocol Version 3.0. Inserted cross-reference to 
new appendix describing Patient Dosing Cards. Relabelled initial duplicate row 
category title “Dosing instructions” as “Dosage levels”. Corrected timing when patients 
can receive their maintenance dose of study treatment (ie, Weeks 8 to 32).

Clarified how study treatments have changed and measures taken to ensure blinding in 
patients randomised after implementation of Protocol Version 3 given the requirement 
to administer two verinurad capsules each day to achieve a dose of 24 mg. Highlighted 
that patients randomised prior to implementation of Protocol Version 3.0 will continue 
to receive only one verinurad capsule each day.

Inserted new Table 5 (Study Treatments [applicable to patients randomised after
implementation of Protocol Version 3.0]) to include additional treatment arm and 
provide important dosing instructions. Inserted cross-reference to new appendix 
describing Patient Dosing Cards.

Clarified that Protocol Version 3.0 can be implemented only when investigational 
products with updated labels are available and only at study sites where all necessary 
approvals are in place.
Section 6.3, Measures to Minimise Bias: Randomisation and Blinding

Updated to include additional treatment arm (24 mg verinurad in combination with 
allopurinol) and 1:1:1:1 randomisation ratio.

Updated to provide details on down titration of study treatment at, or before, Visit 5.

Clarified that sponsor will be blinded to post-randomisation sUA values in order that 
the study integrity is maintained.
Section 8.1.3.9, Dual-emission Computed Tomography and PET Substudy

Changed wording of “termination visit” to “premature treatment discontinuation visit” 
for clarity and consistency of terminology in document.
Section 8.2.1, Clinical Safety Laboratory Assessments

Clarified in Table 8 (Laboratory Safety Variables) that if a patient shows a total 
bilirubin value outside the normal range, direct bilirubin will be automatically 
evaluated by the central laboratory.
Section 9.2, Sample Size Determination


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!
Updated to include additional treatment arm (24 mg verinurad in combination with 
allopurinol), 1:1:1:1 randomisation ratio, number of patients that will be 
randomised/enrolled and statistical power.
Section 9.3, Populations for Analyses, Table 8 – Analysis Populations
!
Corrected for consistency with wording stated in Section 9.4.2 describing the safety 
analysis set and analysis of patients according to their randomised IP assignment.
Section 9.4.1.1, Analysis of the Primary Objective
!
Updated planned analysis to include pooled data from the 24 mg verinurad + 
allopurinol and 12 mg verinurad + allopurinol treatment arms.
!
Updated to include new planned sensitivity analyses of the primary analysis with 
respect to the updated study design in Protocol Version 3.0.
Section 9.4.1.2, Analysis of the Secondary Objectives
!
Updated to include new planned analysis of pooled data from the 24 mg verinurad + 
allopurinol and 12 mg verinurad + allopurinol treatment arms.
Section 9.4.2, Safety Analyses
!
Updated to include new planned analysis of pooled data from the 24 mg verinurad + 
allopurinol and 12 mg verinurad + allopurinol treatment arms.
 
 
Appendix K, Patient Dosing Cards Information
!
Inserted new appendix providing update of Patient Dosing Cards information for: 
(1) patients randomised prior to implementation of Protocol Version 3.0; and 
(2) patients randomised after implementation of Protocol Version 3.0.
Version 2, 30 July 2020
Changes summarised below: 
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Protocol summary, Section 1.1 Schedule of Activities
!
Discrepancy related to footnote “f” has been corrected.
!
Urinalysis has been added as one of the Safety Labs to correct discrepancy.
!
Safety laboratory assessments have been removed from Visit 2.
 
!
Clarification which visits can be performed in patients home due to pandemic has been 
added.
!
Duration of titration and visits schedule have been changed. 
!
One additional week for patients screening has been added.
Protocol summary, Section 1.2 Synopsis
!
Discrepancy between Synopsis and Inclusion 6 in number of weeks of patient´s 
symptoms before enrolment has been corrected.
!
Estimated study timelines has been corrected.
!
Estimated amount of sites and countries has been corrected.
!
!
 
!
Duration of treatment titration has been changed.
!
Dosing schedule (Table 1) has been updated.
!
Statistical methods paragraph – timelines for study endpoint has been changed (from 
Week 28 to Week 32).
!
Study scheme has been updated with extended titration period.
!
Colchicine prophylaxis schedule has been modified due to extended titration. 
Section 2.3 Benefit/Risk Assessment
!
Colchicine prophylaxis schedule has been modified due to extended titration. 
 
 
Section 4.1.1 Overall design (overview)
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!
Estimated amount of sites and countries have been corrected.
Section 4.1.2 Study Procedures
!
Urinalysis has been added as one of the Safety Labs to correct discrepancy in visits: 1, 
3, 4, 5, 6, 7, 8, 9 and Premature Treatment Discontinuation Visit.
!
Information related to providing cooler bag, two sterile 4oz./120ml collection 
containers and two urine collection pans has been added to visits: 2, 5, 7, 8.
Timing of visits’ weeks has been changed based on updated titration and schedule of visits: 
4, 5, 6, 7, 8, 9.
Section 4.1.2.1 Week -5 to -1 (Visit 1)
!
Clarification related to timing of the visit has been added.
!
One additional week for screening has been added.
Section 4.1.2.2 Week -2 to -1 (Visit 2)
!
Clarification related to timing of the visit has been added.
!
sCr has been removed.
Section 4.1.2.3 Week 0 (Visit 3)
!
It has been clarified that two sequential CT scans are allowed for DECT sub study.
Section 4.1.2.4 Week 4 (Visit 4)
!
Information about the time between visits 3 and 4 has been added.
!
Information about Patient Dosing Card has been added.
Section 4.1.2.5 Week 8 (Visit 5)
!
Information about the time between visits 4 and 5 has been added.
!
Information about Patient Dosing Card has been added.
Section 4.1.2.8 Week 28 (Visit 8)
!
!
It has been clarified that two sequential CT scans are allowed for DECT sub-study.
Section 4.1.2.10 Premature Treatment Discontinuation Visit
!
It has been clarified that two sequential CT scans are allowed for DECT sub study.
!
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Section 4.2 Scientific rationale for study design

Duration of treatment titration has been changed.
Section 4.3 Justification of dose

Duration of allopurinol titration has been changed.
Section 5.1 Inclusion Criteria, point 6d

Discrepancy in NT-proBNP testing timing has been corrected.
Section 5.2 Exclusion Criteria

Severe hepatic impairment (point 2) has been refined.

Exclusion criterion (point 30) concerning hypersensitivity to allopurinol or any URAT1 
inhibitor has been revised. Information about intolerance to lactose has been added. 
HLA-B allele testing (point 5) has been changed. Information about mandatory testing 
before randomisation has been added.
Section 5.3.1 Pregnancy

Section has been updated as per new Clinical Study Template.
Section 6.0 Study Treatments

It was clarified, what is considered IP and what non-IP in the study.

Preferences related to IP administration has been added. 
Section 6.1.1 Investigational Products

Titration steps and its duration have been changed.

It was clarified that titration to step 3 target dose will only be allowed if the patient’s 
eGFR was ≥30 ml/min/1.73 m2 at Visits 3 and 4.

Table 4 – dosing instruction has been modified.

Colchicine prophylaxis schedule has been modified due to extended titration. 
Section 6.3 Measures to Minimise Bias: Randomisation and Blinding

Requirement to contact Study Physician prior to dose down titration has been added.
Section 6.4 Treatment Compliance

It was clarified what is acceptable patient’s compliance level and what activities should 
be done to monitor and document it.


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!
The procedure of recording all administered study drugs in eCRF has been clarified.
Section 6.5 Concomitant Therapy, Table 5
!
Information about ACEi therapy has been updated.
 
Section 6.6 Dose modification
!
Titration steps have been modified.
Section 7.1.1 Temporary Discontinuation
!
Rules related to temporary treatment discontinuation has been clarified.
Section 7.3 Withdrawal From the Study
!
Following sentence has been removed: “The patient will return electronic PRO 
devices.”
Section 8.1.1 Peak VO2 and Other Cardiopulmonary Exercise Test Outcomes
!
Time points related to CPET assessment have been corrected.
 
 
 
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Section 8.1.3.9 Dual-emission Computed Tomography and PET Sub study
!
Possibility of using two sequential CT scans if DECT is not available was added. 
Information about radiation exposure has been updated accordingly.
!
It was clarified that second assessment will only be performed in patients who had 
evidence of uric acid crystal deposits at the baseline assessment.
!
Time points related to DECT has been corrected.
Section 8.2. Safety Assessments, Table 7 - Laboratory Safety Variables
!
Discrepancy related to testing urinalysis using dipstick has been corrected.
Section 8.2.4 Electrocardiograms 
!
Following sentence has been removed: “ECGs will be analysed centrally.”
Section 8.3.2 Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information
!
Information related to SAE reporting has been clarified.
 
Section 8.6.1 Assessment of HLA-B Genotype
!
Information about mandatory testing before randomisation has been added.
Section 8.9 Guidelines, study assessments, and procedures during COVID-19 
pandemic
!
Section added.
Section 9.1 Statistical Hypotheses
!
 
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Section 9.5 Interim Analysis
!
Correction to the visit number (Week 28 changed to Week 32) has been corrected.
Section 9.3 Population for Analyses, Table 8 Analysis Populations
!
Information in the table has been modified in order resolve inconsistent wording within 
the Protocol.
Section 9.4.2 Safety Analyses
!
Section has been modified in order resolve inconsistent wording within the Protocol.
Appendix A3 Informed Consent
!
Timelines related to reconsenting patients who are rescreened have been corrected.
Appendix F
Information related to CKD-EPI referenced formula has been corrected.
Version 1, 14 November 2019
Initial creation
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures. The Clinical Study Protocol is publicly registered, and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.
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TABLE OF CONTENTS
1TITLE PAGE...................................................................................................................... 1
VERSION HISTORY........................................................................................................... 2
TABLE OF CONTENTS.................................................................................................... 17
LIST OF TABLES.............................................................................................................. 20
LIST OF FIGURES ............................................................................................................ 20
LIST OF APPENDICES..................................................................................................... 20
1
PROTOCOL SUMMARY................................................................................ 22
1.1
Schedule of Activities....................................................................................... 22
1.2
Synopsis ........................................................................................................... 28
1.3
Study Schema ................................................................................................... 33
2
INTRODUCTION............................................................................................ 34
2.1
Study Rationale ................................................................................................ 34
2.2
Background ...................................................................................................... 35
2.2.1
Verinurad in Combination with Allopurinol...................................................... 35
2.3
Benefit/Risk Assessment................................................................................... 36
3
OBJECTIVES AND ENDPOINTS................................................................... 38
4
STUDY DESIGN ............................................................................................. 39
4.1
Overall Design.................................................................................................. 39
4.1.1
Overview.......................................................................................................... 39
4.1.2
Study Procedures.............................................................................................. 40
4.1.2.1
Week -5 to -1 (Visit 1)...................................................................................... 40
4.1.2.2
Week -2 to -1 (Visit 2), Only if Eligibility Criteria Met as Assessed in Visit 1 .. 40
4.1.2.3
Week 0 (Visit 3) ............................................................................................... 41
4.1.2.4
Week 4 (Visit 4) ............................................................................................... 42
4.1.2.5
Week 8 (Visit 5) ............................................................................................... 42
4.1.2.6
Week 12 (Visit 6) ............................................................................................. 42
4.1.2.7
Week 22 (Visit 7) ............................................................................................. 43
4.1.2.8
Week 32 (Visit 8) ............................................................................................. 43
4.1.2.9
Week 36 (Visit 9) ............................................................................................. 44
4.1.2.10
Premature Treatment Discontinuation Visit....................................................... 44
4.2
Scientific Rationale for Study Design ............................................................... 45
4.2.1
Main Inclusion Criteria Rationale ..................................................................... 45
4.2.2
Main Endpoint Rationale .................................................................................. 46
4.3
Justification for Dose........................................................................................ 47
4.4
End of Study Definition.................................................................................... 47
5
STUDY POPULATION ................................................................................... 48
5.1
Inclusion Criteria .............................................................................................. 48


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5.2
Exclusion Criteria ............................................................................................. 50
5.3
Lifestyle Restrictions ........................................................................................ 52
5.3.1
Pregnancy......................................................................................................... 52
5.3.2
Meals and Dietary Restrictions ......................................................................... 54
5.3.3
Caffeine, Alcohol, and Tobacco........................................................................ 54
5.4
Screen Failures ................................................................................................. 54
6
STUDY TREATMENTS.................................................................................. 55
6.1
Treatments Administered.................................................................................. 55
6.1.1
Investigational Products.................................................................................... 55
6.2
Preparation/handling/storage/accountability...................................................... 56
6.3
Measures to Minimise Bias: Randomisation and Blinding................................. 57
6.3.1
Emergency Unblinding ..................................................................................... 58
6.4
Treatment Compliance...................................................................................... 58
6.5
Concomitant Therapy........................................................................................ 59
6.5.2
Other Concomitant Treatment........................................................................... 61
6.6
Dose Modification ............................................................................................ 61
6.7
Treatment After the End of the Study................................................................ 61
7
DISCONTINUATION OF TREATMENT AND PATIENT WITHDRAWAL . 61
7.1
Discontinuation of Study Treatment.................................................................. 61
7.1.1
Temporary Discontinuation............................................................................... 62
7.1.2
Procedures for Discontinuation of Study Treatment .......................................... 62
7.2
Lost to Follow-up ............................................................................................. 63
7.3
Withdrawal From the Study.............................................................................. 63
7.4
Procedures for Handling Incorrectly Enrolled or Randomised Patients.............. 64
8
STUDY ASSESSMENTS AND PROCEDURES ............................................. 64
8.1
Efficacy Assessments........................................................................................ 65
8.1.1
Peak VO2 and Other Cardiopulmonary Exercise Test Outcomes ....................... 65
8.1.2
Patient Reported Outcomes............................................................................... 66
8.2
Safety Assessments........................................................................................... 70
8.2.1
Clinical Safety Laboratory Assessments............................................................ 70
8.2.2
Physical Examinations...................................................................................... 71
8.2.3
Vital Signs........................................................................................................ 72
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8.2.4
Electrocardiograms........................................................................................... 72
8.3
Collection of Adverse Events............................................................................ 72
8.3.1
Method of Detecting Adverse Events and Serious Adverse Events.................... 73
8.3.2
Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information............................................................................................. 73
8.3.3
Follow-up of Adverse Events and Serious Adverse Events................................ 73
8.3.4
Adverse Event Data Collection ......................................................................... 73
8.3.5
Causality Collection.......................................................................................... 74
8.3.6
Adverse Events Based on Signs and Symptoms ................................................ 74
8.3.7
Adverse Events Based on Examinations and Tests............................................ 75
8.3.8
Hy’s Law.......................................................................................................... 75
8.3.9
Adverse Events of Special Interest.................................................................... 75
8.3.10
Regulatory Reporting Requirements for Serious Adverse Events ...................... 75
8.4
Safety Reporting and Medical Management...................................................... 76
8.4.1
Reporting of Serious Adverse Events................................................................ 76
8.4.2
Pregnancy......................................................................................................... 76
8.4.2.1
Maternal Exposure............................................................................................ 77
8.4.2.2
Paternal Exposure............................................................................................. 77
8.4.3
Overdose .......................................................................................................... 77
8.4.4
Medication Error............................................................................................... 78
8.4.5
Management of Study Treatment-related Toxicities .......................................... 78
8.4.6
Data Monitoring Committee ............................................................................. 79
8.4.7
Clinical Event Adjudication Committee............................................................ 79
8.5.2
Storage and Destruction of Pharmacokinetic Samples....................................... 80
8.6
Genetics............................................................................................................ 80
8.6.1
Assessment of HLA-B Genotype ...................................................................... 80
8.7
Biomarkers ....................................................................................................... 81
8.7.2
Storage, Re-use and Destruction of Biomarker Samples.................................... 82
8.8
Medical Resource Utilisation and Health Economics ........................................ 82
8.9
Guidelines, Study Assessments, and Procedures During COVID-19 Pandemic . 82
9
STATISTICAL CONSIDERATIONS............................................................... 83
9.1
Statistical Hypotheses....................................................................................... 83
9.2
Sample Size Determination............................................................................... 84
9.3
Populations for Analyses .................................................................................. 84
9.4
Statistical Analyses........................................................................................... 85
9.4.1
Efficacy Analyses............................................................................................. 85
9.4.1.1
Analysis of the Primary Objective..................................................................... 85
9.4.1.2
Analysis of the Secondary Objectives ............................................................... 86
9.4.2
Safety Analyses ................................................................................................ 86
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9.4.4
Methods for Multiplicity Control ...................................................................... 87
9.4.5
Data Monitoring Committee ............................................................................. 88
10
REFERENCES................................................................................................. 89
11
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS........................................................................................ 94
LIST OF TABLES
Table SoA
Schedule of Activities.............................................................................. 23
Table 1
Dosing Schedule...................................................................................... 32
Table 2
Objectives and Endpoints......................................................................... 38
Table 3
Highly Effective Methods of Contraception (< 1% failure rate) ............... 54
Table 4
Study Treatments..................................................................................... 56
Table 5
Restricted Medications............................................................................. 59
Table 6
Patient Information to Capture at Each Visit for Analysis of 
Confounding Factors for Reactive Hyperaemia Assessments ................... 69
Table 7
Laboratory Safety Variables..................................................................... 71
Table 8
Analysis Populations ............................................................................... 84
LIST OF FIGURES
Figure 1
Study Schema.......................................................................................... 33
LIST OF APPENDICES
Appendix A
Regulatory, Ethical and Study Oversight Considerations.......................... 94
Appendix B
Adverse Event Definitions and Additional Safety Information............... 100
Appendix C
Handling of Human Biological Samples ................................................ 105
Appendix D
Genetics................................................................................................. 107
Appendix E
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law......................................................................... 111
Appendix F
Actions Required in Cases of a Renal-related or Kidney Stone Adverse 
Event or a Serum Creatinine Elevation................................................... 117
Appendix G
Kansas City Cardiomyopathy Questionnaire .......................................... 120
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Appendix H
Patient Global Impression of Change (PGIC) for Heart Failure 
Symptoms.............................................................................................. 125
Appendix I
Patient Global Impression of Severity (PGIS) for Heart Failure 
Symptoms.............................................................................................. 126
Appendix J
Medication Requiring Adjustment for Co-administration with Colchicine127
Appendix K
Patient Dosing Cards Information.......................................................... 129
Appendix L
Abbreviations ........................................................................................ 135


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1
PROTOCOL SUMMARY
1.1
Schedule of Activities


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Table SoA
Schedule of Activities
Period
Screening
Treatment period
Follow 
up
Visit
1 a
2
3
4*
5* b 6* c
7
8
9
Premature 
treatment 
discontinuation 
visit
Details in CSP section or 
Appendix
Week (Day 1 of)
-5 to -1
-2 to -1
0 (Randomisation)
4
8
12
22
32
36
Window
NA
±3d ±3d
±4d ±7d
±7d
±7d
Informed consent
X
Appendix A 3
Informed consent for 
optional general genetics
X
Appendix D 2
Inclusion/exclusion 
criteria
X
X
X
Sections 5.1 and 5.2
Randomisation
X
Section 6.3
Titration step 1 dose 
dispensed
X
Section 6.1
Titration step 2 dose 
dispensed
X
Section 6.1
Final (Titration step 3) 
dose dispensed
X
X
X
Section 6.1
Dispense colchicine 
prophylaxis
X
X
X
Section 6.1
Study treatment returned
X
X
X
X
X
X
Section 6.2
 
 
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Table SoA
Schedule of Activities
Period
Screening
Treatment period
Follow 
up
Visit
1 a
2
3
4*
5* b 6* c
7
8
9
Premature 
treatment 
discontinuation 
visit
Details in CSP section or 
Appendix
Week (Day 1 of)
-5 to -1
-2 to -1
0 (Randomisation)
4
8
12
22
32
36
Patient Dosing Card
X
X
X
X
X
Appendix K
Cooler bag, two sterile 
4oz./120ml collection 
containers and two urine 
collection pans
X
X
X
X
Routine clinical procedures
Demography
X
Section 5.1
Full physical examination
X
X
Section 8.2.2
Brief physical examination
X
X
X
X
X
X
X
Section 8.2.2
Medical history and 
comorbid conditions
X
Sections 5.1 and 5.2
Vital signs
X
X
X
X
X
X
X
X
X
X
Section 8.2.3
Height
X
Section 8.2.2
Weight
X
X
X
X
X
X
X
X
X
X
Section 8.2.2
ECG
X
X
X
X
X
X
Section 8.2.4
Concomitant medications
X
X
X
X
X
X
X
X
X
Section 6.5
Efficacy measurements
Cardiopulmonary exercise 
test
X
X h
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Table SoA
Schedule of Activities
Period
Screening
Treatment period
Follow 
up
Visit
1 a
2
3
4*
5* b 6* c
7
8
9
Premature 
treatment 
discontinuation 
visit
Details in CSP section or 
Appendix
Week (Day 1 of)
-5 to -1
-2 to -1
0 (Randomisation)
4
8
12
22
32
36
Kansas City 
Cardiomyopathy 
Questionnaire i
X
X
X
X
Section 8.1.2
Patient Global Impression 
of Severity i
X
X
X
X
Section 8.1.2
Patient Global Impression 
of Change i
X
X
Section 8.1.2
sCr, eGFR
X
Serum uric acid (sUA)
X
 
 
 
 
NT-proBNP
X
Section 8.7.1
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Table SoA
Schedule of Activities
Period
Screening
Treatment period
Follow 
up
Visit
1 a
2
3
4*
5* b 6* c
7
8
9
Premature 
treatment 
discontinuation 
visit
Details in CSP section or 
Appendix
Week (Day 1 of)
-5 to -1
-2 to -1
0 (Randomisation)
4
8
12
22
32
36
Routine safety measurements
Adverse events
X (Only 
SAEs)
X (Only SAEs)
X
X
X
X
X
X
X
X
Section 8.3
Pregnancy test (serum or 
urine)
X
X
Section 5.1
Sample for HLA 
genotyping
X
Section 5.2 and 8.6.1
Safety laboratory 
assessments (including 
clinical chemistry, 
haematology, urinalysis)
X
X
X
X
X
X
X
X
X
Section 8.2.1
 
a
Progression to Visit 2 screening is only for patients who fulfil eligibility based on Visit 1 screening; however, Visit 2 can be performed before HLA-B 
results are available.
b
Patients should be reminded to not take study treatment in the morning before Visit 6
c
Patients to take study treatment at clinic (time of study treatment intake should be recorded)
d
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h
All patients should perform CPET at this visit regardless of premature discontinuation of study treatment. CPET and EndoPAT should be performed before 
patients return study treatment
i
All patient reported outcomes (PRO) will be administered using a site-based electronic device. To avoid bias in patient responses, all PRO questionnaires 
must be completed prior to any other study procedures
j
Sub-study to randomise approximately 40 patients in selected sites
k
Applicable only for patients that had UA crystals at baseline
l
*
If a patient cannot be seen on site due to pandemic related restrictions (or any other restrictions due to civil crisis, natural disaster, or public health crisis), 
visit might be performed in the patient’s home. See Section 8.9.
CSP  Clinical Study Protocol; ECG  Electrocardiography; eGFR  estimated glomerular filtration rate; HLA  Human leukocyte antigen; 
; sCr  
serum creatinine; 
; VO2  Volume oxygen
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1.2
Synopsis
International co-ordinating investigator; Dr Dalane Kitzman
Protocol title
A Phase 2, Multicentre, Double-Blind, Placebo and Active Control Efficacy and Safety Study 
to Evaluate Verinurad combined with Allopurinol in Heart Failure with Preserved Ejection 
Fraction
Short title: AMETHYST
Rationale
Evidence shows independent associations between hyperuricaemia and the risk of cardio-renal 
conditions, including heart failure (HF) (Anker et al 2003, Grayson et al 2011, Kodama et al 
2009, Levya et al 1998, Nakagawa et al 2006). Serum uric acid (sUA) is also a strong 
prognostic factor and correlates with other markers of poor prognosis in HF patients with 
preserved ejection fraction (HFpEF), and an estimated 1/2-2/3 of HFpEF patients have 
hyperuricaemia (Odden et al 2014, Palazzuoli et al 2017). 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 is a novel URAT1 inhibitor in Phase 2 
development for chronic kidney disease (CKD) and HF. 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 approximately 82%. HFpEF is 
a microvascular disease likely partly driven by endothelial dysfunction and inflammation in 
coronary vessel walls. Uric acid crystals have been identified in coronary vessel walls in some 
hyperuricaemic patients (Andrés et al 2016, Park et al 2014). The primary aim of this Phase 2 
study is to evaluate the effects of substantial UA lowering on functional endpoints in 
hyperuricaemic HFpEF patients, using a combination of verinurad and allopurinol.
Objectives and endpoints
Primary objective:
Endpoint/variable:
To assess effect of verinurad + allopurinol compared 
to placebo on exercise capacity
Change from baseline at Week 32 in peak volume of 
oxygen (VO2) 
Secondary objectives:
Endpoints/variables:
To assess effect of verinurad + allopurinol compared 
to allopurinol monotherapy on exercise capacity
Change from baseline at Week 32 in peak VO2
To assess effect of verinurad + allopurinol compared 
to placebo and compared to allopurinol monotherapy 
on Kansas City Cardiomyopathy Questionnaire 
(KCCQ)-total symptom score (TSS)
Change from baseline at Week 32 in KCCQ-TSS


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Safety objective:
Endpoint/variable:
To assess the safety and tolerability of verinurad + 
allopurinol as compared to placebo and to allopurinol 
in patients with HFpEF.
Safety and tolerability will be evaluated in terms of 
adverse events (AEs), Vital signs, Clinical laboratory 
and electrocardiogram (ECG).
Assessments related to AEs cover:
•
Occurrence
•
Relationship to study treatment as assessed by 
investigator
•
Intensity
•
Seriousness
•
Death
•
AEs leading to discontinuation of study 
treatment
•
Other action taken related to study treatment, 
including dose reductions and dose interruptions
•
AEs of special interest
Vital signs parameters include systolic and diastolic 
blood pressure, pulse, temperature.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Overall design
A randomised, multicentre, global, double-blind, parallel arm, active- and placebo-controlled, 
Phase 2 study to assess safety and efficacy of 12 mg verinurad and 300 mg allopurinol on 
functional endpoints in patients with hyperuricaemia (sUA > 6 mg/dL) and HFpEF (left 
ventricular ejection fraction (LVEF) ≥45%). Patients who meet eligibility criteria will be 
randomised in a 1:1:1 ratio to verinurad/allopurinol combination, allopurinol, or placebo.
There will be matching placebo for both the verinurad and allopurinol. The verinurad placebo 
will be identical in appearance to verinurad and likewise the allopurinol placebo to 
allopurinol.
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Target patient population
The study will be conducted in male and female patients ≥40 years of age with HFpEF who 
provide informed consent to participate in the study and who are not pregnant and not 
lactating. Eligible patients will have New York Heart Association (NYHA) class II-III at 
enrolment, medical history of typical signs/symptoms of HF > 6 weeks before enrolment, and 
LVEF ≥45% (excluding history of a known, documented LVEF < 40%). Eligible patients will 
also have NT-proBNP ≥125 pg/mL or a history of pulmonary capillary wedge pressure 
≥15 mmHg during rest or pulmonary capillary wedge pressure ≥20 mmHg during exercise. 
Apart from the above criteria, the following is necessary: sUA concentration > 6 mg/dL and 
peak VO2 ≤75% of expected using treadmill, or peak VO2 ≤68% of expected using cycle 
ergometer, based on normal values of peak VO2. Individuals should be able to exercise to near 
exhaustion as exhibited by a respiratory exchange ratio (RER) ≥1.05.
Eligible patients should have an eGFR ≥30 mL/min/1.73 m2.
Study period
The estimated date of first patient enrolled is Q2 2020. Patients will be followed until they 
complete 8 weeks of titration followed by 24 weeks of treatment at target dose plus 4 weeks of 
follow up. The estimated date of the last visit of the last patient is Q2 2022.
Number of patients
Approximately 150 patients (approximately 50 per arm) will be randomised at around 70 sites
in approximately 12 countries. With an estimated screen-failure rate of 65%, up to 
500 patients should be enrolled.
Treatments and treatment duration
Each patient will be randomised to 1 of the following three treatment arms: 12 mg verinurad 
plus 300 mg allopurinol; 300 mg allopurinol; or placebo. Study treatment will be titrated over 
8 weeks. Once target dose has been reached, treatment will continue for 24 weeks. Titration is 
done in discrete steps of 4 weeks to reduce the risk of adverse reactions due to allopurinol. In 
order to prevent increase in inflammation due to rapid crystal dissolution, colchicine 
prophylaxis will be given during the titration period (8 weeks) and during the first 4 weeks of 
treatment at target dose (12 weeks total) and will be distributed as available, currently 500 µg 
within the European Union (EU) and 600 µg within the United States (US). For dosing, see 
the dosing schedule below (Table 1). The tablet and capsule will be taken orally in 
combination once daily.
Patients unable to tolerate the stepped dosage may be down-titrated only by reversing the 
assigned steps within treatment group. Verinurad and allopurinol cannot be unpaired from the 
titration schedule. Patients who cannot tolerate the step-1 dose will be discontinued from 
study treatment and be followed for the remainder of the study.


