Conditions: Asymptomatic Hyperuricemia
Keywords: Gout Uric acid Hyperuricemia Asymptomatic gout Febuxostat Dapagliflozin Uric acid transporter 1 (URAT1) Inhibitor Xanthine Oxidase Inhibitor Sodium-glucose cotransporter 2 (SGLT2) Inhibitor
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 36
Healthy volunteers: no

Brief summary:
This is a randomized, placebo controlled, double-blind, 2-way crossover study conducted on asymptomatic hyperuricemic patients. The core study consists of screening period, 2 treatment periods (verinurad + febuxostat + dapagliflozin/placebo) and follow-up visit

Detailed description:
This is a randomized, placebo controlled, double-blind, 2-way crossover study to assess the effect of intensive UA lowering therapy with verinurad (RDEA3170), febuxostat, and dapagliflozin on urinary excretion of UA, in asymptomatic hyperuricemic patients. Thirty-six asymptomatic hyperuricemic patients aged 18 to 65 years (inclusive) will be enrolled into this study at 2 study centers. Twenty-four patients have been enrolled and completed the study to date. Due to inadequate urine sampling, 12 additional patients were included to ensure an adequate sample size (at least 20 evaluable patients) to evaluate the effects of intensive UA lowering with verinurad, febuxostat and dapagliflozin on urinary excretion of UA. With 24 completers available during the interim analysis, this will provide for a total sample size of 36 evaluable patients.

Before any study specific assessments are performed, potential patients must provide informed consent. Each patient will undergo the below mentioned visits:

* A Screening period of maximum 28 days;
* Two treatment periods during which patients will be resident in the Clinical Unit from Day -2 to Day 1 and from Day 6 to Day 8; and
* A Follow-up Visit within 14 to 28 days after the first administration of Investigational Medicinal Product (IMP) in Treatment Period 2.

On Day -2 of Treatment period 1, patient will be randomized (1:1) to 1 of 2 treatment sequences (AB or BA). Each randomized patient will receive orally once daily fixed dose of the below mentioned 2 treatments for 7 consecutive days (1 treatment per treatment period).

* Treatment A: Verinurad + febuxostat + dapagliflozin
* Treatment B: Verinurad + febuxostat + placebo For each treatment period, baseline measurements will be performed. On Day 1, after all dosing and all assessments have been performed, patients will receive instruction to administer the IMP at home once daily in the morning from Day 2 to Day 6 and the IMP will be dispensed for home dosing. Patients will return to the Clinical Unit on Day 6 and will be residential in the Clinical Unit from Day 6 to Day 8.

Treatment Period 1 and Treatment Period 2 will be separated by a washout period of 7 to 21 days.

Patients will return to the Clinical Unit for a Follow-up Visit, 14 to 28 days after Day 1 of Treatment Period 2.

Arms:
arm 1: Randomized patients will receive orally once daily fixed dose of the following drugs:

verinurad + febuxostat + dapagliflozin; arm 2: Randomized patients will receive orally once daily fixed dose of the following drugs:

verinurad + febuxostat + dapagliflozin matched placebo

Interventions: intervention 1: Verinurad intervention 2: Febuxostat intervention 3: Dapagliflozin intervention 4: Dapagliflozin matched placebo
Intervention descriptions: intervention 1: Randomized patients will receive orally once daily fixed dose of verinurad in 2 treatment sequences AB or BA for 7 consecutive days. Treatment A: verinurad + febuxostat + dapagliflozin; Treatment B: verinurad + febuxostat + placebo intervention 2: Randomized patients will receive orally once daily fixed dose of febuxostat in 2 treatment sequences AB or BA for 7 consecutive days. Treatment A: verinurad + febuxostat + dapagliflozin; Treatment B: verinurad + febuxostat + placebo intervention 3: Randomized patients will receive orally once daily fixed dose of dapagliflozin in 2 treatment sequences AB or BA for 7 consecutive days. Treatment A: verinurad + febuxostat + dapagliflozin; Treatment B: verinurad + febuxostat + placebo intervention 4: Randomized patients will receive orally once daily fixed dose of dapagliflozin matched placebo in 2 treatment sequences AB or BA for 7 consecutive days. Treatment A: verinurad + febuxostat + dapagliflozin; Treatment B: verinurad + febuxostat + placebo

Protocol document:
Prot_001.pdf: 
AstraZeneca
Clinical Study Protocol
Study Code: D5495C00001
Revised According to Protocol Amendment No. 3
Drug Substance: RDEA3170, Febuxostat, Dapagliflozin
CONFIDENTIAL
Final 1.0
Page 1 of 115
10 May 2018
Clinical Study Protocol
Quantifying Uric Acid Excretion with RDEA3170, Febuxostat and 
Dapagliflozin 
PAREXEL Study No.:
Sponsor Study Code:
D5495C00001 
Study Type: 
Drug-Drug Interaction
Victim Drugs:
RDEA3170 and Febuxostat 
Perpetrator Drug:
Dapagliflozin
Pharmacological Class: 
RDEA3170:  URAT1 Inhibitor 
Febuxostat:  Xanthine Oxidase Inhibitor;
Dapagliflozin: SGLT2 Inhibitor  
Development Phase:
Phase 2
Sponsor:
AstraZeneca AB
151 85 Södertälje 
Sweden
Study Centers: 
PAREXEL Early Phase Clinical Unit Baltimore
3001 S. Hanover St. 
Baltimore, MD 21225, United States of America
PAREXEL Early Phase Clinical Unit-Los Angeles
1560 Chevy Chase Drive, Suite 140 
Glendale, CA 91206, United States of America
Original Protocol: 
Final 1.0, 05 September 2017 
Amendment No. 1
Final 1.0, 02 October 2017 
Amendment No. 2
Final 1.0, 02 May 2018 
Amendment No. 3
Final 1.0, 10 May 2018 
This clinical study will be conducted according to the protocol and in compliance with Good 
Clinical Practice, with the Declaration of Helsinki and with other applicable regulatory 
requirements.
Confidentiality Statement
This confidential document is the property of AstraZeneca.  No unpublished information 
contained herein may be disclosed without prior written approval from AstraZeneca.  Access to 
this document must be restricted to relevant parties.
CCI


AstraZeneca
Clinical Study Protocol
Study Code: D5495C00001
Revised According to Protocol Amendment No. 3
Drug Substance: RDEA3170, Febuxostat, Dapagliflozin
CONFIDENTIAL
Final 1.0
Page 2 of 115
10 May 2018
PROTOCOL AMENDMENTS 
Clinical Study Protocol Amendment No. 1, Final 1.0, dated 02 October 2017 
The following changes were made to the original Clinical Study Protocol, Final 1.0, dated 
05 September 2017. 
1.
Administrative details were updated to include laboratories for exploratory samples and 
pharmacogenetic samples.
2.
Time points were clarified for controlled meals and fluid intake, and safety procedures (vital 
signs, 12-lead ECGs and safety laboratory investigations) in the Schedule of Assessments 
(Table 1).  Restrictions regarding meals and fluid intake were aligned accordingly.
3.
Intervals of urine collections were clarified in the footnotes of the Schedule of Assessments 
(Table 1).
4.
The randomization day was changed from Day -2 (Treatment Period 1) to Day -1 (Treatment 
Period 1) 
5.
The definition and confirmation of post-menopausal status were clarified.  Where there is 
uncertainty regarding post-menopausal status, an option was added
to include a 
post-menopausal female after discussion between the PI and the Medical Monitor.
6.
It was added that male patients participating in this study are not required to apply 
contraception.
7.
For fasting plasma glucose, a separate blood sample was added and the total blood volume to 
be collected during the study per patient was updated. 
8.
The format of unique enrolment numbers was adjusted to differentiate between the Baltimore 
and Los Angeles study sites.
9.
ECGs in this study will be recorded using Cardiosoft in 
10. It was included that a Statistical Analysis Plan (SAP) will be written for this study.
11. It was clarified that other study team members may perform certain procedures as designee 
of the PI.
12. Typographical errors were corrected.
CCI