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Table 1
Dosing Schedule
Treatment arm
Week 0-3
Step 1 - titration
Week 4-7
Step 2 - titration
Week 8-12
Step 3 - target 
dose
Week 13-32
Target dose
12 mg verinurad + 
allopurinol
Colchicine 
prophylaxis + 3 mg 
verinurad + 100 mg 
allopurinol
Colchicine 
prophylaxis + 7.5 
mg verinurad + 200 
mg allopurinol
Colchicine 
prophylaxis + 
12 mg verinurad + 
300 mg allopurinol
12 mg verinurad + 
300 mg allopurinol
Allopurinol
Colchicine 
prophylaxis + 100 
mg allopurinol
Colchicine 
prophylaxis + 200 
mg allopurinol
Colchicine 
prophylaxis + 300 
mg allopurinol
300 mg allopurinol
Placebo
Colchicine 
prophylaxis + 
placebo
Colchicine 
prophylaxis + 
placebo
Colchicine 
prophylaxis + 
placebo
Placebo
Data Monitoring Committee
The Data Monitoring Committee (DMC) will be responsible for monitoring the safety of the 
study patients and making appropriate recommendations based on the available data. The 
DMC will function independently of all other individuals associated with the conduct of the 
study, including AstraZeneca (AZ). The committee will operate in accordance with a DMC 
Charter.
Adjudication committee
The study will engage an independent clinical event adjudication (CEA) committee to 
independently review, interpret and adjudicate potential CV events that are experienced by the 
patients.
Statistical methods
The primary endpoint is absolute change from baseline in peak VO2 at Week 32 and will be 
analysed using an analysis of covariance (ANCOVA) model with change from baseline in 
peak VO2 at Week 32 as the dependent variable, treatment as the independent variable and 
baseline peak VO2 included as a covariate. The analysis will include data from all patients at 
Week 32 irrespective of whether the patient has discontinued study treatment or received other 
medications. Missing peak VO2 values at Week 32 will be imputed using a dropout reason-
based multiple imputation approach.
The key secondary endpoint is change from baseline to Week 32 in KCCQ-TSS and will be 
analysed using a mixed model repeated measures (MMRM) model.
The primary and secondary objectives will be analysed using the Full analysis set.


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A hierarchical test sequence will be used for the confirmatory analysis of the primary and 
secondary objectives in order to address the issue of multiple testing. Statistical significance 
will be assessed in the following sequence:
!
Comparison between verinurad + allopurinol and placebo in change from baseline in peak 
VO2 at Week 32
!
Comparison between verinurad + allopurinol and allopurinol monotherapy in change
from baseline in peak VO2 at Week 32
!
Comparison between verinurad + allopurinol and placebo in change from baseline in 
KCCQ-TSS at Week 32
!
Comparison between verinurad + allopurinol and allopurinol monotherapy in change 
from baseline in KCCQ-TSS at Week 32
The testing procedure will continue down the hierarchy if the preceding endpoint is rejected at 
a two-sided 0.05 level and will stop if the preceding endpoint is not rejected at a two-sided 
0.05 level.
1.3
Study Schema
The general study schema is summarised in Figure 1.
Figure 1
Study Schema
a
Based on Fletcher et al 1995
AF  Atrial fibrillation; eGRF  estimated glomerular filtration rate; exPCWP  Pulmonary capillary wedge pressure 
during exercise; HFpEF  Heart failure with preserved ejection fraction; KCCQ  Kansas City Cardiomyopathy 
Questionnaire; LVEF  Left ventricular ejection fraction; NT-proBNP  N-terminal pro b-type natriuretic peptide; 
NYHA  New York Heart Association; RER  Respiratory exchange ratio; rPCWP  Pulmonary capillary wedge 
pressure during rest; sUA  Serum uric acid; VO2  Volume oxygen.
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2
INTRODUCTION
2.1
Study Rationale
Chronic HF (CHF) is a major cause of mortality, hospitalisation and poor quality of life. Even 
with the best possible treatment, the five-year survival rate for HF patients is worse than for 
most cancers (Braunwald 2015). Moreover, the prevalence for CHF continues to increase 
globally. An estimated 38 million people are affected worldwide (Braunwald 2015) with over 
1 million hospitalisations annually in both the US and Europe (Ambrosy et al 2014). The 
annual global economic burden in 2012 was estimated to be $108 billion (Cook et al 2014); 
this will increase dramatically as the population ages.
HF is characterised by dyspnoea, fatigue, and pulmonary congestion and/or 
peripheral oedema due to fluid retention. Patients with signs and symptoms of HF 
are categorised, based on measurement of LVEF, as having HF with reduced LVEF (HFrEF) 
or HF with preserved LVEF (HFpEF). Approximately half of all HF patients have HFpEF 
(Oktay et al 2013). The risk of death for HFpEF patients is high, with an annualised mortality 
rate up to 15% in community settings (Lam et al 2011). Patients with HFpEF have a 
particularly significant unmet medical need given that outcome studies hitherto performed 
have not resulted in any approved pharmacotherapy specifically for this condition. 
Conversely, outcome studies have provided evidence for treatments for HFrEF that can 
improve symptoms and haemodynamics and reduce hospitalisations for HF and mortality. 
These treatments include diuretics, angiotensin converting enzyme inhibitors (ACEi), 
angiotensin II receptor blockers (ARB), ARB neprilysin inhibitors, mineralocorticoid receptor 
antagonists, and beta-blockers (Iwaz et al 2016).
Serum UA is a strong prognostic factor and correlates with other markers of poor 
prognosis in HFpEF patients. An estimated 1/2-2/3 of HFpEF patients have hyperuricaemia 
(Odden et al 2014, Palazzuoli et al 2017). Evidence shows independent associations between 
hyperuricaemia and the risk of hypertension, myocardial infarction, CKD, type 2 diabetes, HF, 
and metabolic syndrome, including obesity (Nakagawa et al 2006, Grayson et al 2011, 
Kodama et al 2009, Levya et al 1998, Anker et al 2003).
A recent prospective crossover trial suggested that HFpEF parameters improved in patients 
treated with UA-lowering therapy (Ogino et al 2019). The exact mechanism by which UA-
lowering therapy may improve HFpEF remains to be established, but the presence of 
proinflammatory UA crystals in cardiac vessel walls (Andrés et al 2016) may contribute to 
endothelial dysfunction, a hallmark of HFpEF. Uric acid-lowering therapy has been proven to 
improve endothelial function, albeit not tested to date in subjects with HFpEF (SURPHER 
study presented by Dr Gaffo at European League Against Rheumatism [EULAR] 2019, data is 
in agreement with data from previous study with allopurinol in NYHA II/III subjects 
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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 HF. 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 approximately 82% (see Investigator’s Brochure [IB], Section 5.2.1).
The purpose of this Phase 2 study is to assess the effect of a combination of verinurad and 
allopurinol on exercise capacity and well-being in patients with HFpEF.
 
 
Monotherapy with potent URAT1 inhibitors has been associated with creatinine elevation in 
some patients, potentially related to increased peak concentrations of urinary UA (uUA) in the 
proximal tubuli of the kidney. Verinurad is therefore given as an extended release formulation 
(ER8), as a low maximum concentration is expected to further reduce the risk of creatinine 
elevations. More importantly, verinurad is to be developed exclusively in a fixed-dose 
combination with an XOI, which will also reduce the production of UA. Treatment with 
verinurad combined with allopurinol or febuxostat has not been associated with an increased 
incidence of creatinine elevations compared to placebo in the studies conducted to date (see 
IB, Section 5.2.3.6).
The clinical evidence to date suggests that the combination of verinurad and allopurinol has an 
acceptable safety profile across multiple patient populations, and there may be a therapeutic 
benefit associated with UA-lowering therapy in HFpEF. Hence, a global, randomised, Phase 2 
study is planned to evaluate the efficacy and safety of verinurad and allopurinol in patients 
with HFpEF and hyperuricaemia.
2.2
Background
Verinurad is a novel URAT1 inhibitor in Phase 2 development. Verinurad combined with the 
XOI allopurinol has been shown to lower sUA by > 70% in patients with recurrent gout in 
Phase 2 studies. A detailed description of the chemistry, pharmacology, efficacy, and safety of 
verinurad is provided in the IB.
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, 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. Serum UA was 
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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 safety profile 
of verinurad may be found in the IB.
The study design aims to minimise potential risks to patients and to ensure adequate 
monitoring. A dual-inhibition approach using lower doses of two 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 
> 1.5× 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 a 
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 Phase 2a study D5495C00007, in which 
patients with diabetes and albuminuria were recruited, the combination of verinurad and 
febuxostat resulted in two creatinine elevation events in both the active treatment group and in 
the placebo control group.
The cumulative safety data observed in the clinical studies conducted in the verinurad clinical 
development programme indicate that verinurad in combination with allopurinol is generally 
well tolerated.
Patients with HFpEF are at increased risk to experience CV events. Furthermore, major CV 
events (MACE) have been identified as a potential risk for lesinurad, which is an approved 
drug with a similar mechanism of action as verinurad. The overall incidence of MACE in the 
lesinurad programme was low, with comparable rates for lesinurad 200 mg in combination 
with an XOI and an XOI alone. The rate was also low, but numerically higher, with lesinurad 
400 mg; however, no causal relationship has been established. The small number of MACE 
observed in the pooled analysis of data from the pivotal Phase III combination therapy studies 
places limitations on assessment of treatment-associated differences in MACE risk and a post-
approval prospective observational cohort study is planned to further evaluate this risk. There 
is no evidence of a CV safety signal in the verinurad clinical programme to date. 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 


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inadequate blood pressure control will be excluded. In addition, all potential CV events will 
be adjudicated by an independent, blinded adjudication committee.
The main risk from allopurinol, severe skin reactions, will be minimised by excluding patients 
carrying the high-risk human leukocyte antigen-B (HLA-B) *58:01 allele and by using a low 
starting dose and slow dose titration of allopurinol.
Patients with gout may experience an acute gout flare event with initiation of UA-lowering 
therapies (Borstad et al 2004). To prevent this, the manufacturer’s prescribing information for 
UA-lowering therapies like lesinurad, allopurinol and febuxostat, as well as the EULAR, 
American College of Rheumatology, and British Society of Rheumatology treatment 
guidelines (Jordan et al 2007, Khanna et al 2012, Zhang et al 2006) recommend acute gout 
flare prophylaxis with colchicine, steroids, or a nonsteroidal anti-inflammatory drug (NSAID) 
when initiating or increasing the dose of such therapies. Thus, to prevent increased 
inflammation due to rapid crystal dissolution, and to reduce the risk of HFpEF exacerbation
due to an inflammatory state, colchicine prophylaxis will be given during the titration period 
(8 weeks) and during the first 4 weeks of treatment at target dose (12 weeks total). Colchicine 
will be administered in all three treatment groups to ensure any difference in effect is not due 
to colchicine therapy. 
There is a significant unmet medical need for HFpEF patients with hyperuricaemia as there 
are currently no available pharmacological therapies known to provide significant clinical 
benefit. Preliminary evidence suggests verinurad combined with allopurinol may demonstrate 
a meaningful benefit, but it cannot be assumed that recruited patients will derive any benefit 
from the treatment administered.
To further safeguard the interests of the patients, a DMC will be established. Refer to Section 
9.4.5 and Appendix A for information regarding the DMC.
Overall, the study has been designed to minimise the risks to participating patients by 
excluding patients at high risk of AEs and by applying appropriate safety monitoring of 
recruited study patients. The doses selected have been carefully considered in light of the 
target patient population. The potential benefits of developing a new treatment for HFpEF 
with hyperuricaemia therefore outweigh the limited risks to the patients exposed to treatment 
with verinurad and allopurinol in this trial.


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3
OBJECTIVES AND ENDPOINTS
Table 2
Objectives and Endpoints
Primary objective:
Endpoint/variable:
To assess effect of verinurad + allopurinol compared 
to placebo on exercise capacity
Change from baseline at Week 32 in peak VO2
Secondary objectives:
Endpoints/variables:
To assess effect of verinurad + allopurinol compared 
to allopurinol monotherapy on exercise capacity
Change from baseline at Week 32 in peak VO2
To assess effect of verinurad + allopurinol compared 
to placebo and compared to allopurinol monotherapy 
on KCCQ-TSS
Change from baseline at Week 32 in KCCQ-TSS
Safety objective:
Endpoint/variable:
To assess the safety and tolerability of verinurad + 
allopurinol as compared to placebo and to allopurinol 
in patients with HFpEF.
Safety and tolerability will be evaluated in terms of 
AEs, Vital signs, Clinical laboratory and ECG.
Assessments related to AEs cover:
•
Occurrence
•
Relationship to study treatment as assessed by 
investigator
•
Intensity
•
Seriousness
•
Death
•
AEs leading to discontinuation of study 
treatment
•
Other action taken related to study treatment, 
including dose reductions and dose interruptions
•
AEs of special interest
Vital signs parameters include systolic and diastolic 
blood pressure, pulse, temperature.
 
 
 
 
 
 
 
 
 
 
 
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Table 2
Objectives and Endpoints
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4
STUDY DESIGN
4.1
Overall Design
4.1.1
Overview
This is a randomised, multicentre, double-blind, parallel arm, active- and placebo-controlled, 
global Phase 2 study to assess the efficacy and safety of verinurad and allopurinol in patients 
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with HFpEF and hyperuricaemia. Patients who meet the eligibility criteria will be randomised 
in a 1:1:1 ratio to 12 mg verinurad plus 300 mg allopurinol, 300 mg allopurinol, or placebo.
Approximately 150 patients (approximately 50 per arm) will be randomised at around 70 sites
in approximately 12 countries. With an estimated screen-failure rate of 65%, up to 500 
patients should be enrolled.
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 3 Objectives 
and Endpoints.
4.1.2
Study Procedures
All randomised patients should follow the visit scheme even if they discontinue treatment. 
(Section 7.1)
4.1.2.1
Week -5 to -1 (Visit 1)
First screening procedures should start maximum 35 days prior to randomisation (V3).

Obtain signed informed consent form (ICF)

Obtain signed informed consent for optional general genetics

Assess inclusion/exclusion criteria

Demography

Full physical examination

Medical history and comorbid conditions

Vital signs

Height

Weight

ECG

Concomitant medications

Collect serious AEs (SAEs)

Pregnancy test (serum or urine)

Sample for HLA genotyping 

Safety laboratory assessments (including clinical chemistry, haematology and urinalysis)

sUA, sCr, eGFR, NT-Pro-BNP
4.1.2.2
Week -2 to -1 (Visit 2), Only if Eligibility Criteria Met as Assessed in Visit 1
Progression to V2 screening is only for patients who fulfil eligibility based on V1 screening; 
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any of the exclusion criteria. V2 should be scheduled minimum 1 week prior to randomisation 
(V3).
!
Assess inclusion/exclusion criteria
!
Vital signs
!
Weight
!
Cardiopulmonary exercise test (CPET)
!
!
Collect SAEs
!
!
Hand out cooler bag, two sterile 4oz./120ml collection containers and two urine collection 
pans
4.1.2.3
Week 0 (Visit 3)
!
Assess inclusion/exclusion criteria
!
Brief physical examination
!
Vital signs
!
Weight
!
ECG
!
KCCQ
!
PGIS
!
Concomitant medications
!
Collect AEs
!
Safety laboratory assessments (including clinical chemistry, haematology and urinalysis)
!
!
!
 
!
 
!
!
Randomisation
!
Titration step 1 dose dispensed: 3 mg verinurad plus 100 mg allopurinol, or 100 mg 
allopurinol plus verinurad placebo, or verinurad placebo and allopurinol placebo. At 
Visit 3, study treatment should be taken after blood drawn.
!
Dispense colchicine prophylaxis
!
Patient Dosing Card given to patient
!
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4.1.2.4
Week 4 (Visit 4)
!
Brief physical examination
!
Vital signs
!
Weight
!
Concomitant medications
!
Collect AEs
!
Safety laboratory assessments (including clinical chemistry, haematology and urinalysis)
!
!
Titration step 2 dose dispensed: 7.5 mg verinurad plus 200 mg allopurinol, or 200 mg 
allopurinol plus verinurad placebo, or verinurad placebo and allopurinol placebo
!
Dispense colchicine prophylaxis
!
Study treatment returned
!
Patient Dosing Card given to patient 
4.1.2.5
Week 8 (Visit 5)
!
Brief physical examination
!
Vital signs
!
Weight
!
Concomitant medications
!
Collect AEs
!
Safety laboratory assessments (including clinical chemistry, haematology and urinalysis)
!
!
Final (titration step 3) dose dispensed: 12 mg verinurad plus 300 mg allopurinol, or 300 
mg allopurinol plus verinurad placebo, or verinurad placebo and allopurinol placebo
!
Dispense colchicine prophylaxis
!
Study treatment returned
!
Hand out two sterile 4oz./120ml collection containers and two urine collection pans
!
Remind patient to not take study treatment in the morning before Visit 6
!
Patient Dosing Card given to patient 
4.1.2.6
Week 12 (Visit 6)
!
Brief physical examination
!
Vital signs
!
Weight
!
ECG
!
Concomitant medications
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!
Collect AEs
!
Safety laboratory assessments (including clinical chemistry, haematology and urinalysis)
!
!
 
!
Patients take study treatment at clinic (dose, date and time of study treatment intake 
should be recorded in patient’s medical records).
!
!
 
!
Final (titration step 3) dose dispensed: 12 mg verinurad plus 300 mg allopurinol, or 300 
mg allopurinol plus verinurad placebo, or verinurad placebo and allopurinol placebo
!
Study treatment returned
!
Patient Dosing Card given to patient
4.1.2.7
Week 22 (Visit 7)
!
Brief physical examination
!
Vital signs
!
Weight
!
KCCQ
!
PGIS
!
Concomitant medications
!
Collect AEs
!
Safety laboratory assessments (including clinical chemistry, haematology and urinalysis)
!
!
!
Final (titration step 3) dose dispensed: 12 mg verinurad plus 300 mg allopurinol, or 300 
mg allopurinol plus verinurad placebo, or verinurad placebo and allopurinol placebo
!
Study treatment returned
!
Patient Dosing Card given to patient
!
 
!
Hand out two sterile 4oz./120ml collection containers and two urine collection pans
4.1.2.8
Week 32 (Visit 8)
!
Brief physical examination
!
Vital signs
!
Weight
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!
CPET
!
ECG
!
KCCQ
!
PGIS
!
PGIC
!
!
Concomitant medications
!
Collect AEs
!
Safety laboratory assessments (including clinical chemistry, haematology and urinalysis)
!
!
 
!
!
 
!
 
!
Study treatment returned
!
Hand out two sterile 4oz./120ml collection containers and two urine collection pans
4.1.2.9
Week 36 (Visit 9)
!
Full physical examination
!
Vital signs
!
Weight
!
ECG
!
Concomitant medications
!
Collect AEs
!
Pregnancy test (serum or urine)
!
Safety laboratory assessment (including clinical chemistry, haematology and urinalysis)
!
!
!
 
4.1.2.10
Premature Treatment Discontinuation Visit
!
Brief physical examination
!
Vital signs
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!
Weight
!
ECG
!
KCCQ
!
PGIS
!
PGIC
!
!
Concomitant medications
!
Collect AEs
!
Safety laboratory assessments (including clinical chemistry, haematology and urinalysis)
!
!
!
 
!
 
!
Study treatment returned
4.2
Scientific Rationale for Study Design
The purpose of this Phase 2 study is to evaluate the effect of substantial UA lowering on 
functional endpoints in hyperuricaemic HFpEF patients, using a combination of verinurad and 
allopurinol for 24 weeks, plus 8 weeks titration. The study will be a randomised, double-blind, 
placebo- and active-controlled study.
Since the URAT1 inhibitor verinurad plus a XOI such as febuxostat or allopurinol can lower 
sUA up to approximately 82%, the crystals formed due to high levels of UA are likely to be 
dissolved, which in turn is believed to lead to better clinical outcomes in HFpEF.
The duration of the study was set to approximately 8 months since microcrystals are expected 
to dissolve and hence inflammation to be reduced within that time. An 8-week titration was 
chosen for the safety of allopurinol. Colchicine prophylaxis will be used to prevent 
inflammation due to microcrystal dissolution.
4.2.1
Main Inclusion Criteria Rationale
In a study by Palazzouli et al (Palazzuoli et al 2017) where hyperuricaemia was defined as ≥6 
mg/dL in women and ≥7 mg/dL in men, the results showed that the non-hyperuricaemic 
HFpEF group showed a statistically significant difference in the outcome of HF 
hospitalisation or death at 6 months as compared to the hyperuricaemic HFpEF group. Since 
we do not have a strong rationale for adjusting sUA levels for gender, the current study will 
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use 6.0 mg/dL as inclusion criteria to test what baseline levels of sUA would be associated 
with a meaningful benefit.
Since the primary endpoint is peak VO2, a NYHA class II-III has been chosen. Class I was 
excluded since a benefit will be difficult to demonstrate since the class I patients by definition 
do not have any limitation of physical activity. Class IV patients are excluded since they will 
probably not be able to perform the CPET.
An NT-proBNP level of ≥125 pg/mL for patients without ongoing atrial fibrillation/flutter, 
and ≥250 pg/mL for patients with ongoing atrial fibrillation or flutter, with the alternative of 
documented pulmonary capillary wedge pressure during rest > 15 or pulmonary capillary 
wedge pressure during exercise > 20 , was chosen according to the European Society of 
Cardiology criteria (Ponikowski et al 2016) because of good sensitivity and specificity for 
identification of HFpEF (Ho et al 2019).
As there is currently no consensus within academia or industry, a LVEF of ≥45% was chosen 
as the definition of HFpEF for this trial. Patients who had a known history of a documented 
LVEF < 40% will be excluded from the study to enrich for patients with HFpEF-dominant 
disease.
4.2.2
Main Endpoint Rationale
Exercise capacity is severely limited in patients with HFpEF and is correlated with 
hospitalisation for HF and outcomes. At the same time, improving exercise capacity for 
patients with HFpEF is by itself clinically meaningful. In contrast to other methods to assess 
exercise capacity (eg, 6-minute walk test), CPET enables quantification of the effort the 
patient has applied during the test.
Patients with HF experience debilitating symptoms that substantially impact daily functioning, 
physical capacity and quality of life. For these reasons, it is important to measure the impact 
of new HF therapies on the HF patient’s symptoms and functioning (Zannad et al 2013). The 
KCCQ instrument quantifies both the frequency of four cardinal HF symptoms (fatigue, 
peripheral oedema, dyspnoea, and orthopnoea) and how distressing are three of the cardinal 
HF symptoms (fatigue, peripheral oedema and dyspnoea). The KCCQ also assesses HF-
related physical limitations, social limitations, self-efficacy, and health-related quality of life. 
First developed in 1996 (Green et al 2000, Spertus et al 2005), over the following two decades 
experience with the KCCQ has grown in industry-sponsored and academic studies and it is 
now the most common disease patient-reported outcome (PRO) instrument collected in HF 
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4.3
Justification for Dose
The verinurad and allopurinol combination therapy doses and regimen selected for this study 
are based on the well-established dose-response relationship between verinurad in 
combination with allopurinol and sUA. The suggested verinurad dose (12 mg) was chosen 
based on PK, pharmacodynamic, and safety data from previous studies in healthy volunteers 
and Phase 2 studies in patients with gout or hyperuricaemia with albuminuria.
Verinurad combined with allopurinol (300 mg once daily) dose-dependently lowered 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. All doses tested in the study were 
considered tolerable and safe. Hence verinurad 12 mg dosed as the ER8 capsule was chosen to 
achieve significantly greater sUA lowering than with allopurinol monotherapy, while still 
being known to be safe and tolerable in earlier studies.
Verinurad monotherapy dose-dependently increases peak uUA excretion (Hall et al 2018), but 
peak uUA excretion is comparable to or lower than before any treatment when verinurad is 
given in combination with an appropriately dosed XOI (Fleischmann et al 2018a, Fleischmann 
et al 2018b). Verinurad is therefore combined with allopurinol 300 mg to reduce the peak 
uUA excretion, as high peak uUA excretion has been associated with creatinine elevations.
Allopurinol will be titrated every 4 weeks in the initial phase of the study 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 guideline recommendations for treatment of gout and recent literature (Khanna et al 
2012, Stamp et al 2016, Richette et al 2017). Verinurad will be titrated along with allopurinol.
In parallel with this study, the Phase 2b SAPPHIRE study (D5495C00002) in patients with 
CKD is underway. The SAPPHIRE study is exploring the effects of 3, 7.5, 12 mg, and 24 mg
verinurad ER8 in combination with allopurinol 300 mg.
4.4
End of Study Definition
The end of study is defined as the last expected visit of the last patient undergoing the study.
A patient is considered to have completed the study when he or she has completed the last 
scheduled visit (Visit 9).
Refer to Appendix A 6 for guidelines for the dissemination of study results.