AstraZeneca
Clinical Study Protocol
Study Code: D5495C00001
Revised According to Protocol Amendment No. 3
Drug Substance: RDEA3170, Febuxostat, Dapagliflozin
CONFIDENTIAL
Final 1.0
Page 3 of 115
10 May 2018
Clinical Study Protocol Amendment No. 2, Final 1.0, dated 02 May 2018 
The changes listed below were made to the Clinical Study Protocol Amendment No. 1, Final 1.0, 
dated 02 October 2017, to include 8 additional patients.
During the Blind Data Review Meeting (BDRM), the unblinded data were reviewed and the 
following patients from site 
 were identified as invalid for purposes of analysis of the 
primary endpoint: 
  Based on these results, it was decided 
to include an additional 8 patients to ensure an adequate sample size (at least 20 evaluable 
patients) to evaluate the effects of intensive uric acid (UA) lowering with RDEA3170, febuxostat 
and dapagliflozin on urinary excretion of UA.   
1.
The protocol was updated to include 8 additional patients to ensure a minimum of 
20 evaluable patients
with complete data as per protocol are included in the 
pharmacodynamics analyses set for statistical analyses, see Section 7.1, Section 8.9.2 and 
Section 11.4.
2.
The Sponsor’s Biostatistician has been changed from 
 to 
see Section 4 and Section 16.2.
3.
Inclusion criterion no. 4 and exclusion criterion no. 19 were updated to clarify that the 
criteria is only applicable to assessments performed at the Screening Visit and Day -2, not at 
each admission to the Clinical Unit, see Section 7.5.1 and Section 7.5.2.
4.
The protocol has been updated to clarify that the peak UA excretion will be the maximum 
UA excreted as measured in mg, in the hourly urine samples during the first 8 hours at 
baseline (Day -1) and on Day 7 during Treatment Period 1 and Treatment Period 2., see 
Section 6.1.1 and Section 11.9.1.
5.
General inconsistencies and typographical errors have been corrected throughout the 
protocol. 
6.
The synopsis has been updated to reflect changes made in the protocol, see PROTOCOL 
SYNOPSIS.
PPD
PPD
PPD
PPD


AstraZeneca
Clinical Study Protocol
Study Code: D5495C00001
Revised According to Protocol Amendment No. 3
Drug Substance: RDEA3170, Febuxostat, Dapagliflozin
CONFIDENTIAL
Final 1.0
Page 4 of 115
10 May 2018
Clinical Study Protocol Amendment No. 3, Final 1.0, dated 10 May 2018
Based on the emerging data, it was decided to adjust the number of additional patients from 8 to 
12 to ensure an adequate sample size to evaluate the effects of intensive UA lowering therapy 
with RDEA3170, febuxostat and dapagliflozin on urinary excretion of UA.
1.
The protocol was updated to include 12 additional patients to ensure a minimum of 
20 evaluable patients with complete data as per protocol are included in the 
pharmacodynamics analyses set for statistical analyses, see Section 7.1, Section 8.9.2 and 
Section 11.4.
2.
The synopsis has been updated to reflect changes made in the protocol, see PROTOCOL 
SYNOPSIS.


AstraZeneca
Clinical Study Protocol
Study Code: D5495C00001
Revised According to Protocol Amendment No. 3
Drug Substance: RDEA3170, Febuxostat, Dapagliflozin
CONFIDENTIAL
Final 1.0
Page 5 of 115
10 May 2018
PROTOCOL SYNOPSIS
Title of the Study
Quantifying Uric Acid Excretion with RDEA3170, Febuxostat and Dapagliflozin
Principal Investigator (PI)
Study Centers
This study will be conducted at 2 study centers.
PAREXEL Early Phase Clinical Unit-Los Angeles 
 
1560 Chevy Chase Drive, Suite 140 
 
Glendale, CA 91206  
United States of America (USA)
PAREXEL Early Phase Clinical Unit Baltimore  
Harbor Hospital  
3001 South Hanover St. 
 