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5
STUDY POPULATION
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 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 screen failures 
(Section 5.4).
In this protocol, “enrolled” patients are defined as those who sign informed consent. 
“Randomised” patients are defined as those who undergo randomisation and receive a 
randomisation number.
For procedures for withdrawal of incorrectly enrolled patients, refer to Section 7.4.
5.1
Inclusion 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:
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 ≥40 years of age at the time of signing the ICF.
Type of patient and disease characteristics
5
Patients with hyperuricaemia defined as sUA level of > 6 mg/dL.
6
Patients with documented diagnosis of symptomatic HFpEF according to all of the 
following criteria:
(a) Have NYHA functional class II-III at enrolment
(b) Have medical history of typical symptoms/signs of HF > 6 weeks before enrolment, 
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treatment. Typical symptoms of HF include breathlessness, orthopnoea, paroxysmal 
nocturnal dyspnoea, reduced exercise tolerance, fatigue, tiredness, increased time to 
recover after exercise, ankle swelling. Typical signs associated with HF include 
elevated jugular venous pressure, hepatojugular reflex, third heart sound (gallop 
rhythm). Less specific symptoms include: weight gain (> 2 kg/week), weight loss (in 
advanced HF), tissue wasting (cachexia), cardiac murmur, peripheral oedema (ankle, 
sacral, scrotal), pulmonary crepitations, reduced air entry and dullness to percussion 
at lung bases (pleural effusion), tachycardia, irregular pulse, tachypnoea, Cheyne-
Stokes respiration, hepatomegaly, ascites, cold extremities, oliguria, narrow pulse 
pressure.
(c) LVEF ≥45%
(d) NT-proBNP ≥125 pg/mL (≥14.75 pmol/L) at Visit 1 for patients without ongoing 
atrial fibrillation/flutter. If ongoing atrial fibrillation/flutter at the time of sample 
collection, NT-proBNP must be ≥250 pg/mL (≥29.51 pmol/L) OR patients must 
have a history of pulmonary capillary wedge pressure ≥15 mmHg during rest or 
pulmonary capillary wedge pressure ≥20 mmHg during exercise.
7
Patients able to exercise to near exhaustion during a CPET as exhibited by RER 
≥1.05 during CPET conducted during screening. If patient does not achieve RER ≥1.05 
the CPET may be repeated once, at least 48 hours but less than 2 weeks (but before 
randomisation) after the initial test; in such cases the second test will serve as baseline.
8
Patients with peak VO2 ≤75% of expected using treadmill, or peak VO2 ≤68% of 
expected using cycle ergometer, based on normal values (Fletcher et al 1995).
9
Patients treated according to locally recognised guidelines on standard-of-care treatment 
for patients with HFpEF. Therapy should have been individually optimised and stable for 
≥4 weeks (except diuretics) and include, unless contraindicated or not tolerated, 
treatment of high blood pressure (targeting a systolic blood pressure < 130 mmHg as 
suggested in 2017 American College of Cardiology/American Heart Association/Heart 
Failure Society of America HF guidelines), ischaemic heart disease, and atrial fibrillation.
10 Patients treated with a sodium-glucose transport protein 2 inhibitor or 
sacubitril/valsartan must be on stable dose for ≥4 weeks before randomisation.
Sex
11 Male or female.
Reproduction
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.


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12 Negative pregnancy test (urine or serum) for female patients of childbearing potential.
Female patients must be 1 year post-menopausal, surgically sterile, or using an acceptable 
method of contraception (with a failure rate of < 1% per year) 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. Refer to Section 5.3.1 for acceptable methods of 
contraception. Patients agreeing to total sexual abstinence can also be included, assuming 
it is their usual lifestyle.
5.2
Exclusion Criteria
Medical conditions
1
eGFR < 30ml/min/1.73 m2 (based on CKD-EPI formula).
2
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.
3
Presence of any condition that precludes exercise testing such as:
(a) Claudication that limits exertion
(b) Uncontrolled bradyarrhythmia or tachyarrhythmia (according to Investigator 
judgement, pacemaker treatment is allowed as long as the same pacing mode/activity 
can be used at baseline and follow-up CPET)
(c) Clinically significant musculoskeletal disease or orthopaedic conditions that limit the 
ability to perform the CPET (eg, arthritis or injury in the foot, leg, knee or hip)
(d) Severe obesity (body mass index ≥50.0 kg/m2)
(e) Amputation with artificial limb without stable prosthesis function for the past 3 
months
(f) Any condition that, in the opinion of the Investigator, would contraindicate CPET 
assessment (eg, severe visual impairment)
(g) Any condition other than HF that, in the opinion of the Investigator, is the primary 
limitation to exercise.
4
Known history of a documented LVEF < 40%.
5
Probable alternative or concomitant diagnoses which in the opinion of the Investigator 
could account for the patient's HF symptoms and signs (eg, anaemia, hypothyroidism).
6
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.
7
Patients diagnosed with tumour lysis syndrome or Lesch-Nyhan syndrome.
8
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.


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9
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.
10 Current acute decompensated HF or hospitalisation due to decompensated HF < 4 weeks 
prior to enrolment.
11 Myocardial infarction, unstable angina, coronary revascularisation (percutaneous 
coronary intervention or coronary artery bypass grafting), ablation of atrial 
flutter/fibrillation, valve repair/replacement, implantation of a cardiac resynchronisation 
therapy device, stroke or transient ischemic attack within 6 months prior to enrolment.
12 Planned coronary revascularisation, ablation of atrial flutter/fibrillation and/or valve 
repair/replacement.
13 Atrial fibrillation with persistent resting heart rate > 110 beats per minute.
14 Primary pulmonary hypertension, chronic pulmonary embolism, severe pulmonary 
disease including chronic obstructive pulmonary disease (COPD) (ie, requiring home 
supplemental oxygen, chronic oral steroid therapy use at a dose equivalent to 10 mg 
prednisone or greater, or hospitalisation for exacerbation of COPD requiring ventilatory 
assist within 12 months prior to enrolment).
15 Previous cardiac transplantation, or complex congenital heart disease. Planned cardiac 
resynchronisation therapy. Prior implantation of a ventricular assistance device or similar 
device, or implantation expected during the course of the study.
16 HF due to known infiltrative cardiomyopathy (eg, amyloid, sarcoid, lymphoma, 
endomyocardial fibrosis, haemochromatosis), active myocarditis, constrictive pericarditis, 
cardiac tamponade, known genetic hypertrophic cardiomyopathy or obstructive 
hypertrophic cardiomyopathy, arrhythmogenic right ventricular 
cardiomyopathy/dysplasia, or uncorrected severe primary valvular disease.
17 Patients diagnosed with long QT syndrome.
18 Uncontrolled hypertension with systolic blood pressure > 160 mmHg and/or diastolic 
blood pressure > 100 mmHg.
19 History of blood dyscrasias: myelosuppression (eg, thrombocytopenia, leukopenia, 
granulocytopenia, pancytopenia) and aplastic anaemia.
20 Patients with the following bilateral upper or lower arm pathology can be randomised into 
the study, but are not allowed to participate in the reactive hyperaemia assessment:
(a) Presence of fistula / arteriovenous (AV) Shunt
(b) Other structural or vascular abnormality.
Prior/concomitant therapy
21 Treated with any drug for hyperuricaemia in the 6 months preceding randomisation. 
Drugs for hyperuricaemia include all XOIs (allopurinol, febuxostat and topiroxostat) and 


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URAT1 inhibitors (lesinurad, verinurad, probenecid, and benzbromarone) and urate 
oxidases (pegloticase, rasburicase).
22 Treated with strong or moderate organic anion transporting polypeptide (OATP) 
inhibitors (Entresto is not considered a strong or moderate OATP inhibitor).
23 Patients treated with strong P-glycoprotein and/or CYP3A4 inhibitors due to the potential 
drug-drug interaction with colchicine (Appendix J).
Prior/concurrent clinical study experience
24 Participation in another clinical study with an investigational product administered 
(currently or within 1 month prior to screening).
25 Participating in a structured exercise training programme in the 1 month prior to 
screening or planned to start during the trial.
Participants of DECT/PET substudy only (substudy cancelled)
26 Not applicable: Criterion removed due to DECT PET substudy cancellation.
Other exclusions
27 Involvement in the planning and/or conduct of the study (applies to both AZ staff and/or 
staff at the study site).
28 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.
29 Screened more than once or previous randomisation in the present study.
30 Known hypersensitivity to any URAT1 inhibitor, allopurinol, or any of its excipients. 
Known intolerance to lactose (an allopurinol excipient) due to hereditary defect.
31 Patients who are pregnant (confirmed with pregnancy test), lactating, or planning to 
become pregnant.
5.3
Lifestyle Restrictions
5.3.1
Pregnancy
The following restrictions apply while the patient is receiving study treatment and for the
specified times before and after.
1
Male patients are not required to use contraception
2
Female patients of childbearing potential must follow the contraception requirement 
defined in Section 5.1 inclusion criterion 12.


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Females of childbearing potential are defined as those who are not surgically sterile (ie, 
bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) or post-
menopausal.
Female patients of childbearing potential who are not abstinent and intend to be sexually 
active with a non-sterilised male partner must use an acceptable (ie, < 1% failure rate per year) 
effective method of contraception (Table 3) 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 (calendar, symptothermal, post-ovulation methods), 
withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea method are not 
acceptable methods of contraception. Female condom and male condom should not be used 
together. All women of childbearing potential must have a negative serum pregnancy test 
result at Visit 1. Female patients should refrain from breastfeeding throughout this period.
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.

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.

Women who are surgically sterile (ie, bilateral salpingectomy, bilateral oophorectomy, or 
complete hysterectomy) are eligible.


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Table 3
Highly Effective Methods of Contraception (< 1% failure rate)
Barrier/intrauterine methods
Hormonal methods

Vasectomised partner

Bilateral tubal occlusion

Copper T intrauterine device

Levonorgestrel-releasing intrauterine 
system (eg, Mirena®) a

Implants: Etonogestrel-releasing implants (eg, 
Implanon® or Norplant®)

Intrauterine device/levonorgestrel intrauterine 
system

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®, Evra 
Patch™, Xulane™) 

Minipill: Progesterone based oral contraceptive pill 
using desogestrel: Cerazette® is currently the only 
highly effective progesterone based pill
a
This is also considered a hormonal method.
5.3.2
Meals and Dietary Restrictions
It is recommended to take the study treatment with food.
5.3.3
Caffeine, Alcohol, and Tobacco
Study treatment should not be taken within an hour of ingesting alcohol. There are no 
restrictions on combining study treatment intake with caffeine or nicotine intake.
5.4
Screen Failures
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.
Individuals who do not meet the criteria for participation in this study (screen failure) at Visit 
1 may be rescreened once. Rescreened patients should be assigned the same patient number as 
for the initial screening. However, rescreening should be documented so that its effect on 
study results, if any, can be assessed.
Screen failure patients should have the reason for study withdrawal recorded in the electronic 
case report form (eCRF).


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6
STUDY TREATMENTS
Study treatment is defined as any investigational product(s) (including marketed product 
comparator and placebo) or medical device(s) intended to be administered to a study 
participant according to the study protocol. Study treatment in this study refers to verinurad, 
allopurinol, verinurad placebo and allopurinol 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.
Colchicine is considered as non-IP, should be used as a prophylaxis as per country label. 
Colchicine will not be supplied centrally by the Sponsor, but its cost will be reimbursed. 
6.1
Treatments Administered
6.1.1
Investigational Products
Each patient will be randomised to receive 12 mg verinurad plus 300 mg allopurinol, 300 mg 
allopurinol, or placebo for 24 weeks at target dose after 8 weeks of titration (Table 4).
Titration will occur in discrete steps of 4 weeks to reduce the risk of skin reactions due to 
allopurinol. To prevent increase in inflammation due to rapid crystal dissolvement, colchicine 
prophylaxis will be given during the titration period and during the first 4 weeks of treatment 
at target dose (12 weeks total) and will be distributed as available, currently 500 μg within the 
EU and 600 μg within the US. For dosing, see the below dosing schedule (Table 4). The 
allopurinol/placebo tablet and verinurad/placebo capsule(s) will be taken orally together once
daily. 
Study treatments will be titrated in discrete steps as shown in Table 4. Titration steps will be 
spaced at 4-week (28 days ± 3 days) intervals to minimise the risk of adverse reactions to 
allopurinol. Patients unable to tolerate the stepped dosage may be down-titrated only by 
reversing the assigned steps within the 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 followed for the remainder of the study.
At Visit 5 (approximately 8 weeks after randomisation), titration to step 3 target dose will 
only be allowed if the patient’s eGFR was ≥30 ml/min/1.73 m2 at Visits 3 and 4. Otherwise, 
patient must stay at step 2 of the titration.


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Table 4
Study Treatments 
Verinurad + allopurinol
Allopurinol
Placebo
Study treatment name
Verinurad + allopurinol
Verinurad placebo + 
allopurinol 
Verinurad placebo + 
allopurinol placebo
Dosage formulation
Verinurad capsule, 
allopurinol tablet
Verinurad placebo 
capsule, allopurinol 
tablet
Verinurad placebo 
capsule, allopurinol 
placebo tablet
Dosage levels
Week 0-3: 3 mg 
verinurad, 100 mg 
allopurinol
Week 4-7: 7.5 mg 
verinurad, 200 mg 
allopurinol
Week 8-32: 12 mg 
verinurad, 300 mg 
allopurinol
Week 0-3: 100 mg 
allopurinol
Week 4-7: 200 mg 
allopurinol
Week 8-32 300 mg 
allopurinol
0 mg / 0 mg
Route of administration
Oral
Oral
Oral
Dosing instructions
All study treatment should be taken in the morning and will generally be better 
tolerated if taken in association with food.
Packaging and labelling
Verinurad capsules and 
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.
Verinurad placebo 
capsules and 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.
Verinurad placebo 
capsules and allopurinol 
placebo 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
AZ
AZ
AZ
6.2
Preparation/handling/storage/accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported 
and resolved before use of the study treatment.
Only patients enrolled in the study may receive study treatment and only authorised site staff 
may supply or administer study treatment. All study treatments must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
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The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
Further guidance and information for the final disposition of unused study treatment are 
provided in the Pharmacy Manual.
6.3
Measures to Minimise Bias: Randomisation and Blinding
All patients will be centrally assigned to randomised study treatment using an interactive web 
response system (IWRS). Randomisation to study treatment will be performed in balanced 
blocks to ensure approximate balance between the three treatment groups verinurad plus 
allopurinol, allopurinol alone, or placebo (1:1:1). The randomisation codes will be computer 
generated and loaded into the IWRS database. Before the study is initiated, the log-in 
information and directions for the IWRS will be provided to each site.
The IWRS system should ensure that a baseline peak VO2 measurement is available for the 
patient before randomisation is allowed.
If a patient withdraws from the study, then his/her enrolment/randomisation code cannot be 
reused. Withdrawn patients will not be replaced.
The IWRS will provide to the Investigator(s) or pharmacists the kit identification number to 
be allocated to the patient at the dispensing visit. Routines for this will be described in the 
IWRS user manual that will be provided to each centre. For patients who need down titration, 
the Investigator will need to use the IWRS for allocation of new study drug kits for the lower 
dose.
Every effort should be taken to discuss the decision related to down titration with AZ Study 
Physician prior to IWRS allocation of new study drug kit.
The randomisation code should not be broken except in medical emergencies when the 
appropriate management of the patient requires knowledge of the treatment randomisation. 
The Investigator documents and reports the action to AZ, without revealing the treatment 
given to patient to the AZ staff.
AZ retains the right to break the code for SAEs that are unexpected and are suspected to be 
causally related to a study treatment 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.


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The AZ study personnel will be blinded to post-randomisation sUA values (assessed using the 
central clinical laboratory) to maintain study integrity.
6.3.1
Emergency Unblinding
The 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 hours after breaking the blind. The date and reason that the blind was broken must 
be recorded in the source documentation and eCRF. 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.
6.4
Treatment Compliance
Any change from the dosing schedule, dose interruptions, dose reductions, or dose 
discontinuations should be recorded in eCRF.
Assigned personnel at study site will be responsible for managing the study treatment from 
receipt by the study site until the destruction or return of all unused study treatment. The 
Investigator(s) is responsible for ensuring that the patient has returned all unused study 
treatment.
Treatment compliance: The patient will be asked about compliance at each study visit starting 
from Visit 3 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 ≤120% of that prescribed. Patients judged to be non-compliant may 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 SoA
and Table 1, 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 drugs (including investigational 
products and colchicine prophylaxis) should be recorded in the appropriate sections of the 
CRF as well as any change from the dosing schedule, dose interruptions, dose reductions, dose 
discontinuations. Each time study drug/colchicine prophylaxis are dispensed, compliance will 
be reinforced. If any patient found to be non-compliant, he/she will be counselled on the 
importance of taking their IP/colchicine as prescribed.


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6.5
Concomitant Therapy
Any medication or vaccine including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements that the 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 route of administration, dose and frequency
Table 5
Restricted Medications
Medication/class of drug:
Usage (including limits for duration permitted and 
special situations where 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
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 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) may 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.
Prohibited medication/class of drug
Any other investigational drugs than provided in this study
Any medication prohibited by the allopurinol package insert
Mercaptopurine
Azathioprine
Any drug administered primarily to lower sUA, including XOIs such as febuxostat or topiroxostat, or URAT1 
inhibitors such as probenicide, lesinurad or benzbromarone
Strong or moderate OATP inhibitors a
Examples: atazanavir, ritonavir, clarithromycin, cyclosporin, erythromycin, gemfibrozil, lopinavir, rifampin 
(single dose), simeprevir
Any medication prohibited by the package insert of colchicine (Appendix J); applicable only while gout 
prophylaxis is being administered
a
Further information is available at: 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabelin
g/ucm093664.htm#table5-2


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ACEi  Angiotensin-converting enzyme inhibitor; ARBs  Angiotensin receptor blockers; OATP  Organic anion 
transport polypeptide; sUA  serum uric acid; URAT1  Uric acid transporter 1; XOI  Xanthine oxidase inhibitor
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI


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6.5.2
Other Concomitant Treatment
Other medication other than that described above, which is considered necessary for the 
patient’s safety and wellbeing, may be given at the discretion of the Investigator and recorded 
in the appropriate sections of the case report form (CRF).
6.6
Dose Modification
Study treatments will be titrated in discrete steps as shown in Table 4. Titration steps will be 
spaced at 4-week intervals to reduce the risk of hypersensitivity skin reactions to allopurinol. 
Patients unable to tolerate the stepped dosage may be down-titrated only by reversing the 
assigned steps within treatment group. Verinurad and allopurinol dosages cannot be unpaired 
from the titration schedule. Patients who cannot tolerate the step 1 dose will be discontinued 
from study treatment and be followed for the remainder of the study.
6.7
Treatment After the End of the Study
After the end of the study patients can be treated with UA lowering therapy and/or other 
therapies for HFpEF or other conditions requiring treatment at the responsible physician’s 
discretion.
7
DISCONTINUATION OF TREATMENT AND PATIENT 
WITHDRAWAL
7.1
Discontinuation of Study Treatment
Discontinuation from study treatment is not the same as withdrawal from the study. If the 
patient temporarily or permanently discontinues study treatment, the patient should remain in 
the study and it is important that the scheduled study visits and data collection continue 
according to the study protocol. Patients may be discontinued from study treatment in the 
following situations:

Patient decision. The patient is at any time free to discontinue treatment, without 
prejudice to further treatment.

AE.

Severe non-compliance with the Clinical Study Protocol (CSP).

Skin reactions and hypersensitivity.

Study drug should be discontinued immediately at the first sign of a skin rash or other 
signs indicative of 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.


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
Development of signs/symptoms of nephrolithiasis or potential renal injury, including 
creatinine elevations.

Guidelines for assessing possible renal injury or kidney stone and altering treatment 
are in Appendix F.

Development of aspartate transaminase (AST) or alanine transaminase (ALT) ≥3× upper 
limit of normal (ULN) together with total bilirubin ≥2× ULN as described in Section 
8.3.8 and Appendix E.

If a patient becomes pregnant during the course of the study, the study treatment should 
be discontinued immediately and an AZ representative notified.
See the schedule of activities (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.
7.1.1
Temporary Discontinuation
Patients may temporarily interrupt study treatment administration, for instance based on 
criteria for Appendix F. In case temporary interruption happens, patient should stop taking 
both IPs (verinurad or placebo and allopurinol or placebo). Temporary interruption of study 
treatment does not mean discontinuation of follow-up or termination of study participation. 
Study assessments should continue. When study treatment is resumed, last dose level taken 
should be administered again. If temporary interruption of study treatment 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 study treatment must be re-titrated 
to avoid allopurinol induced hypersensitivity reactions, after communication with the sponsor 
or sponsor’s representative.
7.1.2
Procedures for 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 eCRF. 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. If the 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 


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information from medical records. The approach taken should be recorded in the medical 
records. A patient who agrees to a modified follow-up is not considered to have withdrawn 
consent or to have withdrawn from the study.
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 (study treatment 
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).
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.
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. 


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See SoA, 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.
7.4
Procedures for Handling Incorrectly Enrolled or Randomised 
Patients
Patients who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive study treatment. There can be no exceptions to this rule. Patients who are 
enrolled, but subsequently found not to meet all the eligibility criteria must not be randomised 
or initiated on study treatment and must be withdrawn from the study. Where a patient does 
not meet all the eligibility criteria but is randomised in error, or incorrectly started on study 
treatment, the following steps need to be taken:

The Investigator or Study Monitor should inform the AZ study physician immediately, 
ensuring patient safety must always be the number one priority.

Study Treatment must be discontinued in all cases where continued treatment is deemed 
to pose a safety risk to the patient. A discussion should occur between the AZ study 
physician and the investigator; a decision may be reached on whether to continue or 
discontinue the patient from study treatment. The AZ study physician must ensure that all 
decisions are appropriately documented.

In those cases where continuation of study treatment is judged not to present a concern 
related to safety and disease management, the rationale for continuing the study treatment 
must be clearly documented. The patient should continue follow up in accordance with 
defined study procedures.
8
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarised in the SoA.
The investigator will ensure that data are recorded on the eCRFs.
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 CRFs. A copy of the completed CRFs 
will be archived at the study site.
Immediate safety concerns should be discussed with the sponsor immediately upon occurrence 
or awareness to determine if the patient should continue or discontinue Study treatment.