Baltimore, MD 21225 
USA
Study Rationale
RDEA3170 is a novel uric acid transporter 1 (URAT1) inhibitor in Phase 2 development.  RDEA3170 combined
with febuxostat has been proven to be a safe and effective therapy to lower serum uric acid (sUA) and manage 
patients with recurrent gout and hyperuricemia (in Japan) in Phase 2 studies.  Inhibition of URAT1 results in 
increased renal excretion of uric acid (UA).  In order to avoid high peak excretion rates, RDEA3170 should be used 
in combination with a xanthine oxidase inhibitor (XOI), such as febuxostat, as RDEA3170 may deliver the most 
potent UA lowering effect via renal excretion reported for any treatment.
Dapagliflozin is a stable, reversible, highly selective and orally active inhibitor of human renal sodium-glucose 
cotransporter 2 (SGLT2), the major transporter responsible for renal glucose reabsorption in the kidney.  Results 
from non-clinical- and clinical studies have shown that dapagliflozin can be used to promote urinary excretion of 
glucose as a safe and effective method of reducing blood glucose levels.  
Given the recent data from the EMPA-REG trial, SGLT2 inhibitors are expected to be commonly used in the 
proposed target patient population for the RDEA3170 + febuxostat combination (chronic kidney disease and/or heart 
failure).  Thus, the objective of the study is to explore whether intensive UA lowering therapy with febuxostat and 
RDEA3170 can be safely combined with dapagliflozin, and if the sUA lowering effects would be additive.
Number of Patients Planned
Thirty-six patients will be randomized to ensure at least 20 evaluable patients at the end of the last treatment period.
Study Period
Estimated date of first patient enrolled:
October 2017
Estimated date of last patient completed:
July 2018
Study Objectives
Primary Objective:
x
To assess the effects of intensive UA lowering therapy with RDEA3170, febuxostat and dapagliflozin on 
urinary excretion of UA.
Primary Objective Outcome Measure
x
Peak UA excretion during the first 8 hours (maximum UA excreted as measured in mg, in an interval out of the 
first 8 hours) on Day 7 of treatment (Day 1 is the first day of treatment).
Secondary Objectives:
x
To assess the effects of intensive UA lowering therapy with RDEA3170, febuxostat and dapagliflozin on sUA 
levels.
PPD


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Clinical Study Protocol
Study Code: D5495C00001
Revised According to Protocol Amendment No. 3
Drug Substance: RDEA3170, Febuxostat, Dapagliflozin
CONFIDENTIAL
Final 1.0
Page 6 of 115
10 May 2018
x
To assess the pharmacokinetics (PK) of RDEA3170 and its main metabolites (M1 and M8), febuxostat and 
dapagliflozin in this patient population.
x
To assess the renal and general safety and tolerability of intensive UA lowering therapy with RDEA3170, 
febuxostat and dapagliflozin.
Secondary Objectives Outcome Measures
x
Serum UA levels after 7 days of treatment. 
x
RDEA3170, M1, M8, febuxostat and dapagliflozin plasma concentrations and PK parameters.
x
Changes in clinical laboratory parameters, including assessment of serum and urinary levels of creatinine and
cystatin C, blood urea nitrogen, serum and urinary electrolytes, urinary pH.  Changes in vital signs.  Rates of 
adverse events (AEs) and serious adverse events (SAEs).
Study Design
This is a randomized, placebo controlled, double-blind, 2-way crossover study to assess the effect of intensive UA 
lowering therapy with RDEA3170, febuxostat, and dapagliflozin on urinary excretion of UA, in asymptomatic 
hyperuricemic patients.  Thirty-six, asymptomatic hyperuricemic patients aged 18 to 65 years (inclusive) will be 
enrolled into this study at 2 study centers.  Twenty-four patients have been enrolled and completed the study to date.  
Due to inadequate urine sampling, it was decided to include 12 additional patients to ensure an adequate sample size
(at least 20 evaluable patients) to evaluate the effects of intensive UA lowering with RDEA3170, febuxostat and 
dapagliflozin on urinary excretion of UA.  Each patient will receive the 2 treatments listed below for 7 consecutive 
days (1 treatment per treatment period).
x
Treatment A: 
9 mg RDEA3170 + 80 mg febuxostat + 10 mg dapagliflozin
x
Treatment B: 
9 mg RDEA3170 + 80 mg febuxostat + placebo
The study will comprise of: 
x
A screening period of maximum 28 days;
x
Two treatment periods during which patients will be resident in the Clinical Unit from Day -2 to Day 1 and 
from Day 6 to Day 8; and
x
A Follow-up Visit within 14 to 28 days after the first administration of Investigational Medicinal Product (IMP) 
in Treatment Period 2.
Before any study specific assessments are performed, potential patients must provide informed consent.  Patients 
that provided informed consent will attend the Screening Visits within 28 days before receiving the first dose of 
IMP. Patients will return to the Clinical Unit on Day -2 of Treatment Period 1 and will be randomized (1:1) to 1 of 
2 treatment sequences (AB or BA) before the start of urine collection on Day -1 of Treatment Period 1.
For each treatment period, baseline measurements will be performed.  Patients receive the IMP for 7 consecutive 
days (Day 1 to Day 7).  Patients will be residential in the Clinical Unit from Day -2 to Day 1.  On Day 1, after all 
dosing and all assessments have been performed, patients will receive instruction to administer the IMP at home 
CCI


AstraZeneca
Clinical Study Protocol
Study Code: D5495C00001
Revised According to Protocol Amendment No. 3
Drug Substance: RDEA3170, Febuxostat, Dapagliflozin
CONFIDENTIAL
Final 1.0
Page 7 of 115
10 May 2018
once daily in the morning from Day 2 to Day 6 and the IMP will be dispensed for home dosing.  Patients will return 
to the Clinical Unit on Day 6 and will be residential in the Clinical Unit from Day 6 to Day 8. 
Treatment Period 1 and Treatment Period 2 will be separated by a washout period of 7 to 21 days.
Patients will return to the Clinical Unit for a Follow-up Visit, 14 to 28 days after Day 1 of Treatment Period 2.
Expected Duration of the Study
Each patient will be involved in the study for 8 to 11 weeks. 
Targeted Study Population
This study will be conducted in male and female asymptomatic hyperuricemic patients aged 18 to 65 years.
Investigational Medicinal Products 
Investigational product
Dosage form and strength
Provider
RDEA3170
9 mg capsules for oral 
administration
AstraZeneca
Febuxostat
80 mg tablets for oral 
administration
PAREXEL
Dapagliflozin
10 mg tablets for oral 
administration
AstraZeneca
Dapagliflozin matched placebo
Placebo
AstraZeneca
Outcome Endpoints
Pharmacodynamic Endpoints:
Where possible, the following pharmacodynamic (PD) variables will be assessed.
x
Uric acid excretion in urine per hour (UUA)
x
Serum UA levels on Day 7 (after 7 days of treatment).
Pharmacokinetic Endpoints:
Where possible, the following PK parameters will be calculated for RDEA3170, M1, M8 febuxostat and 
dapagliflozin using plasma concentrations.
x
Primary PK parameters: $8&ĲAUClast, Cmax
x
Secondary PK parameters: tmax, tlast
Additional PK parameters may be determined where appropriate.
Safety and Tolerability Endpoints:
Safety and tolerability variables will include: 
x
Adverse events
x
Events of diabetic ketoacidosis
x
Vital signs (systolic and diastolic blood pressure [BP], pulse rate)
x
Electrocardiograms (ECGs)
x
Physical examination
x
Weight
x
Laboratory assessments (hematology, clinical chemistry and urinalysis) 
Viral serology and drugs of abuse and alcohol will be assessed for eligibility.  Follicle-stimulating hormone (FSH) 
(post-menopausal females only), pregnancy testing (females only) and use of concomitant medication will also be 
assessed and reported.
. 
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Clinical Study Protocol
Study Code: D5495C00001
Revised According to Protocol Amendment No. 3
Drug Substance: RDEA3170, Febuxostat, Dapagliflozin
CONFIDENTIAL
Final 1.0
Page 8 of 115
10 May 2018
x
Statistical Methods
Presentation and Analysis of Pharmacodynamic Data:
A listing of PD blood sample and urine collection times, as well as derived sampling time deviations will be 
provided.  Serum and urine concentrations will be summarized by treatment using appropriate descriptive statistics.  
Where possible, the following descriptive statistics will be presented: n, geometric mean, geometric coefficient of 
variation (CV), arithmetic mean, arithmetic standard deviation (SD), median, minimum and maximum.
Analysis of the primary variable, maximum UUA, as well as the secondary variable sUA at 7 days will be done.
Analysis of the primary variable and secondary variable sUA will be done on log-transformed values, looking at 
changes at day 7 of treatment (Day 7) from maximum baseline excretion.  A mixed effects Analysis of Variance 
(ANOVA) model, correcting for treatment (dapagliflozin/placebo) and sequence (dapagliflozin-placebo or 
placebo-dapagliflozin) as fixed effects as well as patient within sequence as random effect, will be used.
No adjustment for multiplicity will be done for secondary variables, due to the explorative nature of the study.
In these analyses, an adjustment for multiple comparisons will not be considered.
For all ANOVA models described above the geometric mean ratios, their 95% confidence interval (CI), along with 
the ratios of individual patient values will be plotted to visualize the treatment comparisons.
Presentation and Analysis of Pharmacokinetic Data:
A listing of PK blood sample collection times, as well as derived sampling time deviations will be provided.  Plasma 
concentrations and PK parameters will be summarized by treatment and analyte using appropriate descriptive 
statistics.  Where possible, the following descriptive statistics will be presented: n, geometric mean, geometric CV, 
geometric +SD, geometric –SD arithmetic mean, arithmetic SD, median, minimum and maximum.  For tmax and 
tlast, only n, median, minimum and maximum will be presented.
Plasma concentrations of RDEA3170, M1, M8, febuxostat and dapagliflozin will be presented descriptively by 
analyte, study day/treatment and time point, using both summary tables and figures as well as individual plots of 
plasma concentration vs. time and day per IMP.  Derived PK parameters will be presented descriptively by IMP and 
study day/treatment. 
To assess the potential drug-drug interaction between RDEA3170 and febuxostat given with and without 
dapagliflozin, the natural log-transformed PK parameters Cmax, $8&Ĳ and AUClast of RDEA3170, M1, M8 and 
febuxostat will be separately analyzed using a mixed effects ANOVA model, fitting a fixed effect for treatment and 
random effect for patient.  
For all ANOVA models described above the geometric mean ratios, their 95% CI, along with the ratios of individual 
patient values will be plotted to visualize the treatment comparisons. 
Presentation and Analysis of Safety and Eligibility Data:
Safety data (scheduled and unscheduled) will be presented in the data listings.  Continuous variables will be 
summarized using descriptive statistics (n, mean, SD, minimum, median, maximum) by treatment.  Categorical 
variables will be summarized in frequency tables (frequency and proportion) by treatment.  The analysis of the 
safety variables will be based on the safety analysis set.
Tabulations and listings of data for vital signs, clinical laboratory tests and ECGs, will be presented.  Any new or 
aggravated clinically relevant abnormal medical physical examination finding compared to the baseline assessment 
will be reported as an AE.  Data will be summarized for the observed values at each scheduled assessment, together 
with the corresponding changes (and/or percentage change) from the baseline when baseline is defined.  Clinical 
laboratory data will be reported in the units provided by the clinical laboratory and in Système International units in 
the CSR.
Out-of-range values for safety laboratory, vital signs and ECG will be flagged in individual listings as well as 
summarized descriptively using agreed standard reference ranges and/or extended reference ranges (e.g., AZ, 
program or laboratory ranges).
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Clinical Study Protocol
Study Code: D5495C00001
Revised According to Protocol Amendment No. 3
Drug Substance: RDEA3170, Febuxostat, Dapagliflozin
CONFIDENTIAL
Final 1.0
Page 9 of 115
10 May 2018
Determination of Sample Size
Basis for this sample size calculation is the study RDEA3170-204.  Baseline (as well as Day 7) UUA data are highly 
skewed and hence log-transformation is applied. 
Based on the RDEA3170-204 study, we assume that the within patient SD for the between treatment difference in 
UUA (comparing within patient changes on log-scale from baseline to Day 7 for the respective treatments) is 0.32. 
A study with 10 patients completing each sequence of treatments (dapagliflozin-placebo or placebo-dapagliflozin)
will then (under the assumed SD above) estimate the true, unknown, mean ratio for dapagliflozin/placebo with a 
precision of 16.6% as half-width of the 95% CI. 
Thus, 24 patients in total were randomized to ensure 20 (2*10) patients complete the study (12 randomized patients 
per sequence). 
Twenty patients completing their treatment sequence, is based on previous experience of studies investigating 
relative bioavailability in presence of concomitant treatments, seen as a suitable sample size.  As based on previous 
experience of studies investigating relative bioavailability in presence of concomitant treatments, 12 patients
completing each treatment sequence is considered a suitable sample size.
Interim Analysis of Sample Size and Power of the Statistical Test
During the Blind Data Review Meeting (BDRM), the unblinded data were reviewed and 
 patients from site 
 