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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 
applicable.
Procedures conducted as part of the patient’s routine clinical management (eg, blood count)
and obtained before signing of the ICF may be utilised for screening or baseline purposes 
provided the procedures met the protocol-specified criteria and were performed within the 
time frame defined in the SoA.
8.1
Efficacy Assessments
Primary and secondary efficacy assessments include peak VO2 as assessed during CPET and 
patient-reported outcomes as assessed using the KCCQ (Total Symptom Score domain).
8.1.1
Peak VO2 and Other Cardiopulmonary Exercise Test Outcomes
CPET will be used to assess the change from baseline at Week 32 in peak VO2 consumption 
(primary objective). In addition, the following parameters will be assessed:Change from 
baseline in ventilatory efficiency as measured by VE/VCO2

VO2 at anaerobic threshold

VO2 kinetics at recovery phase

Exercise time
All patients will undergo a CPET with gas-exchange analysis. The methodology will be 
standardised across all participating sites, as described in the CPET Manual. Testing will 
include continuous ECG monitoring by trained personnel and be performed in an area that is 
equipped for cardiopulmonary resuscitation. The primary modality for exercise tests will be 
either a motor-driven treadmill or cycle ergometer. Patients must use the same testing 
modality and the same exercise equipment for all exercise tests during the study.
Whenever possible, CPET should be administered by the same study personnel using the same 
piece of equipment and performed after the other study procedures on that visit day (including 
PROs, NYHA class, acute coronary syndrome signs and symptoms, vital signs, ECG, blood 
sampling, study treatment administration). Patients naïve to exercise protocols (cycle 
ergometer, treadmill, and measurement of oxygen consumption) will be familiarised with the 
technique during screening.All CPETs will be symptom-limited and patients will be strongly 
encouraged to perform a maximum test as indicated by a RER ≥1.05. Patients will be eligible 
for the study if they achieve a RER of ≥1.05. Eligible subjects must also have impaired peak 
VO2. Peak VO2 achieved must be ≤75% of predicted for age and gender when using a 


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treadmill or ≤68% when using a cycle ergometer, as based on normal values (Fletcher et al 
1995). Eligibility will be determined by the CPET Core Lab.All study sites must be qualified 
by the CPET core laboratory prior to the initiation of screening. To qualify, sites will perform 
two exercise tests on the same healthy adult and submit them for core laboratory review. 
Centres may be required to submit additional normal exercise tests during the conduct of the 
study for review by the CPET core lab in order to confirm proper function of testing 
equipment.Data will be recorded and transmitted electronically to a core lab for analysis. The 
CPET manual will be developed for the study and sent to all sites.
8.1.2
Patient Reported Outcomes
Patients will perform the PRO assessments using an electronic tablet during clinic visits at the 
time points indicated in the SoA. All questionnaires must be completed using the electronic 
device; paper questionnaires are not allowed in this study.
Each site must allocate the responsibility for the administration of the PROs to a specific site 
personnel and, if possible, assign a backup person to cover if that individual is absent. A key 
aspect of study success is to have high PRO compliance. Therefore, it is essential that site 
personnel follow the SoA and ensure that the device is charged and set up properly before the 
first patient comes for PRO baseline visit (Visit 3) in order to minimise missing data.
If patients have any medical problems, they should discuss them with their doctor or research 
nurse separately from the PRO assessment.
The research nurse or appointed site staff must remind patients there are no right or wrong 
answers and that the value and relevance of PRO data is to hear directly from patients, without 
interpretation from health care professionals or others, how they function and feel.
The following best practice guidelines should be followed:

The PRO questionnaires must be completed before any other study procedures are 
conducted, including being seen by the investigator. 

The appointed site personnel must show patients how to use the electronic PRO device, in 
accordance with the instructions provided.

To avoid bias, patients must not receive help from relatives, friends or site staff to answer 
or to clarify the PRO questionnaires.

The PRO questionnaires must be completed by the patient in private.

The patient should be given enough time to complete the PRO questionnaires at his or her 
own speed.

On completion of the questionnaires, the tablet should be handed back to the designated 
responsible person, who should check that all questionnaires, relevant for the specific 
visit (SoA), were completed. If any PRO questionnaire was not completed, the site 


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personnel must document the reason why a patient could not complete assessments in the 
REVPRDI module in the eCRF.
The following PROs will be used in this study:
!
KCCQ
!
PGIS
!
PGIC
It will take approximately 10-15 minutes to complete.
Kansas City Cardiomyopathy Questionnaire
The KCCQ (Appendix G) is a 23-item, self-administered disease-specific instrument that has 
shown to be a valid, reliable and responsive measure for patients with HF (Green et al 2000, 
Spertus et al 2005).
The KCCQ was developed to measure the patients’ perception of their health status 
independently, which includes HF-related symptoms (frequency, severity and recent change), 
impact on physical and social function, self-efficacy and knowledge, and how the patients’ HF 
affects their quality of life. Scores are transformed to a range of 0 to 100. Higher scores 
represent a better outcome.
The 23 items in KCCQ can be merged into 10 summary scores. In this study, the KCCQ-Total 
Symptom Score (TSS), KCCQ-Clinical Summary Score (CSS) and KCCQ-Overall Summary 
Score (OSS) will be used.
Patient global impression of change
The PGIC (Appendix H) item is one question and assesses how a patient perceives his or her 
overall change in HF symptoms since the start of the study. Patients will choose from 7 
response options, ranging from ‘much worse’ to ‘much better.’
Patient global impression of severity
The PGIS (Appendix I) item is one question and assesses how a patient perceives his or her 
overall current severity of HF symptoms. Patients will choose from 6 response options, 
ranging from ‘no symptoms’ to ‘very severe.’
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8.2
Safety Assessments
Planned time points for all safety assessments are provided in the SoA.
8.2.1
Clinical Safety Laboratory Assessments
The clinical chemistry, haematology and urinalysis will be performed at a central laboratory.
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Refer to Table 7 for the list of clinical safety laboratory tests to be performed and 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 
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 locally if clinically indicated at the discretion of 
the Investigator. The date and results of those additional samples will be collected on the 
appropriate eCRF.
Table 7
Laboratory Safety Variables
Haematology/haemostasis (whole blood)
Clinical chemistry (serum or plasma)
B-Haemoglobin (Hb)
S/P-Creatinine
B-Leukocyte count
S/P-Bilirubin, total
B-Leukocyte differential count (absolute count)
S/P-Alkaline phosphatise (ALP)
B-Platelet count
S/P-Aspartate transaminase (AST)
S/P-Alanine transaminase (ALT)
Urinalysis 
S/P-Albumin
U-Hb/Erythrocytes/Blood 
S/P-Potassium
U-Protein/Albumin 
S/P-Calcium, total
U-Glucose 
S/P-Sodium
S/P-Creatine kinase (CK)
S/P Bicarbonate
S/P Blood Urea Nitrogen
S/P Phosphate
Note: In case a patient shows an AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN, please 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 total bilirubin value outside the normal range, direct bilirubin will be 
automatically evaluated by the central laboratory.
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 adverse event or a serum creatinine elevation’ for further instructions.
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, 


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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, refer to 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 three blood pressure readings will be 
recorded on the eCRF.
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 eCRF. 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.
AE will be reported by the patient (or, when appropriate, by a caregiver, surrogate, or the 
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The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE. For information on how to follow/up AEs 
refer to Section 8.3.3.
8.3.1
Method of Detecting Adverse Events and Serious Adverse Events
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 Adverse Event and Serious 
Adverse Event Information
Adverse events will be collected from the time of the first dose of study treatment throughout 
the treatment period and including the follow-up period and last contact.
Serious AEs will be recorded from the time of signing of ICF throughout the treatment period 
and including the follow-up period and last contact.
All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as 
indicated in Appendix B. The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available.
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 Adverse Events and Serious Adverse Events
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.
8.3.4
Adverse Event Data Collection
The following variables will be collected for each AE:


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
AE (verbatim)

The date when the AE started and stopped

Maximum intensity

Whether the AE is serious or not

Investigator causality rating against the study treatment(s) (yes or no)

Action taken with regard to study treatment(s)

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 Study treatment 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 study treatment?’
For SAEs, causal relationship will also be assessed for other medication and study procedures. 
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix B to the CSP.
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/you were 
last asked?’ 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 


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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 CSP mandated laboratory tests and vital signs will be summarised in the 
clinical study report (CSR). Deterioration as compared to baseline in protocol-mandated 
laboratory value or vital signs should therefore only be reported as AEs if they fulfil any of the 
SAE criteria or are the reason for discontinuation of treatment with the study treatment.
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 ≥3 × ULN together with total bilirubin ≥2 × ULN may need 
to be reported as SAEs. Refer to Appendix E for further instruction on cases of increases in 
liver biochemistry and evaluation of Hy’s Law.
 
 
 
8.3.10
Regulatory Reporting Requirements for Serious Adverse Events
Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety reporting 
to the regulatory authority, IRB/IEC and investigators.
For all studies except those utilising medical devices investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions according to local regulatory
requirements and sponsor policy and forwarded to investigators as necessary.
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An investigator who receives an investigator safety report describing a SAE or other specific 
safety information (eg, summary or listing of SAEs) from the sponsor will review and then 
file it along with the IB or and will notify the IRB/IEC, if appropriate according to local 
requirements.
8.4
Safety Reporting and Medical Management
8.4.1
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the study 
treatment, or to the study procedure(s). All SAEs will be recorded in the CRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate AZ representatives within one day ie, immediately but no later than 24 hours
of when he or she becomes aware of it.
The designated AZ representative works with the Investigator to ensure that all the necessary 
information is provided to the AZ 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 AZ 
representatives of any follow-up information on a previously reported SAE within one 
calendar day ie, immediately but no later than 24 hours of when he or she becomes aware of 
it.
Once the Investigators or other site personnel indicate an AE is serious in the electronic data 
capture (EDC) system, an automated email alert is sent to the designated AZ representative.
If the EDC system is not available, then the Investigator or other study site staff reports a SAE 
to the appropriate AZ representative by telephone.
The AZ representative will advise the Investigator/study site staff how to proceed. 
For further guidance on the definition of a SAE, see Appendix B of the CSP.
8.4.2
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AZ except for:

If the pregnancy is discovered before the study patient has received any study drug

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If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of 
learning of the pregnancy.
Abnormal pregnancy outcomes (eg, spontaneous abortion, foetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
8.4.2.1
Maternal Exposure
If a patient becomes pregnant during the course of the study, study treatment should be 
discontinued immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study treatment 
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 AZ representatives within 1 day ie, immediately but no later than 24 
hours of when he or she becomes aware of it.
The designated AZ representative works with the Investigator to ensure that all relevant 
information is provided to the AZ Patient Safety data entry site within 1 or 5 calendar days for 
SAEs (Section 8.4.1) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
When the CRF module is used include the following: The PREGREP module in the CRF is 
used to report the pregnancy and the PREGOUT is used to report the outcome of the 
pregnancy.
8.4.2.2
Paternal Exposure
There is no restriction on fathering children or donating sperm during the study.
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 
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
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 AZ study drug occurs in the course of the study, then the Investigator or 
other site personnel inform appropriate AZ representatives immediately, or no later than 24 
hours of when he or she becomes aware of it.
The designated AZ representative works with the Investigator to ensure that all relevant 
information is provided to the AZ Patient Safety data entry site.

For overdoses associated with a SAE, the standard reporting timelines apply, refer to 
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 AZ representatives within 1 day ie, immediately but no later 
than 24 hours of when he or she becomes aware of it.
The designated AZ 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 (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 Study Treatment-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 AEs) from the 
combination study treatment, dosage will be down-titrated to the highest previously-tolerated 
dosage.
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 
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8.4.6
Data Monitoring Committee
An independent DMC will be appointed and will report to AZ. The DMC will be responsible 
for safeguarding the interests of the patients by assessing the safety of the study treatment 
during 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 AZ.
8.4.7
Clinical Event Adjudication Committee
The role of the CEA committee 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 or in the CEA process as specified in the CEA 
committee charter. The CEA committee member/s will not have access to individual treatment 
codes for any patient.
The Investigator’s Manual or other investigator material will specify the information to be 
collected for potential CV events.
 
 
 
 
 
 
 
 
 
 
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!
 
 
 
 
 
 
8.6
Genetics
8.6.1
Assessment of HLA-B Genotype
Skin reactions are the most common reactions for allopurinol, and rarely may include the drug 
hypersensitivity syndrome, Stevens–Johnson syndrome, and toxic epidermal necrolysis. HLA-
B*5801 allele is an important genetic risk factor for these life-threatening conditions. HLA–
B*5801 allele frequency is higher in Korean, Han Chinese, Thai, or African origin compared 
with Caucasian patients. In this study, HLA-B *5801 genotyping is mandatory prior to 
randomisation for all patients. 
 
 
 
 
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8.7
Biomarkers
Samples will be collected and analysed for biomarkers as detailed 
 in the 
SoA.
Some of the planned biomarker analyses may be performed only if the study provides 
evidence of efficacy and may be performed in a staggered fashion to minimise resource spend. 
Results of biomarker analyses may be reported separately from the CSR.
In addition to the biomarkers listed in 
, urine, serum and plasma, from patients 
who have consented for future research, will be collected and stored in a biobank for future 
use. Participation is optional and contingent upon local regulations. The analysis may be 
performed on biomarker variants thought to play a role in inflammation, HF, CKD, 
endothelial function, and the safety of patients treated with study treatment including, but not 
limited to, plasma and urine analytes.
The samples may be used for research to develop methods, assays, prognostics and/or 
companion diagnostics related to disease processes, pathways associated with HF or CKD, 
and/or mechanism of action of the study treatment.
 
 
 
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8.8
Medical Resource Utilisation and Health Economics
Medical resource utilisation and health economics parameters are not evaluated in this study.
8.9
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) 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. 
(c) If a COVID-19 AE/SAE is reported, the investigator should determine whether the 
participant’s investigational product should continue, be interrupted, or stopped.
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 
assessments.
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(b) Conducting the visit by phone, investigational product 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) Visits 4, 5 and 6 may be conducted in the patient’s home if site is closed or local 
regulations prohibit patients from travelling to site due to COVID-19. Safety 
laboratory tests are required. 
 
(d) If labs collected for safety assessments cannot be collected 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 Study Physician how to re-start 
treatment and titrate the IP to maintenance treatment.
(e) Visits by phone or in patient’s house might be performed solely due to COVID-19 
pandemic. In any other cases, all the visits have to be performed at the site.
References:
FDA Guidance for Industry. Conduct of clinical trials of medical products during the COVID-
19 public health emergency; 2021. [cited 17 Sep 2021]. Available from: 
https://www.fda.gov/media/136238/download.
European Medicines Agency. Implications of coronavirus disease (COVID-19) on 
methodological aspects of ongoing clinical trials; 2020. [cited 17 Sep 2021]. Available from: 
https://www.ema.europa.eu/en/implications-coronavirus-disease-covid-19-methodological-
aspects-ongoing-clinical-trials.
European Medicines Agency. Guidance to sponsors on how to manage clinical trials during 
the COVID-19 pandemic; 2020. [cited 17 Sep 2021]. Available from: 
https://www.ema.europa.eu/en/news/guidance-sponsors-how-manage-clinical-trials-during-
covid-19-pandemic. 
9
STATISTICAL CONSIDERATIONS
9.1
Statistical Hypotheses
For all statistical tests, the null hypothesis is that there is no difference between treatment 
groups, with a two-sided alternative. Each hypothesis will be tested at a significance level of 
5%. A multiplicity correction procedure will be applied (refer to Section 9.4.4 “Methods for 
multiplicity control” for details).
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Objective
Hypothesis tested
Primary
To assess effect of verinurad + allopurinol 
compared to placebo on exercise capacity
No difference in mean change from baseline at 
32weeks in peak VO2 consumption between treatment 
groups
Secondary
To assess effect of verinurad + allopurinol 
compared to allopurinol monotherapy on exercise 
capacity
No difference in mean change from baseline at 
32weeks in peak VO2 consumption between treatment 
groups
To assess effect of verinurad + allopurinol 
compared to placebo and compared to allopurinol 
monotherapy on KCCQ-TSS.
No difference in mean change from baseline at 32 
weeks in KCCQ total symptom score between 
treatment groups
9.2
Sample Size Determination
The study will employ a 1:1:1 randomisation ratio between 12 mg verinurad + allopurinol, 
allopurinol, and placebo. Based on this design with 50 patients randomised to the verinurad + 
allopurinol group and to the placebo group, respectively, and assuming a standard deviation 
for the primary endpoint of 2 mL/kg/min, the width of 95% confidence intervals for estimated 
differences between treatments will be about 1.57 ml/kg/min. The minimum detectable 
treatment difference for statistical significance in a two-group t-test with a two-sided 
significance level of 5% given the assumptions above is 0.794 mL/kg/min. 
The assumed standard deviation of 2 mL/kg/min is derived from Borlaug (Borlaug et al 2018) 
and from Redfield (Redfield et al 2013).
For approximately 3 × 50 = 150 patients to be randomised, up to 500 patients should be 
screened, matching an assumed proportion of screening failures of up to 65%.
9.3
Populations for Analyses
For purposes of analysis, the following populations are defined:
Table 8
Analysis Populations
Analysis set
Description
Enrolled
All patients who sign the main ICF
Full Analysis Set (FAS)
All patients who have been randomised to study treatment, irrespective of 
their protocol adherence and continued participation in the study.
Patients will be analysed according to their randomised study treatment 
assignment, irrespective of the treatment actually received.
The FAS will be considered the primary analysis set for the primary and 
secondary variables 
 
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Table 8
Analysis Populations
Analysis set
Description
Safety analysis set
All patients randomly assigned to study treatment and who take at least 
1 dose of study treatment.
Patients will be analysed according to their randomised study treatment 
assignment, irrespective of the treatment actually received.
The Safety analysis set will be considered the primary analysis set for all 
safety variables.
 
9.4
Statistical Analyses
All personnel involved with the analysis of the study will remain blinded until database lock.
Analyses will be performed by a Contract Research Organisation designated by AZ. A 
comprehensive statistical analysis plan (SAP) for the analyses to be included in the CSR will 
be developed and finalised before the final data base lock. This section is a summary of the 
planned statistical analyses of the primary and secondary endpoints. Any deviations from this 
plan will be reported in the CSR.
9.4.1
Efficacy Analyses
9.4.1.1
Analysis of the Primary Objective
The primary efficacy variable for the analysis of the primary objective is the absolute change 
from baseline in peak VO2 at Week 32, calculated as the value at Week 32 minus the baseline 
value. This will be analysed using an ANCOVA model with change from baseline in peak 
VO2 at Week 32 as the dependent variable, treatment as independent variable and baseline 
peak VO2 included as a covariate. Baseline peak VO2 will be the peak VO2 value from the last 
exercise capacity test before randomisation.
The analysis will include data from all patients at Week 32 irrespective of whether the patient 
has discontinued study drug or received other medications. Missing peak VO2 values at 
Week 32 will be imputed using a dropout reason-based multiple imputation approach; missing 
data in the verinurad + allopurinol group  following the intercurrent events death, withdrawal 
of consent, loss to follow-up or premature discontinuation of study drug due to an AE will be 
imputed based on the peak VO2 values in the placebo group whereas missing values for all 
other patients will be imputed assuming missing at random, ie, based on the peak VO2 values 
in their own respective treatment group.
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Estimated mean change from baseline per treatment group and difference between treatments 
(verinurad + allopurinol vs placebo) will be presented along with 95% confidence intervals 
and p-value.
Sensitivity analyses to assess the robustness of the primary analysis with respect to the 
handling of missing data will be performed and will include i) using the principles described 
above but imputing all missing values according to the placebo group ii) excluding patients 
with missing values from the analysis.
9.4.1.2
Analysis of the Secondary Objectives
Active treatment vs allopurinol monotherapy
The estimate of the treatment effect of verinurad + allopurinol vs allopurinol monotherapy 
will be extracted from the analysis described for the analysis of the primary objective in 
Section 9.4.1.1. For the assessment of statistical significance of this comparison, please see 
Section 9.4.4.
Kansas City Cardiomyopathy Questionnaire - KCCQ
The variable for the analysis of the secondary objective to assess the effect of verinurad + 
allopurinol compared to placebo and compared to allopurinol monotherapy on KCCQ-TSS 
will be the change from baseline at Week 32 of the KCCQ-TSS. Baseline is defined as the 
value at the randomisation visit. Change from baseline at each post-baseline KCCQ collection 
time point will be calculated as the value at the corresponding post-baseline time point minus 
the baseline value.
The analysis will include data from all patients irrespective of whether the patient has 
discontinued study drug or received other medications. Missing KCCQ-TSS values will be 
handled using the same method as described for the analysis of the primary objective in 
Section 9.4.1.1.
Change from baseline to Week 32 for KCCQ-TSS will be analysed in a MMRM model. The 
model will include terms for treatment group, visit, visit*treatment group, and baseline TSS 
measurement as a covariate. The model will be used to derive a least squares estimate of the 
treatment difference with 95% confidence interval and corresponding two-sided p-value. The 
p-value for the treatment difference at Week 32 will be the basis for the confirmatory 
statistical testing (Section 9.4.4).
9.4.2
Safety Analyses
All safety analyses will be performed on the Safety Analysis Set. Patients will be analysed 
according to their randomised study treatment assignment, irrespective of the treatment 
actually received. Patients who receive study treatment which is not consistent with the 
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The assessment of safety will be based on the analyses of AEs, vital signs, ECGs and 
laboratory evaluations.
Safety data will be summarised descriptively and will not be formally tested. 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
In order to address the issue of multiple testing and control the Type I error rate at an overall 
two-sided 0.05 level, a hierarchical test sequence will be used for the confirmatory analysis of 
the primary and secondary objectives. Statistical significance will be assessed in the following 
sequence:
!
Comparison between verinurad + allopurinol and placebo in change from baseline in peak 
VO2 at Week 32
!
Comparison between verinurad + allopurinol and allopurinol monotherapy in change 
from baseline in peak VO2 at Week 32
!
Comparison between verinurad + allopurinol and placebo in change from baseline in 
KCCQ-TSS at Week 32
!
Comparison between verinurad + allopurinol and allopurinol monotherapy in change 
from baseline in KCCQ-TSS at Week 32
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The testing procedure will continue down the hierarchy if the preceding endpoint is rejected at 
a two-sided 0.05 level and will stop if the preceding endpoint is not rejected at a two-sided 
0.05 level.
9.4.5
Data Monitoring Committee
A DMC will be utilised for this study. Appendix A 5 provides more details on the rationale for 
and the remit of the committee.


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10
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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 ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant documents 
(eg, advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study 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 AZ 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 responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
A 3
Informed Consent Process
The investigator or his/her representative will explain the nature of the study to the patient or 
his/her legally authorised representative and answer all questions regarding the study. 
Patients must be informed that their participation is voluntary. Patients or their legally 
authorised representative will be required to sign a statement of informed consent that meets 
the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability 
and Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study 
centre.
The medical record must include a statement that written informed consent was obtained 
before the patient was enrolled in the study and the date the written consent was obtained. The 
authorised person obtaining the informed consent must also sign the ICF.
Patients must be re-consented to the most current version of the ICF(s) during their 
participation in the study.
A copy of the ICF(s) must be provided to the patient or the patient’s legally authorised 
representative. 
 
 
A patient who is rescreened is not required to sign another ICF if the rescreening occurs 
within 35 days from the previous ICF signature date. 
 
 
 
 
 
 
 
 
 
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A 4
Data Protection
Each patient will be assigned a unique identifier by the sponsor. Any patient records or data 
sets transferred to the sponsor will contain only the identifier; patient names or any 
information which would make the patient identifiable will not be transferred. 
The patient must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the patient. 
The patient must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorised personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
A 5
Committees Structure
The safety of all AZ clinical studies is closely monitored on an on-going basis by AZ 
representatives in consultation with Patient Safety. Issues identified will be addressed; for 
instance this could involve amendments to the Clinical Study Protocol and letters to 
Investigators.
Data monitoring committee (DMC) 
An independent DMC will be appointed and will report to AZ. The DMC will be responsible 
for safeguarding the interests of the patients in the study by assessing the safety of the study 
treatment during 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 AZ. The DMC will ensure that the study meets high standards of 
ethics and patient safety.
Clinical event adjudication (CEA) 
The role of the 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, 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. The precise responsibilities and procedures applicable for CEA will be detailed in the 
CEA charter.


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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 Closure
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 AZ, 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 treatment, 

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 eCRF. All reasons for discontinuation of 
treatment must be documented.
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the patient’s interests.
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 treatment development
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 adverse event is the development of any untoward medical occurrence in a subject or 
clinical study subject administered a medicinal product and which does not necessarily have a 
causal relationship with this treatment. An AE can therefore be any unfavourable and 
unintended sign (eg, an abnormal laboratory finding), symptom (for example nausea, chest 
pain), or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product. 
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no study treatment has been administered.
B 2
Definitions of Serious Adverse Event
A serious adverse event 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-subject hospitalisation or prolongation of existing hospitalisation 

Results in persistent or significant disability or incapacity

Is a congenital abnormality or birth defect

Is an important medical event that may jeopardise the subject or may require medical 
treatment to prevent one of the outcomes listed above
Adverse Events (AEs) 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 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 subject was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
subject’s death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (eg, hepatitis that resolved without hepatic failure).
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 subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.
B 5
Important Medical Event or Medical Treatment
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 jeopardise the subject or may require 
medical treatment to prevent one or more outcomes listed in the definition of serious. These 
should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.

Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine

Intensive treatment in an emergency room or at home for allergic bronchospasm

Blood dyscrasias (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 subject actually received the suspect 
drug? Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug?

Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?

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 AZ 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 IWRS errors)

Wrong drug administered to participant (excluding IWRS errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from 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 AZ Biobank Team during the entire life cycle.
If required, AZ 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, AZ 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 AZ

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 AZ 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) 
(https://www.iata.org/whatwedo/cargo/dgr/Pages/download.aspx) classifies infectious 
substances into 3 categories: Category A, Category B or Exempt
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. Infectious substances meeting these 
criteria which cause disease in humans or both in humans and animals must be assigned to UN 
2814. Infectious substances which cause disease only in animals must be assigned to UN 
2900:
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, C, D, and E viruses. 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 - Substances which do not contain infectious substances or substances which are 
unlikely to cause disease in humans or animals are not subject to these Regulations unless they 
meet the criteria for inclusion in another class.