were identified as invalid for purposes of analysis of the primary endpoint. 
Based on these results, it was decided to include an additional 12 patients to ensure an adequate sample size to 
evaluate the effects of intensive UA lowering with RDEA3170, febuxostat and dapagliflozin on urinary excretion of 
UA.  This will allow for 36 evaluable patients overall; of these it is expected that at least 20 patients will provide 
evaluable data for the primary endpoint. 
CCI
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P
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Clinical Study Protocol
Study Code: D5495C00001
Revised According to Protocol Amendment No. 3
Drug Substance: RDEA3170, Febuxostat, Dapagliflozin
CONFIDENTIAL
Final 1.0
Page 10 of 115
10 May 2018
1.
TABLE OF CONTENTS
PROTOCOL AMENDMENTS ...................................................................................................... 2 
Clinical Study Protocol Amendment No. 1, Final 1.0, dated 02 October 2017.......................... 2 
Clinical Study Protocol Amendment No. 2, Final 1.0, dated 02 May 2018 ............................... 3 
Clinical Study Protocol Amendment No. 3, Final 1.0, dated 10 May 2018 ............................... 4 
PROTOCOL SYNOPSIS ............................................................................................................... 5 
1. 
TABLE OF CONTENTS ...................................................................................................... 10 
1.1. 
List of Tables.................................................................................................................. 17 
1.2. 
List of Figures ................................................................................................................ 17 
2. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS.......................................... 18 
3. 
ETHICAL AND REGULATORY REQUIREMENTS ........................................................ 22 
3.1. 
Ethical Conduct of the Study ......................................................................................... 22 
3.2. 
Patient Data Protection................................................................................................... 22 
3.3. 
Ethics and Regulatory Review ....................................................................................... 22 
3.4. 
Insurance ........................................................................................................................ 23 
3.5. 
Informed Consent........................................................................................................... 23 
3.6. 
Changes to the Protocol and Informed Consent Document ........................................... 23 
4. 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE............................ 24 
5. 
INTRODUCTION................................................................................................................. 28 
5.1. 
Background Information ................................................................................................ 28 
5.2. 
RDEA3170..................................................................................................................... 30 
5.2.1. 
Pre-Clinical Findings .............................................................................................. 30 
5.2.2. 
Clinical Studies....................................................................................................... 30 
5.2.2.1. 
Safety Results .................................................................................................. 30 
5.2.2.2. 
Clinical Efficacy.............................................................................................. 31 
5.2.2.3. 
Pharmacokinetics............................................................................................. 32 
5.3. 
Febuxostat ...................................................................................................................... 32 