Clinical study samples will fall into Category B or exempt under IATA regulations

Clinical study samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging 
(https://www.iata.org/whatwedo/cargo/dgr/Documents/DGR-60-EN-PI650.pdf)

Biological samples transported in dry ice require additional dangerous goods specification 
for the dry-ice content


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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 
potential PHL criteria at any point during the study.
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including central and all 
local laboratory evaluations even if collected outside of the study visits; for example, PHL 
criteria could be met by an elevated ALT from a central laboratory and/or elevated 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 AZ clinical project representatives, in review and 
assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria are met. 
HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than Drug Induced Liver Injury (DILI) caused by the study treatment. 
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 Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥3× Upper Limit of 
Normal (ULN) together with Total Bilirubin (TBL) ≥2× ULN at any point during the study 
following the start of study medication irrespective of an increase in Alkaline Phosphatase 
(ALP).
Hy’s Law (HL)
AST or ALT ≥3× ULN together with TBL ≥2× ULN, where no other reason, other than the 
IMP, can be found to explain the combination of increases, eg, elevated ALP indicating 
cholestasis, viral hepatitis, another drug. 


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For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur.
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 (also sent to AZ 
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 AZ representative

Request a repeat of the test (new blood draw) by the central laboratory without delay

Complete the appropriate unscheduled laboratory CRF module(s) with the original local 
laboratory test result
When the identification criteria are met from central or local laboratory results the Investigator 
will without delay:

Determine whether the patient meets PHL criteria (refer to Section 2 within this Appendix
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 AZ representative

Determine whether the patient meets PHL criteria (refer to Section 2 Definitions within 
this Appendix 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:

Inform the AZ representative that the patient has not met PHL criteria

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:

Notify the AZ 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 patients that met PHL criteria prior to starting study treatment, the investigator is not 
required to submit a PHL SAE unless there is a significant change# in the patient’s 
condition.

The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study patients’ follow-up (including any further laboratory testing) 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. Completes 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. 
# 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.


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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 
study treatment, to ensure timely analysis and reporting to health authorities within 15 
calendar days from date PHL criteria was met. The AZ Global Clinical Lead or equivalent and 
Global Safety Physician will also be involved in this review together with other subject matter 
experts as appropriate.
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.
Where there is an agreed alternative explanation for the 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 study treatment:

Send updated SAE (report term ‘Hy’s Law’) according to AZ 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:

Provides 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 study 
treatment and seriousness criteria is medically important, according to CSP process for 
SAE reporting.


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
Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are still met. Update the previously submitted PHL SAE report 
following CSP process for SAE reporting, according to the outcome of the review and 
amending the reported term if an alternative explanation for the liver biochemistry 
elevations is determined.
E 6
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
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


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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 
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. 
F1 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.
F2 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 CKD-EPI formula (Levey et al) should be used to estimate GFR for enrolment criteria, 
baseline value and subsequent on-study measurements.
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 


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depletion, hypotension etc, should be corrected before following the recommendations given 
below.
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
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 two 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 two 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
Levey et al 2009
Levey AS, Stevens LA, Schmid CH, Zhang Y, Castro AF 3rd, Feldman HI, et al. A new
equation to estimate glomerular filtration rate. Annals of Internal Medicine 2009;150(9):604-
12.


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Appendix G
Kansas City Cardiomyopathy Questionnaire
The KC Cardiomyopathy Questionnaire
The following questions refer to your heart failure and how it may affect your life. Please read 
and complete the following questions. There are no right or wrong answers. Please mark the 
answer that best applies to you.
1
Heart failure affects different people in different ways. Some feel shortness of breath 
while others feel fatigue. Please indicate how much you are limited by heart failure 
(shortness of breath or fatigue) in your ability to do the following activities over the past 
2 weeks.
Place an X in one box on each line
Activity
Extremely 
Limited
Quite a bit 
Limited
Moderately 
Limited
Slightly 
Limited
Not at all 
Limited
Limited for 
other reasons or 
did not do the 
activity
Dressing yourself
□
□
□
□
□
□
Showering/Bathing
□
□
□
□
□
□
Walking 1 block on 
level ground
□
□
□
□
□
□
Doing yardwork, 
housework or 
carrying groceries
□
□
□
□
□
□
Climbing a flight of 
stairs without 
stopping
□
□
□
□
□
□
Hurrying or jogging 
(as if to catch a bus)
□
□
□
□
□
□


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2
Compared with 2 weeks ago, have your symptoms of heart failure (shortness of breath, 
fatigue, or ankle swelling) changed?
My symptoms of heart failure have become…
Much 
worse
Slightly worse
Not changed
Slightly better Much better
I’ve had no symptoms over 
the last 2 weeks
□
□
□
□
□
□
3
Over the past 2 weeks, how many times did you have swelling in your feet, ankles or legs 
when you woke up in the morning?
Every morning
3 or more times a 
week, but not 
every day
1-2 times a week
Less than once a 
week
Never over the 
past 2 weeks
□
□
□
□
□
4
Over the past 2 weeks, how much has swelling in your feet, ankles or legs bothered you?
It has been...
Extremely
Quite a bit
Moderately
Slightly
Not at all
I’ve had no
bothersome
bothersome
bothersome
bothersome
Bothersome
swelling
□
□
□
□
□
□
5
Over the past 2 weeks, on average, how many times has fatigue limited your ability to do 
what you want?
All of the 
time
Several times 
per day
At least 
once a day
3 or more times 
per week but 
not every day
1-2 times 
per week
Less than once 
a week
Never over 
the past 2 
weeks
□
□
□
□
□
□
□


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6
Over the past 2 weeks, how much has your fatigue bothered you?
It has been...
Extremely
Quite a bit
Moderately
Slightly
Not at all
I’ve had
bothersome
bothersome
bothersome
bothersome
bothersome
no fatigue
□
□
□
□
□
□
7
Over the past 2 weeks, on average, how many times has shortness of breath limited your 
ability to do what you wanted?
All of the 
time
Several times 
per day
At least 
once a day
3 or more times 
per week but not 
every day
1-2 times 
per week
Less than 
once a week
Never over 
the past 2 
weeks
□
□
□
□
□
□
□
8
Over the past 2 weeks, how much has your shortness of breath bothered you?
It has been...
Extremely
Quite a bit
Moderately
Slightly
Not at all
I’ve had no
bothersome
bothersome
bothersome
bothersome
bothersome
shortness of breath
□
□
□
□
□
□
9
Over the past 2 weeks, on average, how many times have you been forced to sleep sitting 
up in a chair or with at least 3 pillows to prop you up because of shortness of breath?
Every night
3 or more times a 
week, but not every day
1-2 times a week
Less than once 
a week
Never over the 
past 2 weeks
□
□
□
□
□


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10 Heart failure symptoms can worsen for a number of reasons. How sure are you that you 
know what to do, or whom to call, if your heart failure gets worse?
Not at all sure
Not very sure
Somewhat sure
Mostly sure
Completely sure
□
□
□
□
□
11 How well do you understand what things you are able to do to keep your heart failure 
symptoms from getting worse? (for example, weighing yourself, eating a low salt diet 
etc.)
Do not understand 
at all
Do not 
understand very 
well
Somewhat 
understand
Mostly 
understand
Completely 
understand
□
□
□
□
□
12 Over the past 2 weeks, how much has your heart failure limited your enjoyment of life?
It has extremely 
limited my 
enjoyment of life
It has limited my 
enjoyment of life 
quite a bit
It has moderately 
limited my 
enjoyment of life
It has slightly 
limited my 
enjoyment of life
It has not limited 
my enjoyment of 
life at all
□
□
□
□
□
13 If you had to spend the rest of your life with your heart failure the way it is right now, 
how would you feel about this?
Not at all 
satisfied
Mostly dissatisfied
Somewhat 
satisfied
Mostly 
satisfied
Completely satisfied
□
□
□
□
□


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14 Over the past 2 weeks, how often have you felt discouraged or down in the dumps
because of your heart failure?
I felt that way all 
of the time
I felt that way 
most of the time
I occasionally 
felt that way
I rarely felt that 
way
I never felt that way
□
□
□
□
□
15 How much does your heart failure affect your lifestyle? Please indicate how your
heart failure may have limited your participation in the following activities over the past 
2 weeks?
Place an X in one box on each line
Activity
Severely 
Limited
Limited 
quite a bit 
Moderately 
Limited
Slightly 
Limited
Did not 
limit at all
Does not 
apply or did 
not do for 
other reasons
Hobbies, 
recreational 
activities
□
□
□
□
□
□
Working or 
doing household 
chores
□
□
□
□
□
□
Visiting family 
or friends out of 
your home
□
□
□
□
□
□
Intimate 
relationship 
with loved ones
□
□
□
□
□
□


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Appendix H
Patient Global Impression of Change (PGIC) for Heart 
Failure Symptoms
Overall, how would you rate the change in your heart failure symptoms since starting this 
study?
Much better
Moderately better
A little better
About the same
A little worse
Moderately worse
Much worse


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Appendix I
Patient Global Impression of Severity (PGIS) for Heart 
Failure Symptoms
Overall, how would you rate the severity of your heart failure symptoms today?
No symptoms
Very mild
Mild
Moderate
Severe
Very Severe


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Appendix J
Medication Requiring Adjustment for Co-administration 
with Colchicine


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Appendix K
Patient Dosing Cards Information
All patients in the study will receive a Patient Dosing Card at each visit with IP dispensation 
(ie, Visits 3, 4, 5, 6 and 7). The Patient Dosing Cards information is only applicable to patients 
who follow the standard dose titration schedule (ie, dispensed dose of study treatment 
tolerated and no down-titration required).
Patient Dosing Card (Visit 3)
During your visit today you will receive 2 bottles of Study Medication. This is enough 
Study Medication to last until Visit 4.

1 GREEN label bottle (100 mg 
allopurinol or matching placebo).

Please take 1 tablet from the green label
bottle every day.

1 WHITE label bottle (3 mg verinurad 
or matching placebo).

Please take 1 capsule from the white 
label bottle every day.
EACH DAY you will take your study medications in the morning (preferably with food) as 
follows:

1 TABLET from the GREEN label bottle.

1 CAPSULE from the WHITE label bottle.
Please take colchicine as advised by your doctor.
Important:
You should NEVER take more than one tablet or capsule from the same bottle in one 
day. You will NEVER take more than 2 pills in a single day.
You will continue to take your study medications each day for the remainder of the study as 
described above, unless you received other instructions from the study team.


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Reminder
Before You Take Your Medication:

Make Sure You Are Only Taking 2 Pills In Total (1 Pill From Each Label Colour
Bottle).
If you ever have any questions about your study medications and how you should be taking 
them, contact your study doctor immediately.
Patient Dosing Card (Visit 4)
As per the standard dose titration schedule, during your visit today you will receive 
3 bottles of Study Medication. This is enough Study Medication to last until Visit 5.

2 GREEN label bottles (100 mg 
allopurinol or matching placebo).

Please take 2 tablets from the green
label bottle every day.

1 WHITE label bottle (7.5 mg 
verinurad or matching placebo).

Please take 1 capsule from the white 
label bottle every day.
EACH DAY you will take your study medications in the morning (preferably with food) as 
follows:

2 TABLETS from the GREEN label bottle (always from the same bottle until it is 
empty, then from the next bottle of the same label colour).

1 CAPSULE from the WHITE label bottle.
Please take colchicine as advised by your doctor.
Important:
You should NEVER take more than 2 tablets and 1 capsule from the same bottle in 
one day. The extra GREEN label bottle is to be opened when you run out. You will 
NEVER take more than 3 pills in a single day.


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You will continue to take your study medications each day for the remainder of the study as 
described above, unless you received other instructions from the study team.
Reminder
Before You Take Your Medication:

Make Sure You Are Only Taking 3 Pills In Total (2 Pills From The Green Label Bottle 
And 1 Pill From The White Label Bottle).
Extra GREEN label bottle is ONLY used when you run out.
If you ever have any questions about your study medications and how you should be taking 
them, contact your study doctor immediately.
Patient Dosing Card (Visit 5)
As per the standard dose titration schedule, during your visit today you will receive 
2 bottles of Study Medication. This is enough Study Medication to last until Visit 6.

1 BLUE label bottle (300 mg 
allopurinol or matching placebo).

Please take 1 tablet from the blue label 
bottle every day.

1 WHITE label bottle (12 mg verinurad 
or matching placebo).

Please take 1 capsule from the white 
label bottle every day.
EACH DAY you will take your study medications in the morning (preferably with food) as 
follows:

1 TABLET from the BLUE label bottle.

1 CAPSULE from the WHITE label bottle.
Please take colchicine as advised by your doctor.
Remember to NOT take your study medications on the morning of your next study 
visit (Visit 6).


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Important:
You should NEVER take more than one tablet or capsule from the same bottle in one 
day. You will NEVER take more than 2 pills in a single day.
You will continue to take your study medications each day for the remainder of the study as 
described above, unless you received other instructions from the study team.
Reminder
Before You Take Your Medication:

Make Sure You Are Only Taking 2 Pills In Total (1 Pill From Each Label Colour
Bottle).
If you ever have any questions about your study medications and how you should be taking 
them, contact your study doctor immediately.
Patient Dosing Card (Visit 6)
As per the standard dose titration schedule, during your visit today you will receive 
5 bottles of Study Medication. This is enough Study Medication to last until Visit 7.

2 BLUE label bottles (300 mg 
allopurinol or matching placebo).

Please take 1 tablet from the blue label 
bottle every day.

3 WHITE label bottles (12 mg 
verinurad or matching placebo).

Please take 1 capsule from the white 
label bottle every day.
EACH DAY you will take your study medications in the morning (preferably with food) as 
follows:

1 TABLET from the BLUE label bottle (always from the same bottle until it is 
empty, then from the next bottle of the same label colour).

1 CAPSULE from the WHITE label bottle (always from the same bottle until it is 
empty, then from the next bottle of the same label colour).


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Important:
You should NEVER take more than one tablet or capsule from the same bottle in one 
day. Extra bottles are to be opened when you run out. You will NEVER take more than 
2 pills in a single day.
You will continue to take your study medications each day for the remainder of the study as 
described above, unless you received other instructions from the study team.
Reminder
Before You Take Your Medication:

Make Sure You Are Only Taking 2 Pills In Total (1 Pill From Each Label Colour
Bottle).
Extra bottles are ONLY used when you run out.
If you ever have any questions about your study medications and how you should be taking 
them, contact your study doctor immediately.
Patient Dosing Card (Visit 7)
As per the standard dose titration schedule, during your visit today you will receive 
5 bottles of Study Medication. This is enough Study Medication to last until Visit 8, 
your end of treatment visit.

2 BLUE label bottles (300 mg 
allopurinol or matching placebo).

Please take 1 tablet from the blue label 
bottle every day.

3 WHITE label bottles (12 mg 
verinurad or matching placebo).

Please take 1 capsule from the white 
label bottle every day.
EACH DAY you will take your study medications in the morning (preferably with food) as 
follows:


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
1 TABLET from the BLUE label bottle (always from the same bottle until it is 
empty, then from the next bottle of the same label colour).

1 CAPSULE from the WHITE label bottle (always from the same bottle until it is 
empty, then from the next bottle of the same label colour).
Important:
You should NEVER take more than one tablet or capsule from the same bottle in one 
day. Extra bottles are to be opened when you run out. You will NEVER take more than 
2 pills in a single day.
You will continue to take your study medications each day for the remainder of the study as 
described above, unless you received other instructions from the study team.
Reminder
Before You Take Your Medication:

Make Sure You Are Only Taking 2 Pills In Total (1 Pill From Each Label Colour
Bottle).
Extra bottles are ONLY used when you run out.
If you ever have any questions about your study medications and how you should be taking 
them, contact your study doctor immediately.


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Appendix L
Abbreviations
Abbreviation or special 
term
Explanation
18-F-FDG
18F-fluorodeoxyglucose
ACEi
angiotensin converting enzyme inhibitor
AE
adverse event
ALT
alanine transaminase
ANCOVA
analysis of covariance
ARB
angiotensin II receptor blocker
AST
aspartate transaminase
AV
Arteriovenous
AZ
AstraZeneca
CEA
clinical event adjudication
CHF
chronic heart failure
CKD
chronic kidney disease
COPD
chronic obstructive pulmonary disease
CRF
case report form (electronic/paper)
CPET
cardiopulmonary exercise test
CSP
clinical study protocol
CSR
clinical study report
CSS
clinical summary score
CT
computed tomography
CV
Cardiovascular
DECT
dual-emission computed tomography
DMC
data monitoring committee
DNA
deoxyribonucleic acid
ECG
Electrocardiography
eCRF
electronic case report form
EDC
electronic data capture
E/E’
Ratio of the transmitral early peak velocity (E) over early diastolic mitral 
annulus velocity (E’)
eGFR
estimated glomerular filtration rate
ER8
verinurad extended release formulation
EU
European Union
FDG
Fluorodeoxyglucose
GDF15
growth/differentiation factor 15
GLS
global longitudinal strain


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Abbreviation or special 
term
Explanation
HF
heart failure
HFpEF
heart failure with preserved left ventricular ejection fraction
HFrEF
heart failure with reduced left ventricular ejection fraction
HLA
human leukocyte antigen
hsCRP
high-sensitivity C-reactive protein
IB
investigator’s brochure
hsTrop
high-sensitivity troponin
ICF
Informed consent form
IEC
independent ethics committee
IRB
institutional review board
IWRS
interactive web response system
IL-1β
interleukin 1 beta
IL-6
interleukin 6
IWRS
interactive web response system
KCCQ
Kansas City Cardiomyopathy Questionnaire
LAVI
left atrial volume index
LVEF
left ventricular ejection fraction
LVH
left ventricular hypertrophy
MMRM
mixed model repeated measures
MSU
monosodium urate
NSAID
nonsteroidal anti-inflammatory drug
NT-proBNP
N-terminal pro b-type natriuretic peptide
NYHA
New York Heart Association 
OSS
overall summary score
PET
positron-emission tomography
PGIC
patient global impression of change
PGIS
patient global impression of severity
PK
Pharmacokinetics
PRO
patient-reported outcome
QTcF
QT interval corrected by the Fridericia formula
RER
respiratory exchange ratio
RVSP
right ventricular systolic pressure
SAE
serious adverse event 
SAP
statistical analysis plan
CCI


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Abbreviation or special 
term
Explanation
SoA
schedule of activities
sUA
serum uric acid
sCr
serum creatinine
sCystC
serum cystatin C
TSS
total symptom score
UA
uric acid
ULN
upper limit of normal
URAT1
uric acid transporter 1
US
United States
VE/VCO2
minute ventilation over carbon dioxide production
VO2
volume of oxygen
XO
xanthine oxidase
XOI
xanthine oxidase inhibitor
CCI


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SAP_001.pdf: 
Statistical Analysis Plan  
 
 
 
 
 
 
 
 
 
 
 
 
 
AstraZeneca 
RDEA3170 – D5496C00005 
 
 
 
 
 
 
 
 
 
 
 
               02 June 2022 
 
CONFIDENTIAL AND PROPRIETARY 
 1 of 58 
 
 
Statistical Analysis Plan 
Drug Substance      Verinurad 
Study Code 
D5496C00005 
Edition Number 
4.0 
Date 
02 June 2022 
A Phase 2, Multicentre, Double-Blind, Placebo and Active Control Efficacy 
and Safety Study to Evaluate Verinurad combined with Allopurinol in 
Heart Failure with Preserved Ejection Fraction (AMETHYST) 
 
 
 


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Statistical A nal ysis Pla n   
 
 
 
 
 
 
 
 
 
 
 
 
 
Astra Ze n eca  
R D E A 3 1 7 0 –  D 5 4 9 6 C 0 0 0 0 5  
 
 
 
 
 
 
 
 
 
 
 
               0 2 J u ne  2 0 2 2  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 3  of 5 8  
 
 
T A B L E O F C O N T E N T S  
TI T L E P A G E  ............................................................................................................................. 1  
T A B L E O F C O N T E N T S  .......................................................................................................... 3  
LI S T O F A B B R E VI A TI O N S  ................................................................................................... 6  
A M E N D M E N T HI S T O R Y  ....................................................................................................... 8  
1  
S T U D Y D E T AI L S  ............................................................................................... 1 0  
1. 1  
St u d y o bjecti ves  .................................................................................................... 1 0  
1. 1. 1  
Pri mar y o bjecti ve  .................................................................................................. 1 0  
1. 1. 2  
Sec o n dar y o bje cti ves  ............................................................................................ 1 0  
1. 1. 3  
Safet y o bjecti ve  .................................................................................................... 1 0  
 
 
1. 2  
St u d y desi g n  ......................................................................................................... 1 2  
1. 3  
N u m ber o f s u bjects ............................................................................................... 1 4  
2  
A N A L Y SI S S E T S  ................................................................................................ 1 4  
2. 1  
Defi niti o n of a nal ysis sets  ..................................................................................... 1 4  
2. 1. 1  
E nr olle d set  ........................................................................................................... 1 4  
2. 1. 2  
F ull a nal ysis set ..................................................................................................... 1 5  
2. 1. 3  
Safet y a nal ysis set  ................................................................................................. 1 5  
 
 
2. 2  
Vi olati o ns a n d de viati o ns  ..................................................................................... 1 5  
2. 2. 1  
I m p ort a nt pr ot oc ol de viati o ns ............................................................................... 1 5  
3  
P RI M A R Y A N D S E C O N D A R Y V A RI A B L E S  ................................................. 1 6  
3. 1  
Ge neral defi niti o ns ................................................................................................ 1 6  
3. 1. 1  
Visit wi n d o w defi niti o ns  ...................................................................................... 1 6  
3. 1. 2  
Baseli ne ................................................................................................................. 1 7  
3. 1. 3  
Missi n g val ues  ...................................................................................................... 1 7  
3. 1. 4  
Pri or/c o nc o mita nt me dicati o ns  ............................................................................. 1 8  
3. 2  
E n d p oi nts  .............................................................................................................. 1 8  
3. 2. 1  
Pri mar y effic ac y e n d p oi nt ..................................................................................... 1 8  
3. 2. 2  
Sec o n dar y effic ac y e n d p oi nt ................................................................................. 1 8  
3. 2. 3  
E x pl orat or y e n d p oi nts  ........................................................................................... 1 9  
3. 2. 3. 1  
Ot her K C C Q sc ores  .............................................................................................. 1 9  
3. 2. 3. 2  
P GI S  ...................................................................................................................... 1 9  
3. 2. 3. 3  
P GI C  ..................................................................................................................... 2 0  
3. 2. 3. 4  
G o ut flares  ............................................................................................................ 2 0  
3. 2. 3. 5  
Ser u m uric aci d  ..................................................................................................... 2 0  
3. 2. 3. 6  
Reacti ve h y perae mia  ............................................................................................. 2 0  
3. 2. 3. 7  
Ec h ocar di o gra p h y ass ess me nt of car di ac str uct ur e a n d f u ncti o n  ......................... 2 0  
3. 2. 3. 8  
Car di o vasc ular a n d heart fail ure e v e nts  ................................................................ 2 1  
3. 2. 3. 9  
Bi o mar kers  ............................................................................................................ 2 1  
 
 
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Statistical A nal ysis Pla n   
 
 
 
 
 
 
 
 
 
 
 
 
 
Astra Ze n eca  
R D E A 3 1 7 0 –  D 5 4 9 6 C 0 0 0 0 5  
 
 
 
 
 
 
 
 
 
 
 
               0 2 J u ne  2 0 2 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  of 5 8  
 
 
 
 
 
 
 
 
3. 3  
Safet y e n d p oi nts .................................................................................................... 2 2  
3. 3. 1  
A d verse e ve nts  ...................................................................................................... 2 2  
3. 3. 2  
La b orat or y v aria bles  ............................................................................................. 2 3  
3. 3. 3  
T wel ve -le a d E C Gs ................................................................................................ 2 4  
3. 3. 4  
Vital si g ns  ............................................................................................................. 2 4  
3. 3. 5  
P h ysical e xa mi nati o n  ............................................................................................ 2 5  
4  
A N A L Y SI S M E T H O D S  ...................................................................................... 2 5  
4. 1  
Ge neral pri nci ples  ................................................................................................. 2 5  
4. 1. 1  
Esti ma n d of t he pri mar y a n d sec o n dar y efficac y e n d p oi nts  ................................. 2 6  
4. 1. 2  
Met h o ds f or m ulti plicit y c o ntr ol  ........................................................................... 2 8  
4. 2  
A nal ysis met h o ds  .................................................................................................. 2 8  
4. 2. 1  
S u bject dis p ositi o n  ................................................................................................ 2 8  
4. 2. 2  
I m pa ct of C O VI D-1 9 o n st u d y visits  .................................................................... 2 9  
4. 2. 3  
De m o gra p h y d ata a n d s u bject c haracteristics  ....................................................... 2 9  
4. 2. 4  
St u d y treat me nt a d mi nistrati o n  ............................................................................. 2 9  
4. 2. 5  
Pri mar y effic ac y e n d p oi nt: veri n ura d + all o p uri n ol vs place b o  ........................... 3 0  
4. 2. 6  
Pri mar y effic ac y e n d p oi nt: veri n ura d + all o p uri n ol vs all o p uri n ol  ...................... 3 5  
4. 2. 7  
Sec o n dar y effic ac y  e n d p oi nt ................................................................................. 3 6  
 
 
4. 2. 9  
Safet y e n d p oi nts .................................................................................................... 4 0  
4. 2. 9. 1  
A d verse e ve nts  ...................................................................................................... 4 0  
4. 2. 9. 2  
A dj u dicate d e v e nts ................................................................................................ 4 1  
4. 2. 9. 3  
La b orat or y d ata  ..................................................................................................... 4 1  
 
 
4. 2. 9. 5  
E C Gs  ..................................................................................................................... 4 2  
4. 2. 9. 6  
Vital si g ns  ............................................................................................................. 4 3  
5  
I N D E P EN D E N T D A T A M O NI T O RI N G C O M MI T T E E (I D M C) 
A N A L Y S E S  ......................................................................................................... 4 3  
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  .............................................. 4 3  
7  
R E F E R E N C E S  ..................................................................................................... 4 3  
8  
A P P E N DI X  .......................................................................................................... 4 4  
8. 1  
Partial dates f or a d vers e e ve nts a n d pri or/c o n c o mita nt me dicati o n  ..................... 4 4  
8. 2  
T he K C Car di o m y o pat h y Q uesti o n naire  .............................................................. 4 7  
8. 3  
K C C Q Sc ori n g I nstr u cti o ns  .................................................................................. 5 2  
8. 4  
A nc h or -b ase d a n al ysis f or esti mati n g t hres h ol ds f or cli nicall y mea ni n gf ul 
wit hi n -patie nt c ha n ge ............................................................................................ 5 7  
 
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Statistical Analysis Plan  
 
 
 
 
 
 
 
 
 
 
 
 
 
AstraZeneca 
RDEA3170 – D5496C00005 
 
 
 
 
 
 
 
 
 
 
 
               02 June 2022 
 
CONFIDENTIAL AND PROPRIETARY 
 5 of 58 
 
 
LIST OF TABLES 
Table 1 
Dosing Schedule .......................................................................................... 14 
Table 2 
Visit Windows ............................................................................................. 16 
Table 3 
Vital Signs Reference Ranges ..................................................................... 24 
Table 4 
Primary and Secondary Efficacy Endpoints Estimands .............................. 27 
 
LIST OF FIGURES 
Figure 1 
Study Schema .............................................................................................. 12 
 


Statistical Analysis Plan  
 
 
 
 
 
 
 
 
 
 
 
 
 
AstraZeneca 
RDEA3170 – D5496C00005 
 
 
 
 
 
 
 
 
 
 
 
               02 June 2022 
 
CONFIDENTIAL AND PROPRIETARY 
 6 of 58 
 
 
LIST OF ABBREVIATIONS 
Abbreviation or special 
term 
Explanation 
AE 
Adverse event  
ANCOVA 
Analysis of covariance 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AZ 
AstraZeneca 
CC 
Complete case 
CFB 
Change from baseline 
CI 
Confidence interval 
CPET 
Cardiopulmonary exercise test 
CSP 
Clinical study protocol 
CSR 
Clinical study report 
CSS 
Clinical summary score 
CV 
Cardiovascular 
DAE 
Discontinuation of investigational product due to adverse event 
DBP 
Diastolic blood pressure 
DRMI 
Drop-out reason-based multiple imputation 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
PRO 
patient reported outcome 
FAS 
Full analysis set  
HF 
Heart failure 
HFpEF 
Heart failure with preserved ejection fraction 
ICF 
Informed consent form 
IDMC 
Independent data monitoring committee 
IP 
Investigational product  
IPD 
Important protocol deviation 
ITT 
Intent-to-treat 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
LLOQ 
Lower limit of quantification 
LSMD 
Least squares means difference 
LSMEANS 
Least squares means 


Statistical A nal ysis Pla n   
 
 
 
 
 
 
 
 
 
 
 
 
 
Astra Ze n eca  
R D E A 3 1 7 0 –  D 5 4 9 6 C 0 0 0 0 5  
 
 
 
 
 
 
 
 
 
 
 
               0 2 J u ne  2 0 2 2  
 
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 8  
 
 
A b bre vi ati o n or s peci al 
ter m 
E x pl a n ati o n  
 
 
M A R  
Missi n g at ra n d o m  
M C P  
M ulti ple c o m paris o ns pr oce d ure  
Me d D R A  
Me dical dicti o nar y f or re g ulat or y acti vities  
MI  
M ulti ple i m p utati o n  
M M R M  
Mi x e d m o del f or re peate d meas ures  
O S S  
O verall s u m mar y sc ore  
P D  
Pr ot oc ol d e viati o n  
P GI C  
Patie nt Gl o bal I m pressi o n of C ha n ge  
P GI S  
Patie nt Gl o bal I m pressi o n of Se verit y  
 
 
P R O  
Patie nt re p orte d o utc o me  
P T  
Preferre d ter m  
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 D  
Sta n dar d de viati o n  
SI  
S yste m i nter nati o nal ( u nits)  
S O C  
S yste m or ga n class  
s U A 
Ser u m uric aci d  
T B L  
T otal bilir u bi n  
T S S  
T otal s y m pt o m sc ore  
 
 
U L N  
U p per li mit of n or mal  
V O 2  
O x y ge n v ol u me  
 
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Statistical Analysis Plan  
 
 
 
 
 
 
 
 
 
 
 
 
 
AstraZeneca 
RDEA3170 – D5496C00005 
 
 
 
 
 
 
 
 
 
 
 
               02 June 2022 
 
CONFIDENTIAL AND PROPRIETARY 
 8 of 58 
 
 
AMENDMENT HISTORY 
Category*: 
Change refers to 
Date 
Description of change 
In line 
with the 
CSP? 
Rationale 
Other 
08 July 2021 
Removed ‘Three Arm’ from title. 
Yes 
Implementation of Protocol Version 3.0.  Patients 
randomised after implementation are assigned to 
one of 4 treatment arms as part of modified study 
design. 
Other 
08 July 2021 
Updated protocol version number. 
Yes 
New Protocol Version 3.0. 
Statistical analysis 
method for the primary 
or secondary endpoints 
08 July 2021 
Updated study design to include new planned 
analysis of pooled data from the 24 mg 
verinurad + allopurinol and 12 mg verinurad + 
allopurinol treatment arms. 
Yes 
Protocol Version 3.0 includes an additional 
treatment arm.   
Other 
08 July 2021 
Re-labelled study schema figure as Part (A) 
and inserted new study schema as Part (B). 
Yes 
Schema dependent on patient randomisation prior to 
or after implementation of Protocol Version 3.0. 
Other 
08 July 2021 
Added additional dosing schedule for the 24 
mg verinurad + allopurinol arm. 
Yes 
Protocol Version 3.0 includes an additional 
treatment arm.   
Other 
08 July 2021 
Updated to include additional treatment arm 
(24 mg verinurad in combination with 
allopurinol) and 1:1:1:1 randomisation ratio. 
Yes 
Protocol Version 3.0 includes an additional 
treatment arm.   
Statistical analysis 
method for the primary 
or secondary endpoints 
08 July 2021 
Added new sensitivity analyses of the primary 
and secondary analyses. 
Yes 
Protocol Version 3.0 includes an additional 
sensitivity analysis.   
Statistical analysis 
method for the primary 
or secondary endpoints 
08 July 2021 
Added distribution-based analysis for 
estimating group-level minimal clinically 
important difference analyses for primary and 
secondary endpoints. 
Yes 
Protocol Version 3.0 includes additional 
distribution-based analyses.   
Other 
08 July 2021 
Removed safety analyses text in Section 7 
(Changes of Analysis from Protocol) 
Yes 
SAP and Protocol Version 3.0 are in alignment with 
the definition of the Safety Analysis Set.  


Statistical A nal ysis Pla n   
 
 
 
 
 
 
 
 
 
 
 
 
 
Astra Ze neca  
R D E A 3 1 7 0 –  D 5 4 9 6 C 0 0 0 0 5  
 
 
 
 
 
 
 
 
 
 
 
               0 2 J u ne  2 0 2 2  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 9  of 5 8  
 
 
Ot her  
0 8 J ul y  2 0 2 1  
Re m o ve d D E C T/ P E T e n d p oi nts  
N o  
S u bst u d y ca ncelle d . 
Pri mar y or sec o n dar y 
e n d p oi nts  
0 8 J ul y  2 0 2 1  
C ha n ge d t w o of t he se nsiti vit y a nal yses t o 
s u p ple me ntal a nal yses 
Yes  
I C H 9 a d de n d u m clarificati o n of differe n ces 
bet wee n se nsiti vit y a n d s u p ple me ntal a n al yses.  
Statistical a n al ysis 
met h o d f or t he pri mar y 
or sec o n dar y e n d p oi nts 
0 8 J ul y  2 0 2 1  
A d de d pr ot oc ol versi o n t o a nal ysis c o variates  
Yes  
Acc o u nti n g f or p ote ntial differe n ces d ue t o pr ot oc ol 
versi o ns.  
 
 
 
 
 
  
Ot her  
1 9  N o ve m ber  
2 0 2 1  
Re m o ve d 2 4 m g veri n ura d ar m , i nteri m 
a nal ysis, a n d refere nces t o D E C T a n d 
P E T/ C T.  
Yes  
U p date d base d o n C S P versi o n 4. 0  
Ot her  
0 2 J u ne  2 0 2 2  
Re m o ve d A Es of s pecial i nterest  a n d M A C E.  
U p date d f or e dits a n d clarificati o ns . U p date 
treat me nt c o m plia nce defi niti o n. 
Yes  
A Es of s pecial i nterest a n d M A C E n ot nee de d.  
Mi n or e dits. Treat me nt c o m plia n ce de p e n de nt o n 
visit.  
* Pre -s pecifie d cate g ories are  
Pri mar y or sec o n dar y e n d p oi nts; Statisti cal a nal ysis met h o d f or t he pri mar y or sec o n dar y e n d p oi nts; Deri vati o n of pri mar y or sec o n dar y e n d p oi nts; M ulti ple 
Testi n g Pr o ce d ure; Data prese ntati o ns; Ot her  
 
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Statistical Analysis Plan  
 
 
 
 
 
 
 
 
 
 
 
 
 
AstraZeneca 
RDEA3170 – D5496C00005 
 
 
 
 
 
 
 
 
 
 
 
               02 June 2022 
 
CONFIDENTIAL AND PROPRIETARY 
 10 of 58 
 
 
1 
STUDY DETAILS 
This statistical analysis plan (SAP) has been developed based on the AstraZeneca clinical 
study protocol (CSP) D5496C00005 version 4.0 (September 20, 2021) and outlines the 
analyses to be generated for the global clinical study report (CSR). Additional analyses 
required for regional submissions will be prespecified in a separate analysis plan and will be 
submitted to the appropriate authorities. 
1.1 
Study objectives 
1.1.1 
Primary objective 
Primary objective: 
Endpoint/variable: 
To assess effect of verinurad + allopurinol compared to 
placebo on exercise capacity   
Change from baseline at Week 32 in peak VO2 
consumption 
VO2 Oxygen volume.  
 
1.1.2 
Secondary objectives 
Secondary objective: 
Endpoint/variable: 
To assess effect of verinurad + allopurinol compared to 
allopurinol monotherapy on exercise capacity   
Change from baseline at Week 32 in peak VO2 
consumption 
To assess effect of verinurad + allopurinol compared to 
placebo and compared to allopurinol monotherapy on 
Kansas City Cardiomyopathy Questionnaire (KCCQ)-
Total Symptom Score (TSS)  
Change from baseline at Week 32 in KCCQ-
TSS 
 
VO2 Oxygen volume.   
 
1.1.3 
Safety objective 
Safety Objective: 
Endpoint/Variable: 
To assess the safety and tolerability 
of verinurad + allopurinol as 
compared to placebo and to 
allopurinol in patients with HFpEF. 
Safety and tolerability will be evaluated in terms of AEs, vital signs, 
clinical laboratory, and ECG. Assessments related to AEs cover   
• 
Occurrence  
• 
Relationship to study treatment as assessed by                
                    investigator  
• 
Intensity   
• 
Seriousness  
• 
Death  
• 
AEs leading to discontinuation of study treatment  
• 
Other action taken related to study treatment, including    
                    dose interruptions  
  
Vital signs parameters include systolic and diastolic blood pressure, 
pulse, temperature. 
 
AE Adverse event.  ECG Electrocardiogram.  HFpEF Heart failure with preserved ejection fraction. 
 


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Statistical A nal ysis Pla n   
 
 
 
 
 
 
 
 
 
 
 
 
 
Astra Ze n eca  
R D E A 3 1 7 0 –  D 5 4 9 6 C 0 0 0 0 5  
 
 
 
 
 
 
 
 
 
 
 
               0 2 J u ne  2 0 2 2  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 1 4  of 5 8  
 
 
T a ble 1  
D osi n g Sc he d ule  
Tre at me nt 
Ar m  
Wee k 0 -3  
Ste p 1 - Titr ati o n  
Wee k 4 -7  
Ste p 2 - Titr ati o n  
Wee k 8 -1 2  
Ste p 3 –  T ar get D ose  
Wee k 1 3 -3 2  
T ar get D ose  
1 2 m g 
veri n ura d + 
all o p uri n ol 
 
C olc hici ne 
pr o p h yla xis + 3 m g 
veri n ura d + 1 0 0 m g 
all o p uri n ol 
C olc hici ne 
pr o p h yla xis + 7. 5 m g 
veri n ura d + 2 0 0 m g 
all o p uri n ol 
C olc hici ne 
pr o p h yla xis + 1 2 m g 
veri n ura d + 3 0 0 m g 
all o p uri n ol 
1 2 m g 
veri n ura d + 
3 0 0 m g 
all o p uri n ol 
All o p uri n ol  
C olc hici ne 
pr o p h yla xis + 1 0 0 
m g all o p uri n ol  
C olc hici ne 
pr o p h yla xis + 2 0 0 m g 
all o p uri n ol 
C olc hici ne 
pr o p h yla xis + 3 0 0 m g 
all o p uri n ol 
3 0 0 m g 
all o p uri n ol 
Place b o  
C olc hici ne 
pr o p h yla xis + 
place b o  
C olc hici ne 
pr o p h yla xis + 
place b o  
C olc hici ne 
pr o p h yla xis + place b o  
Place b o  
 
1. 3  
N u m ber of s u bjects  
T he  st u d y will e m pl o y a 1: 1: 1 ra n d o misati o n rati o bet wee n 1 2 m g veri n ura d + all o p uri n ol, 
all o p uri n ol, a n d place b o.  Base d o n t his desi g n wit h 5 0 patie nts ra n d o mise d t o t he veri n ura d + 
all o p uri n ol gr o u p a n d t o t he place b o gr o u p res p ecti vel y, a n d ass u mi n g a sta n dar d de viati o n f or 
t he pri mar y e n dp oi nt of 2 m L/ k g/ mi n , t he wi dt h of 9 5 % c o nfi de n ce i nter vals f or esti mate d 
differe n ces b et wee n tr eat me nts will be a b o ut 1. 5 7 ml/ k g/ mi n.  T he mi ni m u m detecta ble 
treat me nt differe nce f or statistical si g nifica nce i n a t w o-gr o u p t -test wit h a t w o-si de d 
si g nificance le v el of 5 % gi ve n t he ass u m pti o ns a b o ve is 0. 7 9 4  m L/ k g/ mi n.  
 
T he ass u me d sta n dar d de viati o n of 2 m L/ k g/ mi n  is deri ve d fr o m B orla u g (B orla u g et al 2 0 1 8 ) 
a n d fr o m Re dfiel d (R e dfi el d et al 2 0 1 3 ).  
 
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 o ur a n al ysis sets are d efi ne d bel o w: E nr olle d, f ull a nal ysis set ( F A S), safet y a nal ysis set,  
 
. If n o si g ne d i nf or me d c o ns e nt is c ollecte d (i m p orta nt 
pr ot oc ol de viati o n), t he n t he patie nt will be e xcl u d e d fr o m all a nal ysis sets defi ne d bel o w.  
2. 1. 1  
E nr olle d set  
T his a nal ysis set c o m prises all patie nts w h o si g n t he mai n i nf or me d c o ns e nt f or m (I C F) a n d 
will be use d f or re p orti n g of dis p ositi o n a n d scree ni n g fail ures. 
C CI


Statistical A nal ysis Pla n   
 
 
 
 
 
 
 
 
 
 
 
 
 
Astra Ze n eca  
R D E A 3 1 7 0 –  D 5 4 9 6 C 0 0 0 0 5  
 
 
 
 
 
 
 
 
 
 
 
               0 2 J u ne  2 0 2 2  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 1 5  of 5 8  
 
 
2. 1. 2  
F ull a n al ysis set  
All patie nts w h o ha ve bee n ra n d o mise d t o st u d y treat me nt will be i ncl u de d i n t he F A S, 
irres pecti ve of t heir pr ot o c ol a d here nce a n d c o nti n ue d partici pati o n i n t he st u d y. Patie nts will 
be a nal yse d acc or di n g t o t heir ra n do mis e d st u d y tr eat me nt assi g n me nt, irres pecti ve of t he 
treat me nt act u all y recei ve d. Data fr o m patie nts w h o wit h dra w c o nse nt will be i ncl u de d u p t o 
t he date of t heir st u d y ter mi nati o n.  
T he F A S will be c o nsi dere d t he pri mar y a nal ysis set f or t he pri mar y a n d  sec o n dar y varia bles 
a n d f or t he e x pl orat or y efficac y v aria bles.  
All efficac y a n al yses will be perf or me d usi n g a n i nte nt -t o-treat (I T T) a p pr oac h base d o n t h e 
F A S. F or c o nsiste nc y, de m o gra p hic a n d bas eli ne c haract eristics will be pres e nte d usi n g t he 
F A S.  
2. 1. 3  
S a fet y a n al ysis s et 
T he Safet y a n al ysis set c o nsists of all patie nts w h o ha ve recei ve d at least 1 d ose of st u d y 
treat me nt.  Patie nts will be a nal yse d acc or di n g t o t heir ra n d o mise d st u d y tr eat me nt 
assi g n me nt, irres pecti ve of t he treat me nt act uall y recei v e d.  
A ll safet y s u m maries will be base d o n t his a nal ysis set. 
 
 
 
 
 
 
2. 2  
Vi ol ati o ns a n d de vi ati o ns  
2. 2. 1  
I m p ort a nt pr ot oc ol d e vi ati o ns 
I m p ort a nt pr ot oc ol de viati o ns (I P Ds) are a s u bset of pr ot ocol de viati o ns ( P Ds) t hat ma y 
si g nifica ntl y i m pact t he c o m plete ness, acc urac y, a n d/ or relia bilit y of t he st u d y data or t hat 
ma y si g nifica ntl y affect a patie nt’s ri g hts, safet y, or well -bei n g.  
T he fi nal list of I P Ds will be d oc u me nte d pri or t o u n bli n di n g t he  st u d y data a n d will i ncl u de 
b ut ma y n ot be li mite d t o t he f oll o wi n g de viati o ns:  
•  
Patie nt was ra n d o mise d b ut di d n ot meet i ncl usi o n criteria  
•  
Patie nt was ra n d o mise d b ut met e xcl usi o n criteria  
•  
 Patie nt recei ve d/t o o k t he wr o n g st u d y treat me nt or i nc orrect d ose or t o o k me dicati o n 
fr o m o nl y o ne b ottle at a n y ti me of t he st u d y peri o d 
C CI


Statistical Analysis Plan  
 
 
 
 
 
 
 
 
 
 
 
 
 
AstraZeneca 
RDEA3170 – D5496C00005 
 
 
 
 
 
 
 
 
 
 
 
               02 June 2022 
 
CONFIDENTIAL AND PROPRIETARY 
 16 of 58 
 
 
• 
Patient received any prohibited medication from those listed in Table 6 of the CSP 
• 
Patient developed discontinuation criteria but continued on investigational product (IP) 
 
IPDs will be summarised by the highest level deviation category and will be based on the 
FAS. IPDs or PDs related to the ongoing and emerging novel coronavirus (COVID-19) will be 
summarised for the FAS population overall and by randomised treatment group. Patients with 
IPDs or PDs related to COVID-19 will be listed.  
 
IPDs will not be used to exclude any patient from any analysis set, nor to exclude any data 
from patients included in an analysis set.  
3 
PRIMARY AND SECONDARY VARIABLES 
3.1 
General definitions 
3.1.1 
Visit window definitions 
For endpoints that present visit-based data, the variables will be summarised based on the 
scheduled days with analysis visit windows. The analysis visit windows will be based on the 
collection schedule listed in the protocol and variables will be windowed to the closest 
scheduled visit for that variable.  
Analysis visit windows have been constructed so that every observation collected can be 
allocated to a particular visit, including unscheduled assessments. No analysis visit windows 
will be defined for screening visits. 
The window for the analysis visits following baseline will be constructed in such a way that 
the upper limit of the interval falls halfway between the two visits (the lower limit of the first 
post-baseline visit will be Day 2). Analysis visit will be mapped based on study day windows 
in Table 2 below. 
Table 2 
Visit Windows 
Visit Name 
Visit Study Day 
Study Days (Visit Window) 
Week 4 (Visit 4)  
Day 28 
2 to 42 
Week 8 (Visit 5) 
Day 56 
43 to 70 
Week 12 (Visit 6)  
Day 84 
71 to 119 
Week 22 (Visit7) 
Day 154 
120 to 189 
Week 32 (Visit 8) 
Day 224 
190 to 230 
Week 36 (Visit 9) 
Day 252 
231 to end of study 
 


Statistical Analysis Plan  
 
 
 
 
 
 
 
 
 
 
 
 
 
AstraZeneca 
RDEA3170 – D5496C00005 
 
 
 
 
 
 
 
 
 
 
 
               02 June 2022 
 
CONFIDENTIAL AND PROPRIETARY 
 17 of 58 
 
 
If multiple readings are recorded within a single visit window, the rules below will be applied.  
• 
If there are 2 or more observations within the same visit window, then the 
non-missing observation closest to the scheduled visit will be used in the analysis.  
• 
If 2 observations are equidistant from the scheduled visit, then the non-missing 
observation with the earlier collection date will be used in the analysis.  
• 
If 2 or more observations are collected on the same day, then the non-missing 
observation with the earlier collection time will be included in the analysis. If any 
observations’ collection time is missing the mean of the observations will be used in 
the analysis.  
If a visit window does not contain any observations, then the data will remain missing.  
For the patient-report questionnaires collected by electronic patient reported outcomes 
(ePRO), the following rules will be applied: 
For overall analyses not based on any particular study visit (eg, maximum post-baseline 
value), all data will be listed and/or analysed, including any repeat or unscheduled visits, 
unless otherwise specified. For safety endpoints, all post-baseline results will be included in 
these overall analyses. 
3.1.2 
Baseline  
In general, the last recorded value on or not after the date of randomisation will serve as the 
baseline measurement for efficacy endpoints while the last recorded value prior to first dose of 
study treatment will serve as the baseline measurement for safety endpoints. When time of 
assessment is not recorded or missing, it is assumed that assessments recorded on the date of 
first dose of study treatment were performed prior to dosing, except in cases of protocol-
specified post-dose assessments. If there is no value prior to randomisation (or the first dose of 
study treatment, depending on the endpoint), then the baseline value will not be imputed and 
will be set to missing. No data known to be collected post first dose will be used in 
determining the baseline value, unless otherwise specified. 
Baseline serum creatinine will be the highest of all creatinine measurements collected before 
randomisation. 
3.1.3 
Missing values 
A treatment policy estimand will be applied to the analysis of the primary and secondary 
endpoints whereby all data up to Week 32 are included, regardless of whether the patient has 
discontinued study drug or received other medications. 
 


Statistical Analysis Plan  
 
 
 
 
 
 
 
 
 
 
 
 
 
AstraZeneca 
RDEA3170 – D5496C00005 
 
 
 
 
 
 
 
 
 
 
 
               02 June 2022 
 
CONFIDENTIAL AND PROPRIETARY 
 18 of 58 
 
 
Missing values for the primary and secondary endpoints at post-baseline visits up to and 
including Week 32 (Visit 8) will be imputed using a dropout reason-based multiple imputation 
(DRMI) approach.  Additionally, sensitivity analyses to assess the robustness of the primary 
analysis with respect to the handling of missing data will be performed. Missing values at 
baseline will not be imputed and change from baseline will be set to missing if the baseline 
assessment is missing. 
 
Details for the imputation and sensitivity analyses can be found in Section 4.2.5. Missing data 
will not be imputed for the safety and exploratory analyses.  
3.1.4 
Prior/concomitant medications 
A medication will be regarded as prior if it was stopped on or before the date of randomisation 
(medication stop date ≤ date of randomisation). A medication will be regarded as concomitant 
if the start date is after the date of randomisation, or if it started on or prior to the date of 
randomisation and ongoing after the date of randomisation. 
The handling of partial/missing dates for AEs and prior/concomitant medications is detailed in 
Appendix 8.1.  
3.2 
Endpoints 
3.2.1 
Primary efficacy endpoint 
The primary efficacy endpoint is the absolute change from baseline (Visit 2) in peak VO2 at 
Week 32 (Visit 8), calculated as the value at Week 32 minus the baseline value, as assessed by 
a cardiopulmonary exercise test (CPET). 
The primary modality for a CPET will be either a motor-driven treadmill or cycle ergometer.  
Patients must use the same testing modality and the same exercise equipment for all exercise 
tests during the study. The modality for each CPET will be recorded. Peak VO2 is the 
maximum rate of oxygen consumption measured during the exercise test, and will be 
expressed in millilitres oxygen per kilogram of body mass per minute (mL/kg/min). 
3.2.2 
Secondary efficacy endpoint 
The secondary efficacy endpoint is the absolute change from baseline (Visit 3) in KCCQ Total 
Symptom Score (TSS) to Week 32 (Visit 8), calculated as the value at Week 32 minus the 
baseline value.  
The KCCQ is a 23-item, self-administered ePRO instrument that quantifies physical 
limitations, symptoms, self-efficacy, social interference, and quality of life, and has been 
shown to be a valid, reliable and responsive measure for patients with HF (Green et al 2000). 
The KCCQ was developed to measure the patient’s perception of their health status 
independently, which includes HF-related symptoms (frequency, burden and recent change), 


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Statistical Analysis Plan  
 
 
 
 
 
 
 
 
 
 
 
 
 
AstraZeneca 
RDEA3170 – D5496C00005 
 
 
 
 
 
 
 
 
 
 
 
               02 June 2022 
 
CONFIDENTIAL AND PROPRIETARY 
 23 of 58 
 
 
using the latest version of the Medical Dictionary for Regulatory Activities (MedDRA) per the 
Data Management Plan. 
The following events are considered treatment emergent: 
• 
Adverse events with an onset date on or after first dose of IP 
• 
Worsening of pre-existing events on or after first dose of IP 
Pre-treatment (prior) adverse events are defined as those with a start prior to the day of first 
dose of study treatment.  
If an AE has a missing onset date then unless the stop date of the AE indicates otherwise, this 
will be considered an on-treatment AE. Similarly, if an AE has a partial onset date, then unless 
the partial onset date or the stop date indicates otherwise, this will be considered an on-
treatment AE. 
Adverse events that have missing causality (after data querying) will be assumed to be related 
to study drug. 
 
3.3.2 
Laboratory variables 
Blood and urine samples for determination of clinical chemistry, haematology and urinalysis 
parameters will be taken at the times detailed in Section 1.1 (SoA) of the CSP and will be 
assessed in a central laboratory.  The parameters outlined in Section 8.2.1 (Table 7) of the 
CSP will be collected.   
In summaries, figures, and listings, lab results and normal ranges will be presented in System 
International (SI) units.   
Changes in haematology and clinical chemistry variables between baseline and each post-
baseline assessment will be calculated.  For values recorded with a reading greater than or less 
than (‘>’, ‘<’) symbol, the reported numeric value will be used for analysis and the value with 
the symbol will be included in the listings, unless otherwise specified.  For example, a value 
of <0.01 will be analysed as 0.01 and listed as <0.01. 
Absolute values will be compared to the relevant reference range and classified as low (below 
range), normal (within range or on limits) or high (above range). The central reference ranges 
will be used for laboratory variables. All absolute values falling outside the reference ranges 
will be flagged. 
Urinalysis data will be categorised as negative, trace, positive (+), or strongly positive (++, 
+++, or ++++) at each timepoint. 


Statistical Analysis Plan  
 
 
 
 
 
 
 
 
 
 
 
 
 
AstraZeneca 
RDEA3170 – D5496C00005 
 
 
 
 
 
 
 
 
 
 
 
               02 June 2022 
 
CONFIDENTIAL AND PROPRIETARY 
 24 of 58 
 
 
For the liver function tests: aspartate Aminotransferase (AST), alanine Aminotransferase 
(ALT), alkaline phosphatase (ALP), and total bilirubin (TBL), the multiple of the central 
laboratory upper limit of the normal (ULN) range will be calculated for each data point. 
Multiple = Value / ULN 
 
That is, if the ALT value was 72 IU/L (ULN=36) then the multiple would be 2. 
Patients who meet any of the following criteria at any point during the study will be flagged: 
• AST ≥ 3x ULN  
• ALT ≥ 3x ULN  
• TBL ≥ 2xULN 
 
 
3.3.3 
Twelve-lead ECGs 
ECG measurements will be assessed at the times detailed in Section 1.1 (Table SoA) of the 
CSP, with the baseline visit being defined as the last available non-missing measurement(s) 
prior to first dose of study treatment.  
The ECG assessment (normal, abnormal but not clinically significant, or abnormal and 
clinically significant; and QT interval, QTcF) will be recorded in the eCRF.  Any clinically 
significant findings will be reported as AEs or in the Medical History, as appropriate.   
3.3.4 
Vital signs 
Temperature, pulse rate, weight, and blood pressure will be assessed at times detailed in 
Section 1.1 (Table SoA) of the CSP.  
Changes in vital signs variables between baseline and each subsequent scheduled assessment 
will be calculated. The change from baseline is defined as the post-baseline visit value minus 
the baseline visit value.  There will be no imputation for missing values. 
Absolute values will be compared to the reference ranges in Table 3 below and classified as 
low (below range), normal (within range or on limits) or high (above range).  All values 
falling outside the reference ranges will be flagged. 
Table 3 
Vital Signs Reference Ranges 
Parameter 
Standard Units 
Lower Limit 
Upper Limit 
Diastolic Blood Pressure (DBP) 
mmHg 
60 
120 
Systolic Blood Pressure (SBP) 
mmHg 
100 
160 
Pulse Rate 
Beats/min 
50 
120 


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Table 4 
Primary and Secondary Efficacy Endpoints Estimands 
MCP Multiple comparisons procedure. FAS Full analysis set.   Dropout reason-based multiple imputation. MI Multiple imputation. LSMD Least squares means 
difference. CFB Change from baseline. ANCOVA Analysis of covariance. MMRM Mixed model for repeated measures. 
 
Statistical 
Category 
Estimand 
 
Section 
Endpoint (Population) 
Intercurrent Event Strategy 
Population Level Summary 
(Analysis) 
Primary Objective: To assess effect of verinurad + allopurinol compared to placebo and compared to allopurinol monotherapy on exercise capacity 
Primary/MCP 
Change from baseline at Week 32 
in peak VO2 consumption (FAS) 
Included in analysis regardless of having discontinued study 
drug or received other medications (treatment policy) using 
DRMI approach 
Mean difference between 
treatments (LSMD from CFB 
ANCOVA at Week 32) 
4.2.5 
Sensitivity 
Change from baseline at Week 32 
in peak VO2 consumption (FAS) 
Included in analysis regardless of having discontinued study 
drug or received other medications (treatment policy) using MI 
approach  
Mean difference between 
treatments (LSMD from CFB 
ANCOVA at Week 32) 
4.2.5 
Secondary Objective: To assess effect of verinurad + allopurinol compared to placebo and compared to allopurinol monotherapy on KCCQ-TSS  
Secondary/MCP 
Change from baseline at Week 32 
in KCCQ-TSS (FAS) 
Included in analysis regardless of having discontinued study 
drug or received other medications (treatment policy) using 
DRMI approach 
Mean difference between 
treatments (LSMD from CFB 
MMRM to Week 32) 
4.2.7 
Sensitivity 
Change from baseline at Week 32 
in KCCQ-TSS (FAS) 
Sensitivity analyses as described for the primary objective 
Mean difference between 
treatments (LSMD from CFB 
MMRM to Week 32) 
4.2.5 


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The number of patients randomised by region, country and site will also be summarised by 
treatment group in the full analysis set. 
4.2.2 
Impact of COVID-19 on study visits 
Impact of the COVID-19 pandemic on study visits will be evaluated by summarising the 
number and percentage of patients at each visit by treatment and contact mode (remote-audio, 
remote-video, home visit, or on-site visit). 
4.2.3 
Demography data and subject characteristics 
Demography and patient characteristics will be summarised by treatment group and for total 
in the FAS. 
Age will be derived from the date of informed consent minus date of birth, rounded down to 
the nearest integer. For patients where date of birth is not recorded, the age as recorded in the 
electronic case report form (eCRF) will be used. 
Medical history will be summarised separately for past and current conditions by MedDRA 
preferred term (PT) within MedDRA system organ class (SOC).   
4.2.4 
Study treatment administration 
Duration of each study IP administration will be summarised by treatment group for the safety 
analysis set and will be calculated in days as: 
Duration of exposure = min (last dose date of IP, date of death)-first dose date of IP + 1. 
Study treatment compliance in percent will be summarised by treatment group for the safety 
analysis set and calculated as:  
Study treatment compliance = (total doses administered/total doses expected) x 100.  
Total doses administered will also be summarised by treatment group for the safety analysis 
set. The total number of doses administered is based on dispensed doses minus returned 
unused doses and will be calculated as:  
Total doses administered = dispensed doses  – returned doses + 1 (excluding records with 
missing returned doses information). 
The total number of doses expected includes all visits with protocol scheduled IP 
administration on or before a patient’s IP discontinuation or treatment completion date and 
will be calculated as: 


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Total doses expected = {min(treatment/study discontinuation, last treatment date) - 
min(treatment start, dispensed doses date, Visit 3) + 1} * 2 + extra dose (where extra dose is 
the number of days between visit 4 and visit 5 as patients took 1 more tablet than other 
periods). 
Patients who didn’t receive a study IP will have zero compliance for this study IP.  
Tabular summaries for the percentage of patients by the reason for discontinuation of 
randomised treatment as well as for withdrawal from the study will be presented by treatment 
to describe why patients discontinue from randomised treatment or withdraw from the study.  
Tabular summaries for the percentage of patients with treatment interruptions and resumptions 
due to sCr elevations will be presented by treatment. 
 
Kaplan-Meier (KM) estimates of the cumulative proportion of patients which have 
discontinued treatment during the treatment period will be calculated and plotted, with the 
number of patients at risk of discontinuation indicated at each specific time point in the plot. 
Time will be defined as number of days from randomisation until discontinuation 
(discontinuation date - randomisation date + 1), or for patients who do not discontinue, from 
randomisation to censoring (censor date - randomisation date + 1). Censor date will be the 
earliest date of date of withdrawal or death when applicable, otherwise the date of the last 
treatment visit (visit 8), whichever occurs first. 
4.2.5 
Primary efficacy endpoint: verinurad + allopurinol vs placebo 
The efficacy variable for the analysis of the primary objective to assess the effect of verinurad 
+ allopurinol compared to placebo on exercise capacity is the absolute change from baseline 
in peak VO2 at Week 32. Patients will be analysed using the FAS according to randomised 
treatment.  
 
The null hypothesis is that there is no difference in mean change from baseline at Week 32 in 
peak VO2 consumption between verinurad + allopurinol and placebo.  The alternative 
hypothesis is that there is a difference in mean change from baseline between verinurad + 
allopurinol and placebo, ie, 
H0: Difference in mean CFB (verinurad + allopurinol vs placebo) = 0 
Ha: Difference in mean CFB (verinurad + allopurinol vs placebo) ≠ 0 
Summary statistics for peak VO2 at each visit and change from baseline VO2 at Week 32 will 
be presented by treatment group and visit.   
Change from baseline in peak VO2 at Week 32 between the treatment groups will be 
compared using ANCOVA analysis, with change from baseline as the dependent variable, 
treatment as the independent variable and baseline peak VO2 included as covariate.  


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Results will be presented in terms of least square means (LSMEANS), treatment differences 
in LSMEANS, 95% confidence intervals (CI), and p-values.  
The analysis will include data from all patients at Week 32 irrespective of whether the patient 
has died, discontinued study drug, or received other medications. Missing peak VO2 values at 
Week 32 will be imputed using a dropout reason-based multiple imputation approach 
(DRMI); missing data in the verinurad + allopurinol group (12 mg verinurad + allopurinol 
treatment arms) due to potentially treatment-related reasons namely following the intercurrent 
events death, withdrawal of consent, loss to follow-up or premature discontinuation of study 
drug due to an AE will be imputed based on the peak VO2 values in the placebo group 
whereas missing values for all other patients will be imputed assuming missing at random 
(MAR), ie, based on the peak VO2 values in their own respective treatment group. Missing 
values at baseline will not be imputed. 
 
One mitigation to minimise the amount of missing data this study is to allow patients to down-
titrate dosage by reversing the assigned steps within treatment group. Patients who cannot 
tolerate the step-1 dose will be discontinued from the study treatment but will still be followed 
for the remainder of the study.   
The normality assumption of the ANCOVA models will be checked graphically by producing 
histograms and normal probability plots of the residuals from the model estimated excluding 
patients with missing peak VO2 values from the analysis. 
Primary peak VO2 analysis under the treatment policy estimand using a dropout reason-based 
multiple imputation (DRMI) approach  
The predictive mean matching imputation algorithm in the SAS PROC MI procedure will be 
used to ensure that imputed values fall within permissible ranges. The algorithm will use 
placebo arm patient data to impute missing values due to potentially treatment-related reasons 
in the verinurad + allopurinol group, and use data within each respective treatment arm to 
impute missing values for all other reasons in remaining patients. The algorithm starts by 
fitting a linear regression model to peak VO2 values at Week 32 in patients without missing 
values, including baseline peak VO2  as covariate. A set of regression coefficients is drawn 
from the posterior predictive distribution of the estimated coefficients. The set of drawn 
coefficients is then used to calculate predicted values for all patients, including those with 
missing values. For each patient with missing values, the algorithm finds a set of K closest 
matching predicted values among patients without missing values. Finally, an imputed 
replacement value is drawn at random from the observed values of these closest matching 
patients. The algorithm is repeated, creating M imputation datasets. A seed of 230185 will be 
used with K=5 closest values and M=100 datasets will be imputed. ANCOVA analyses of 
each of the imputed datasets will be performed as described for the primary analysis in 


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Section 4.2.5. Results from each fitted model will be combined using Rubin's rules 
implemented with the PROC MIANALYZE SAS procedure. 
Sensitivity analyses under the treatment policy estimand using multiple imputation (MI) 
To examine the sensitivity of the results of the primary analysis to departures from the 
underlying assumptions, a sensitivity analysis will be performed. The sensitivity analysis will 
include data from all patients at Week 32 irrespective of whether the patient has discontinued 
study drug or received other medications. The following sensitivity analysis will be 
performed: 
• Missing peak VO2 values at Week 32 will be imputed using multiple imputation as 
described above but all imputations will be based on values in the placebo group. 
 
Supplementary analyses for the primary endpoint 
Two supplementary analyses will be performed to gain additional insights into the 
understanding of the treatment effect on the primary endpoint. All supplementary analyses 
will include data from all patients up to Week 32 irrespective of whether the patient has 
discontinued study drug or received other medications.  
 
• Supplementary analysis 1 – Complete case (CC): Missing peak VO2 values at Week 32 
will not be imputed and patients with missing values will be excluded from the 
analysis.    
• Supplementary analysis 2– Rank ANCOVA: Change from baseline at Week 32 in 
peak VO2 will be transformed into ranks incorporating deaths using fractional rank 
with the mean method to handle ties. 
The rank ANCOVA supplementary analysis 2 is to assess the potential effect of non-normality 
of the primary endpoint and different handling of the intercurrent event death. In this analysis, 
change from baseline at Week 32 in peak VO2 as well as the baseline peak VO2 values will be 
transformed into ranks using fractional ranking with the mean method to handle ties. The 
ANCOVA model will have ranked change from baseline as the dependent variable, treatment 
as the independent variable, ranked baseline values included as covariate. Patients who die 
before Week 32 will be given the worst ranks. Among patients who die, patients will be 
ranked according to the time from randomisation until death, with shorter times given worse 
ranks. Missing peak VO2 data following intercurrent events other than death will be imputed 
using the same multiple imputation procedure as described for the primary analysis, prior to 
ranking, and combined with Rubin’s rules.  


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As the point estimate from the rank ANCOVA analysis lack a clear clinical interpretation, a 
supplementary Hodges–Lehmann (HL) estimate of the median difference between treatment 
groups in change from baseline at Week 32 in peak VO2, together with a 95% CI, will be 
estimated. The HL estimate is the median of all possible pairwise differences between 
verinurad + allopurinol and placebo patients. Deaths will be handled in a similar way as in the 
rank ANCOVA analysis, where change from baseline values for patients who died are set to a 
temporary negative change value lower than all observed change values, with lower negative 
change values given to patients with shorter time from randomisation to death. The estimation 
will be made for each imputed data set, and estimates will be combined using Rubin's rules.  
 
Subgroup analyses for the primary endpoint 
To explore the uniformity of the detected overall treatment effect on the primary efficacy 
endpoint, subgroup analyses will be performed for the following factors: 
• CPET exercise mode (treadmill, cycle ergometer). 
• LVEF at baseline (<50%, 50-60%, >60%) 
• History of atrial fibrillation at baseline (yes, no) 
• Dispensed prophylactic colchicine at randomisation (yes, no) 
For each of the subgroup variables, a separate ANCOVA model will be fitted using the same 
terms as used in the primary analysis but additionally including the subgroup variable and the 
subgroup variable-by-treatment interaction term. Missing values in peak VO2 will be handled 
in the same way as in the primary analysis. Patients with missing values in the subgroup 
variables is expected to be minimal, and will not be imputed but excluded before analysis. 
Similar output will be presented for each subgroup as for the primary analysis. The p-value for 
the interaction term will be presented, when applicable. Resulting treatment differences per 
subgroup in LS means and their 95% CIs will be presented in a forest plot. These subgroup 
analyses are considered as exploratory, and p-values for subgroup estimates and interaction 
terms will therefore not be adjusted for multiplicity but interpreted descriptively.  
 
If any category of a subgroup variable contains less than 20% of the patients, an ANCOVA 
model similar to the primary analysis will instead be fitted excluding patients from that 
category. Descriptive data will be summarised for patients in the excluded category.  
Anchor-based analysis for estimating thresholds for clinically meaningful within-patient 
change 


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Anchor-based analyses will be conducted to derive thresholds for meaningful within-patient 
change from baseline in the primary endpoint, i.e the level of change that an individual patient 
will perceive as meaningful. Anchor-based analysis is used to estimate a threshold for an 
endpoint which translates to a meaningful within-patient change by utilising anchor variables 
as the reference. Missing values will not be imputed, instead only patients with complete data 
at baseline and Week 32 will be included. This analysis will be made using the FAS, using 
data from all treatment arms combined.  
For the primary endpoint, change from baseline at Week 32 in peak VO2, the following anchor 
variables will be used (described in Appendix 8.4): 
• Change from baseline at Week 32 in KCCQ item 1F (limitation in patient’s ability of 
“Hurrying or jogging (as if to catch a bus)”), 
• Change from baseline at Week 32 in KCCQ item 1E (limitation in patient’s ability of 
“Climbing a flight of stairs without stopping”). 
Further details on the anchor analyses are described in Appendix 8.4. 
 
Distribution-based analysis for estimating group-level minimal clinically important difference  
To support the responder analyses by thresholds for clinically meaningful within-patient 
change from baseline on an individual level, distribution-based methods will be used to derive 
a value to be considered a minimal clinically important difference when comparing group-
level averages in the primary endpoint. The analysis of group-level averages is not directly 
related to the analysis of responders and responder thresholds (described above). The group-
level averages (means or medians) represent a mixture of some patients who improved and 
other patients who deteriorated. The anchor-based thresholds for individual-level within-
patient change, which generally only look at one direction of change at a time (improvement 
or deterioration), are expected to be larger than what constitutes the magnitude of minimal 
clinically meaningful difference between group-level averages. Essentially, the two concepts 
are fundamentally different and should not be confused and as described in the FDA public 
workshop guidance from 2018 (FDA 2018), we note the following key discrepancies between 
the concepts of meaningful “within-patient change” and meaningful “between-group mean 
differences”: 
Individual within-patient change is different than between-group mean difference or treatment 
effect. From a regulatory standpoint, FDA is more interested in what constitutes a meaningful 
within-patient change in scores from the patient perspective (i.e., individual patient level). The 
between-group mean difference is the difference between the average score change between 
two study arms that is commonly used to evaluate treatment difference, but it does not address 
the individual within-patient change that is used to evaluate whether a meaningful score 


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change is observed. A treatment effect is different than a meaningful within-patient change. 
The terms minimally clinically important difference (MCID) and minimum important 
difference (MID) do not define meaningful within-patient change if derived from group-level 
data. 
Missing values will not be imputed, instead only patients with complete data at baseline and 
Week 32 will be included. This analysis will be made using the FAS, using data from all 
treatment arms combined. The distribution-based method used will be the one-half SD 
method. The one-half SD method is based on the effect size of a change score. It is suggested 
that 0.5 corresponds to a “medium” effect size, relative to the SD (Cohen 1977). The minimal 
important difference is thus calculated by dividing the SD of the primary endpoint at baseline 
by 2 in all patients combined. In addition, the distribution-based method will be supported by 
anchor-based analyses of meaningful within-patient change described below, using the 
smallest levels of the anchors, to triangulate a single value to be considered the minimal 
clinically important group-level difference. The difference between average change in peak 
VO2 in each treatment group will then be compared to this value. 
4.2.6 
Primary efficacy endpoint: verinurad + allopurinol vs allopurinol  
The efficacy variable for the analysis of the secondary objective to assess the effect of 
verinurad + allopurinol compared to allopurinol monotherapy on exercise capacity is the 
absolute change from baseline in peak VO2 at Week 32. Patients will be analysed using the 
full analysis set according to randomised treatment.  
Mean change from baseline at Week 32 in peak VO2 consumption between verinurad + 
allopurinol and allopurinol monotherapy will be analysed using a similar ANCOVA model as 
outlined for the primary efficacy endpoint in Section 4.2.5.   
The analysis will include data from all patients irrespective of whether the patient has 
discontinued study drug or received other medications. Missing peak VO2 at Week 32 values 
will be handled using the same method as described for the analysis of the primary objective 
in Section 4.2.5.   
The estimate of the treatment effect of verinurad + allopurinol compared to allopurinol 
monotherapy will be extracted from the analysis described for the analysis of the primary 
objective as described in Section 4.2.5.   
All sensitivity, supplementary, and subgroup analyses will be performed as described in 
Section 4.2.5. 
Testing strategy to account for multiplicity considerations is addressed in Section 4.1.2. 


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4.2.7 
Secondary efficacy endpoint 
The efficacy variable for the analysis of the secondary objective to assess the effect of 
verinurad + allopurinol compared to placebo and compared to allopurinol monotherapy on 
KCC-TSS is the absolute change from baseline in KCCQ-TSS to Week 32. The analysis set 
will be the FAS.  
 
Summary statistics for KCCQ-TSS at each visit and change from baseline KCCQ-TSS at 
week 22 and 32 will be presented by treatment group and visit. KCCQ-TSS ePRO 
questionnaire completion status and reasons for not completing will be summarised by 
treatment group and visit. 
Mean change from baseline in KCCQ-TSS to Week 32 between the treatment groups will be 
compared using a mixed model repeated measure (MMRM) model, with change from baseline 
to week 22 and 32 (visit 7 and 8) as the dependent variable, treatment as the independent 
variable, and visit, visit and treatment interaction, and baseline KCCQ-TSS included as 
covariates. Baseline KCCQ-TSS will be the KCCQ-TSS value at Week 0 (Visit 3). Visit will 
be fitted as a categorical variable. An unstructured covariance matrix will be used with 
degrees of freedom calculated using the Kenward-Roger approach. If the estimation does not 
converge, the following covariance structures will be used in order until convergence is met: 
Toeplitz, compound symmetric, variance components. 
Normality assumptions will be checked graphically by producing histograms and normal 
probability plots of the residuals from the model estimated excluding patients with missing 
KCCQ-TSS values from the analysis. 
Results will be presented in terms of least square means (LSMEANS), treatment differences 
in LSMEANS, 95% confidence intervals (CI), and p-values for Week 22 (Visit 7) and Week 
32 (Visit 8).  The results for change from baseline to Week 32 will be of primary interest and 
will be the basis for the confirmatory testing. Graphical displays of KCCQ-TSS LS mean 
change from baseline by treatment and visit will also be presented.    
Testing strategy to account for multiplicity considerations is addressed in Section 4.1.1. 
The analysis will include data from all patients irrespective of whether the patient has 
discontinued study drug or received other medications. Missing KCCQ-TSS values at Week 
22 and Week 32 will be imputed in a sequential manner with previous measures as covariates 
using a DRMI approach as described below. Missing values at baseline will not be imputed.  
Secondary KCCQ-TSS analysis under the treatment policy estimand using a dropout reason-
based multiple imputation (DRMI) approach  


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The imputation procedure for missing KCCQ-TSS values will follow the same procedure as in 
the primary analysis described in Section 4.2.5.  Missing values at Week 22 and Week 32 will 
be imputed in a sequential manner.  Missing Week 22 values will be imputed first and will be 
included as a covariate in imputing Week 32.  
Sensitivity analyses under the treatment policy estimand using multiple imputation (MI) 
To examine the sensitivity of the results of the secondary analysis to departures from the 
underlying assumptions, a sensitivity analysis will be performed. The sensitivity analyses will 
include data from all patients irrespective of whether the patient has discontinued study drug 
or received other medications. The sensitivity analyses will be performed in a similar manner 
as in Section 4.2.5. 
• Missing  KCCQ-TSS values at Week 22 and Week 32 will be imputed using multiple 
imputation as described above but all imputations will be based on values in the 
placebo group. 
Supplementary analyses  
Three supplementary analyses will be performed to gain additional insights into the 
understanding of the treatment effect on the secondary endpoint. The supplementary analyses 
will include data from all patients irrespective of whether the patient has discontinued study 
drug or received other medications. The supplementary analyses will be performed in a 
similar manner as in Section 4.2.5. 
 
• Supplementary analysis 1 - CC: Missing KCCQ-TSS values at Week 22 and Week 32 
will not be imputed and patients with missing values will be excluded from the 
analysis.    
• Supplementary analysis 2 – Rank ANCOVA: Change from baseline at Week 32 in 
KCCQ-TSS will be transformed into ranks using fractional ranking with mean method 
to handle ties.  Week 22 assessments will be disregarded and not used in the analysis. 
Anchor-based analysis for estimating thresholds for clinically meaningful within-patient 
change 
Anchor-based analyses will be conducted to derive thresholds for meaningful within-patient 
change in the secondary endpoint in a similar manner as for the primary endpoint. Missing 
values will not be imputed, instead only patients with complete data at baseline and Week 32 
will be included. This analysis will be made using the FAS population, using data from all 
treatment arms combined.  


Statistical Analysis Plan  
 
 
 
 
 
 
 
 
 
 
 
 
 
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For the secondary endpoint, change from baseline in KCCQ-TSS, the following anchor 
variables will be used (described in Appendix 8.4): 
• Change from baseline at Week 32 in PGIS, 
• The Week 32 assessment of PGIC. 
Further details on the anchor analyses are described in Appendix 8.4. 
Distribution-based analysis for estimating group-level minimal clinically important difference  
As described above, for the primary endpoint, distribution-based methods will be used to 
interpret what constitutes a minimal clinically important difference between group-level 
averages (means or medians). The main distribution-based method used for the secondary 
endpoint will be the standard error of measurement (SEM) method. The SEM will be 
calculated using baseline data as the standard deviation of secondary endpoint at baseline 
multiplied by the square root of 1 minus the reliability (internal consistency) of the KCCQ-
TSS instrument at baseline. A difference of 1 SEM has been suggested as a minimal clinically 
important difference in a score (Wyrwich 1999). In other words: 
1 𝑆𝐸𝑀= 𝑆𝐷∗√(1 −𝑟𝑋), 
where 𝑟𝑋 represents the reliability coefficient of the score, calculated as Cronbach’s alpha, as a 
measure of internal consistency. Cronbach’s alpha will be calculated as: 
𝑟𝑋=
𝑘
𝑘−1 (1 −
∑
𝜎𝑖
2
𝑘
𝑖=1
𝜎𝑋
2
), 
where k equals the number of items in KCCQ-TSS, 𝜎𝑖
2 is the variance in score of item i, and 
𝜎𝑋
2 is the variance of the sum of the scores of all k items, using the numerical values assigned 
to the verbal response options in the KCCQ scoring algorithm in Appendix 9.3.  The SEM 
method will be supplemented by values calculated using the one-half standard deviation 
method described for the primary endpoint, as well as the anchor-based analyses of 
meaningful within-patient change described below in order to triangulate a single value to 
be  considered the minimal clinically important group-level difference in the secondary 
endpoint. The difference between group average change scores by treatment group will then 
be compared to this value. 
Missing values will not be imputed, instead only patients with complete data at baseline and 
Week 32 will be included. This analysis will be made using the FAS, using data from all 
treatment arms combined. 
 


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Statistical A nal ysis Pla n   
 
 
 
 
 
 
 
 
 
 
 
 
 
Astra Ze n eca  
R D E A 3 1 7 0 –  D 5 4 9 6 C 0 0 0 0 5  
 
 
 
 
 
 
 
 
 
 
 
               0 2 J u ne  2 0 2 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 1  of 5 8  
 
 
st u d y treat me nt a n d A Es a n d S A Es ca usi n g disc o nti n uati o n fr o m t he st u d y will als o be 
s u m marise d.   
A Es a n d S A Es will be s u m marise d b y preferre d ter m a n d i n vesti gat or’s ca usalit y assess me nt  
a n d ma xi m u m i nte nsit y. If a patie nt r e p orts m ulti ple occ urre nces of t he sa m e A E wit hi n t he 
sa me st u d y peri o d, t he m a xi m u m i nte nsit y will be ta ke n as t he hi g hest rec or de d ma xi m u m 
i nte nsit y (t he or der bei n g mil d, m o derate, a n d se v ere). 
Ke y patie nt i nf or mati o n will be prese nte d f or pati e nts wit h a d verse e ve nts wit h o utc o me of 
deat h, seri o us a d v erse e v e nts, a n d a d verse e v e nts lea di n g t o disc o nti n uati o n of treat me nt.  
T he latest versi o n of t he Me d D R A dicti o nar y will be use d f or c o di n g of t he A Es.  
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
4. 2. 9. 3  
L a b or at or y d at a  
All pr ot oc ol -s pecifie d c o nti n u o us la b orat or y para meters will be s u m marise d descri pti vel y b y 
a bs ol ute val ue at e ac h visit b y treat me nt gr o u p, t o get her wit h t he c orres p o n di n g c ha n ges  fr o m 
baseli ne. All para meters will be s u m marise d i n SI u nits. Res ults re p orte d b y t he ce ntral 
la b orat or y i n c o n v e nti o nal u nits will be c o n verte d t o SI u nits f or re p orti n g. 
Ke y patie nt i nf or mati o n will be prese nte d f or pati e nts wit h p ost -baseli ne v al ues o u tsi de of 
la b orat or y refere nce ra n g es. 
C CI


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CONFIDENTIAL AND PROPRIETARY 
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QTcF intervals will be summarised by treatment group. This will consist of a summary of the 
number and percentage of patients with a post-baseline QTcF interval greater than 450 ms, 
480 ms, and 500 ms and the number and percentage of patients with an increase from baseline 
in QTcF interval of greater than 30 ms and 60 msec. A shift plot showing maximum post-dose 
QTcF change from baseline (with reference lines at 30 ms and 60 ms) will also be produced. 
4.2.9.6 
Vital signs 
Descriptive statistics and change from baseline for vital signs data will be presented for each 
treatment group by visit. Baseline to maximum post-baseline and baseline to minimum 
postbaseline value shift tables will be generated, as applicable for each parameter and will 
include patients with both baseline and post-baseline data. 
 
 
5 
INDEPENDENT DATA MONITORING COMMITTEE (IDMC) 
ANALYSES 
Refer to the IDMC charter 
 
6 
CHANGES OF ANALYSIS FROM PROTOCOL 
Patients who completed treatment at Week 28 under CSP version 1.0 will have their Week 28 
assessment counted as their Week 32 assessment.  The scheduled Week 28 visit falls within 
the Week 32 assessment window as defined in CSP version 2.0.   
Sensitivity analyses added for the secondary endpoint.  
7 
REFERENCES 
Borlaug et al 2018 
Borlaug BA, Anstrom KJ, Lewis GD, Shah SJ, Levine JA, Koepp GA, et al. Effect of 
inorganic nitrite vs placebo on exercise capacity among patients with heart failure with 
preserved ejection fraction: The INDIE-HFpEF randomised clinical trial. JAMA 
2018;320(17):1764-1773.  
Cohen J 1977 
Cohen J. Statistical power analysis for the behavioral sciences.  Academic Press. 1977 


Statistical Analysis Plan  
 
 
 
 
 
 
 
 
 
 
 
 
 
AstraZeneca 
RDEA3170 – D5496C00005 
 
 
 
 
 
 
 
 
 
 
 
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Coon et al 2018 
Coon CD, Cook KF, Moving from significance to real-world meaning: methods for 
interpreting change in clinical outcome assessment scores.  Qual Life Res 2018;27(1):33-40 
Fletcher et al 1995 
Fletcher GF, Balady G, Froelicher VF, Hartley LH, Haskell WL, Pollock ML. Exercise 
standards. Circulation 1995;91(2):580-615.   
Green et al 2000 
Green CP, Porter CB, Bresnahan DR, Spurtus JA. Development and evaluation of the Kansas 
City Cardiomyopathy Questionnaire: A new health status measure for heart failure. Journal of 
the American College of Cardiology 2000;35(5):1245-1255.   
Levey et al 2009 
Levey AS, Stevens LA, Schmid CH, Zhang Y, Castro AF, Feldman HI, et al. A new equation 
to estimate glomular filtration rate. Annals of Internal Medicine 2009;150(9):604-12 
Redfield et al 2013 
Redfield MM, Chen HH, Borlaug BA, Semigran MJ, Lee KL, Lewis G, et al. Effect of 
phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with 
preserved ejection fraction: a randomised clinical trial. JAMA 2013;309(12):1268-1277.  
FDA 2018 
Patient-focused drug development guidance public workshop: Methods to identify what is 
important to patients & select, develop or modify fit-for-purpose clinical outcomes 
assessments.  Retrieved July 05, 2021, from https://www.fda.gov/media/116277/download 
Wyrwich 1999 
Wyrwich K, Tierney W, Wolinsky F. Further evidence supporting a SEM-based criterion for 
identifying meaningful intra-individual changes in health-related quality of life. J Clin 
Epidemiol 1999;52:861–873. 
8 
APPENDIX 
8.1 
Partial dates for adverse events and prior/concomitant medication 
Dates missing the day, or both the day and month of the year will adhere to the following 
conventions in order to classify treatment-emergent AEs and to classify prior/concomitant 
medications: 
Adverse Events  
• The missing day of onset of an AE will be set to: 


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o the first day of the month that the event occurred if the onset YYYY-MM is 
after the YYYY-MM of the first study treatment. 
o the day of the first study treatment if the onset YYYY-MM is the same as 
YYYY-MM of the first study treatment. 
o the date of informed consent if the onset YYYY-MM is before the YYYY-MM 
of the first treatment. 
• The missing day of resolution of an AE will be set to the last day of the month of the 
occurrence.  If the patient died in the same month, then set the imputed date to the 
death date. 
• If the onset date of an AE is missing both the day and month, the onset date will be set 
to: 
o January 1 of the year of onset if the onset year is after the year of the first study 
treatment. 
o the date of the first treatment if the onset year is the same as the year of the first 
study treatment. 
o the date of informed consent if the onset year is before the year of the first 
study treatment. 
• If the resolution date of an AE is missing both the day and month the date will be set to 
December 31 of the year of occurrence.  If the patient died in the same year, then set 
the imputed date to the death date. 
 
 
Prior/concomitant medication  
• The missing day of start date of a therapy will be set to the first day of the month that 
the event occurred.   
• The missing day of end date of a therapy will be set to the last day of the month of the 
occurrence. 
• If the start date of a therapy is missing both the day and month, the onset date will be 
set to January 1 of the year of onset. 


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• If the end date of a therapy is missing both the day and month, the date will be set to 
December 31 of the year of occurrence. 
• If the start date of a therapy is null and the end date is not a complete date, the start 
date will be set to the date of the first study visit. 
• If the start date of a therapy is null and the end date is a complete date and the end date 
is after the date of the first study visit, the start date will be set to the date of the first 
study visit. Otherwise, the start date will be set to the end date of the therapy. 
• If the end date of a therapy is null and the start date is not a complete date, the end date 
will be set to the study end date. 
• If the end date of a therapy is null and the start date is a complete date and the start 
date is prior to the study end date, the end date will be set to the study end date. 
Otherwise, the end date will be set to the start date of the therapy. 
 
 
 


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8.2 
The KC Cardiomyopathy Questionnaire 
 
The following questions refer to your heart failure and how it may affect your life. 
Please read and complete the following questions.  There are no right or wrong answers.  
Please mark the answer that best applies to you. 
1. Heart failure affects different people in different ways.  Some feel shortness of 
breath while others feel fatigue.  Please indicate how much you are limited by heart 
failure (shortness of breath or fatigue) in your ability to do the following activities 
over the past 2 weeks. 
 
Place an X in one box on each line 
Activity 
Extremely 
Limited 
Quite a bit 
Limited 
Moderately 
Limited 
Slightly 
Limited 
Not at all 
Limited 
Limited for 
other reasons or 
did not do the 
activity 
A. Dressing yourself 
□ 
□ 
□ 
□ 
□ 
□ 
B. Showering/ Bathing 
□ 
□ 
□ 
□ 
□ 
□ 
C. Walking 1 block on 
level ground 
□ 
□ 
□ 
□ 
□ 
□ 
D. Doing yardwork, 
housework or carrying 
groceries 
□ 
□ 
□ 
□ 
□ 
□ 
E. Climbing a flight of 
stairs without stopping 
□ 
□ 
□ 
□ 
□ 
□ 
F. Hurrying or jogging 
(as if to catch a bus) 
□ 
□ 
□ 
□ 
□ 
□ 
 
 
 


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2. Compared with 2 weeks ago, have your symptoms of heart failure (shortness of breath, 
fatigue, or ankle swelling) changed? 
My symptoms of heart failure have become… 
Much 
worse 
Slightly 
worse 
Not changed 
Slightly 
better 
Much 
better 
I’ve had no symptoms 
over the last 2 weeks 
□ 
□ 
□ 
□ 
□ 
□ 
 
3. Over the past 2 weeks, how many times did you have swelling in your feet, ankles or legs 
when you woke up in the morning? 
Every morning 
3 or more times a 
week, but not 
every day 
1-2 times a week 
Less than once a 
week 
Never over the 
past 2 weeks 
□ 
□ 
□ 
□ 
□ 
 
4. Over the past 2 weeks, how much has swelling in your feet, ankles or legs bothered you? 
It has been ... 
Extremely 
Quite a bit 
Moderately 
Slightly 
Not at all 
I’ve had no 
bothersome 
bothersome 
bothersome 
bothersome 
Bothersome 
swelling 
□ 
□ 
□ 
□ 
□ 
□ 
 
5. Over the past 2 weeks, on average, how many times has fatigue limited your ability to do 
what you want? 
All of the 
time 
Several  
times per day 
At least 
once a day 
3 or more times 
per week but not 
every day 
1-2 times 
per week 
Less than once 
a week 
Never over 
the past 2 
weeks 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
 
 
 


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6. Over the past 2 weeks, how much has your fatigue bothered you? 
It has been ... 
Extremely 
Quite a bit 
Moderately 
Slightly 
Not at all 
I’ve had 
bothersome 
bothersome 
bothersome 
bothersome 
bothersome 
no fatigue 
□ 
□ 
□ 
□ 
□ 
□ 
 
 
7. Over the past 2 weeks, on average, how many times has shortness of breath limited your 
ability to do what you wanted? 
All of the 
time 
Several 
times per day 
At least 
once a day 
3 or more times 
per week but not 
every day 
1-2 times 
per week 
Less than 
once a week 
Never over 
the past 2 
weeks 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
 
8. Over the past 2 weeks, how much has your shortness of breath bothered you? 
It has been ... 
Extremely 
Quite a bit 
Moderately 
Slightly 
Not at all 
I’ve had no 
bothersome 
bothersome 
bothersome 
bothersome 
bothersome 
shortness of breath 
□ 
□ 
□ 
□ 
□ 
□ 
 
9. Over the past 2 weeks, on average, how many times have you been forced to sleep sitting 
up in a chair or with at least 3 pillows to prop you up because of shortness of breath? 
Every night 
3 or more times a  
week, but not every day 
1-2 times a week 
Less than once a 
week 
Never over the past 
2 weeks 
□ 
□ 
□ 
□ 
□ 
 
10. Heart failure symptoms can worsen for a number of reasons.  How sure are you 
that you know what to do, or whom to call, if your heart failure gets worse? 
Not at all sure 
Not very sure 
Somewhat sure 
Mostly sure 
Completely sure 
□ 
□ 
□ 
□ 
□ 
 
 
 


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11. How well do you understand what things you are able to do to keep your heart failure 
symptoms from getting worse? (for example, weighing yourself, eating a low salt diet etc.) 
Do not understand at 
all 
Do not understand 
very well 
Somewhat 
understand 
Mostly understand 
Completely 
understand 
□ 
□ 
□ 
□ 
□ 
 
12. Over the past 2 weeks, how much has your heart failure limited your enjoyment of life? 
It has extremely 
limited my 
enjoyment of life 
It has limited my 
enjoyment of life 
quite a bit 
It has  
moderately limited 
my enjoyment of 
life 
It has slightly limited 
my enjoyment of life 
It has not limited 
my enjoyment of 
life at all 
□ 
□ 
□ 
□ 
□ 
 
13. If you had to spend the rest of your life with your heart failure the way it is right now, how 
would you feel about this? 
Not at all 
satisfied 
Mostly dissatisfied 
Somewhat 
satisfied 
Mostly 
satisfied 
Completely satisfied 
□ 
□ 
□ 
□ 
□ 
 
14. Over the past 2 weeks, how often have you felt discouraged or down in the dumps because of 
your heart failure? 
I felt that way 
all of the time 
I felt that way 
most of the time 
I occasionally 
felt that way 
I rarely felt that 
way 
I never felt that 
way 
□ 
□ 
□ 
□ 
□ 
 
 
 


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15. How much does your heart failure affect your lifestyle? Please indicate how your heart 
failure may have limited your participation in the following activities over the past 2 weeks? 
 
 
Place an X in one box on each line 
Activity 
Severely 
Limited 
Limited 
quite a bit  
Moderately 
Limited 
Slightly 
Limited 
Did not 
limit at all 
Does not apply 
or did not do 
for other 
reasons 
A. Hobbies, 
recreational 
activities 
□ 
□ 
□ 
□ 
□ 
□ 
B. Working or 
doing household 
chores 
□ 
□ 
□ 
□ 
□ 
□ 
C. Visiting 
family or friends 
out of  your home 
□ 
□ 
□ 
□ 
□ 
□ 
D. Intimate 
relationship with 
loved ones 
□ 
□ 
□ 
□ 
□ 
□ 
 
 
 
 
 
 


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8.3 
KCCQ Scoring Instructions 
 
The 23 items and corresponding 15 questions are listed in Appendix 8.2. The 6 items in 
question 1 constitute the physical limitations score. Question 2 is for the symptom stability 
domain. Questions 3, 5, 7, and 9 constitute the symptom frequency domain, and questions 4, 
6, and 8 constitute the symptom burden domain. Questions 10 and 11 constitute the self-
efficacy domain. Questions 12, 13, and 14 constitute quality of life domain. Question 15 is for 
the social limitation domain. 
It is not possible to leave individual assessment questions unanswered on the ePRO instrument 
and it is checked at each visit to ensure completion. However, for physical limitation and 
social limitation domain, the response to the items/questions could be “Limited for other 
reasons or did not do” and “Does not apply or did not do for other reasons”, respectively. The 
response represents the scenario that the question doesn’t apply and the score is not calculable 
(NC). For example, if a patient stays at home, the item “Hurrying or jogging (as if to catch a 
bus)” is not answerable, and the corresponding scale score will be not calculable. If at a time 
point, at least 4 items in physical limitation score selected “Limited for other reasons or did 
not do”, or at least 3 items in social limitation selected “Does not apply or did not do for other 
reasons”, the corresponding PLS or social limitation domain at the time point will be 
considered as NC.Each KCCQ item or question is scored by assigning each response an 
ordinal value, beginning with 1 for the response that implies the lowest level of functioning. If 
at least half of the components within the domain are not NC (for physical limitation and 
social limitation), then the domain score can be calculated by summing the responses of the 
questions actually answered within the domain. Scale scores are transformed to a 0 to 100 
range by subtracting the lowest possible scale score, dividing by the range of the scale, and 
multiplying by 100. If the domain has more than one component, the domain score will be the 
mean value of the transformed score over the actually answered components. Higher scores 
represent a better outcome. The scoring algorithm of each domain and summary score is 
described in detail below. 
1. Physical Limitation 
• Code responses to each of Questions 1a-f as follows: 
Extremely limited = 1 
Quite a bit limited = 2 
Moderately limited = 3 
Slightly limited = 4 
Not at all limited = 5 
Limited for other reasons or did not do = <missing value> 
 


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• If at least three of Questions 1a-f are not missing, then compute 
Physical Limitation Score = 100*[mean(Questions 1a-f actually answered) – 1]/4 
2. Symptom Stability 
• Code the response to Question 2 as follows: 
Much worse = 1 
Slightly worse = 2 
Not changed = 3 
Slightly better = 4 
Much better = 5 
I’ve had no symptoms over the last 2 weeks = 3 
 
• Compute 
Symptom Stability Score = 100*[(Question 2) – 1]/4 
 
3. Symptom Frequency 
• Code responses to Questions 3, 5, 7, and 9 as follows: 
Question 3 
Every morning = 1 
3 or more times a week but not every day = 2 
1-2 times a week = 3 
Less than once a week = 4 
Never over the past 2 weeks = 5 
 
Questions 5 and 7 
All of the time = 1 
Several times a day = 2 
At least once a day = 3 
3 or more times a week but not every day = 4 
1-2 times a week = 5 
Less than once a week = 6 
Never over the past 2 weeks = 7 
 
Question 9 
Every night = 1 
3 or more times a week but not every day = 2 
1-2 times a week = 3 
Less than once a week = 4 
Never over the past 2 weeks = 5 


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• Compute: 
S3 = [(Question 3) – 1]/4 
S5 = [(Question 5) – 1]/6 
S7 = [(Question 7) – 1]/6 
S9 = [(Question 9) – 1]/4 
 
Symptom Frequency Score = 100*[mean(S3, S5, S7, and S9)] 
 
 
4. Symptom Burden 
• Code responses to each of Questions 4, 6, and 8 as follows: 
Extremely bothersome = 1 
Quite a bit bothersome = 2 
Moderately bothersome = 3 
Slightly bothersome = 4 
Not at all bothersome = 5 
I’ve had no swelling/fatigue/shortness of breath = 5 
 
• Compute 
Symptom Burden Score = 100*[mean(Questions 4, 6, and 8 ) – 1]/4 
 
5. Total Symptom Score 
• Total Symptom Score = mean of the following available summary scores: 
Symptom Frequency Score  
Symptom Burden Score  
 
6. Self-Efficacy 
• Code responses to Questions 10 and 11 as follows: 
Question 10 
Not at all sure = 1 
Not very sure = 2 
Somewhat sure = 3 


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Mostly sure = 4 
Completely sure = 5 
 
Question 11 
Do not understand at all = 1 
Do not understand very well = 2 
Somewhat understand = 3 
Mostly understand = 4 
Completely understand = 5 
 
• Compute 
Self-Efficacy Score = 100*[mean(Questions 10 and 11) – 1]/4 
 
7. Quality of Life 
• Code responses to Questions 12, 13, and 14 as follows: 
Question 12 
It has extremely limited my enjoyment of life = 1 
It has limited my enjoyment of life quite a bit = 2 
It has moderately limited my enjoyment of life = 3 
It has slightly limited my enjoyment of life = 4 
It has not limited my enjoyment of life at all = 5 
 
Question 13 
Not at all satisfied = 1 
Mostly dissatisfied = 2 
Somewhat satisfied = 3 
Mostly satisfied = 4 
Completely satisfied = 5 
 
Question 14 
I felt that way all of the time = 1 
I felt that way most of the time = 2 
I occasionally felt that way = 3 
I rarely felt that way = 4 
I never felt that way = 5 
 
• Compute 
Quality of Life Score = 100*[mean(Questions 12, 13, and 14) – 1]/4 
 


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8. Social Limitation 
• Code responses to each of Questions 15a-d as follows: 
Severely limited = 1 
Limited quite a bit = 2 
Moderately limited = 3 
Slightly limited = 4 
Did not limit at all = 5 
Does not apply or did not do for other reasons = <missing value> 
 
• If at least two of Questions 15a-d are not missing, then compute 
Social Limitation Score = 100*[mean(Questions 15a-d actually answered) – 1]/4 
 
9. Overall Summary Score 
• Overall Summary Score = mean of the following available summary scores: 
Physical Limitation Score 
Total Symptom Score 
Quality of Life Score 
Social Limitation Score 
 
10. Clinical Summary Score 
• Clinical Summary Score = mean of the available summary scores: 
 
Physical Limitation Score  
Total Symptom Score 
 
 
 


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8.4 
Anchor-based analysis for estimating thresholds for clinically 
meaningful within-patient change 
 
Anchor-based analysis is used to estimate a threshold for an endpoint which constitutes a 
clinically meaningful within-patient change by utilising anchor variables as a reference. 
Anchors will be relevant ePRO responses from the patients measuring the same concept as the 
endpoint in question.  
Note that, in the tables below, the order of responses in the PGIS and PGIC scales have been 
reversed from the way they are presented in the CSP (Very severe to No symptoms instead of 
the other way around). This is only a visual re-ordering so that the order of the (arbitrary) 
numerical coding values assigned to the response levels go from low to high, so that a change 
> 0 signifies "improvement" for all anchors.   
Categorisation of anchors 
The ordinal responses of KCCQ 1F, KCCQ 1E, PGIS, and PGIC at baseline and/or Week 32 
will be assigned numerical values starting at 1 indicating the lowest level 
function/symptom/change. The numerical coding for each variable is shown in Table 5. 
Patients are allowed to respond to KCCQ 1F and KCCQ 1E using the option “Limited for 
other reasons or did not do” (in accordance with the KCCQ-23). Such responses will not be 
coded numerically and those responses are excluded from the anchor-based analyses. 
Table 5      Ordinal response coding of anchor variables at baseline and/or Week 32. 
KCCQ 1F 
KCCQ 1E 
PGIS 
PGIC 
1 
"Extremely limited" 
1 
"Extremely limited" 
1 
“Very severe” 
-3 
"Much worse"  
2 
"Quite a bit limited" 
2 
"Quite a bit limited" 
2 
“Severe” 
-2 
"Moderately worse" 
3 
"Moderately limited" 
3 
"Moderately limited" 
3 
“Moderate” 
-1 
"A little worse" 
4 
"Slightly limited" 
4 
"Slightly limited" 
4 
“Mild” 
0 
"About the same" 
5 
"Not at all limited" 
5 
"Not at all limited" 
5 
“Very mild” 
1 
"A little better" 
  
6 
"No symptoms" 
2 
"Moderately better" 
  
  
  
  
  
  
3 
"Much better" 
Using the coded numerical values variables, change from baseline anchors at Week 32 in 
KCCQ 1F, KCCQ 1E, and PGIS will be calculated as the difference in numerical value (Week 
32 – baseline). Change from baseline anchors in KCCQ 1F and 1E ranges from -4 to 4, while 
change from baseline in PGIS ranges from -5 to 5. For these change anchor variables, negative 
values indicate a decrease from baseline to Week 32 and thus a deterioration of function or 
symptoms. 


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Change from baseline in KCCQ 1F, KCCQ 1E, and PGIS will be categorised into 6-category 
variables as: 
• “Large improvement”: ≥+3 points 
• “Moderate improvement”: +2 points, 
• “Small improvement”: +1 point,  
• “Stable”: 0,  
• “Small deterioration”: -1 points,  
• “Moderate deterioration”: -2 point.  
• “Large deterioration”: ≤-3 points.  
 
PGIC will also be analysed as a 6-category variable with categories defined as: 
• “Large improvement”: +3 points 
• “Moderate improvement”: +2 points, 
• “Small improvement”: +1 point,  
• “Stable”: 0,  
• “Small deterioration”: -1 points,  
• “Moderate deterioration”: -2 point.  
• “Large deterioration”: -3 points.   
 
Correlations between change from baseline in peak VO2 and KCCQ-TSS and their 
corresponding anchors, both uncategorised (raw score) and categorised anchor variables, will 
be estimated using Spearman’s correlation coefficient, recognizing that the anchor variables 
are ordinal variables (even when assigned numerical values for the calculations).  An anchor is 
generally considered adequate if the estimated correlation coefficient greater than or equal to 
0.3 (Coon et al 2018). 
Descriptive statistics (N, mean, SD, median, quartiles, minimum, and maximum) will be 
presented for the primary and secondary endpoint across categories of their corresponding 
categorised anchor variables. To assist the interpretation of the anchor-based analysis, 
empirical cumulative distribution (CDF) function and probability density function (PDF) plots 
of the primary and secondary endpoint by anchor categories will be constructed. The results 
from these analyses will be used in an effort to find agreement across different types of 
evidence for a single threshold which represents clinically meaningful within-patient change 
for each endpoint, for both improvement and deterioration.  
 


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