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Drug Substance: RDEA3170, Febuxostat, Dapagliflozin
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5.3.1. 
Safety Clinical Trials Experience ........................................................................... 32 
5.3.2. 
Pharmacodynamics ................................................................................................. 33 
5.3.3. 
Pharmacokinetics .................................................................................................... 33 
5.4. 
Dapagliflozin.................................................................................................................. 34 
5.4.1. 
Safety Clinical Trials Experience ........................................................................... 34 
5.4.2. 
Pharmacodynamics ................................................................................................. 34 
5.4.3. 
Pharmacokinetics .................................................................................................... 34 
5.5. 
Study Rationale .............................................................................................................. 35 
5.6. 
Dose Rationale ............................................................................................................... 35 
5.7. 
Choice of Study Population, Risk-Benefit Assessment and Risk Mitigation ................ 36 
6. 
STUDY OBJECTIVES ......................................................................................................... 39 
6.1. 
Primary Objective .......................................................................................................... 39 
6.1.1. 
Primary Objective Outcome Measure:.................................................................... 39 
6.2. 
Secondary Objectives..................................................................................................... 39 
6.2.1. 
Secondary Objective Outcome Measures:.............................................................. 39 
6.3. 
Exploratory Objectives................................................................................................... 39 
6.3.1. 
Exploratory Objectives Outcome Measures: .......................................................... 40 
7. 
OVERALL DESIGN AND PLAN OF THE STUDY........................................................... 41 
7.1. 
Overall Study Design ..................................................................................................... 41 
7.1.1. 
End of Study ........................................................................................................... 42 
7.1.2. 
Interim Analyses ..................................................................................................... 42 
7.1.3. 
Expected Duration of the Study.............................................................................. 42 
7.2. 
Study Flow Chart and Schedule of Assessments ........................................................... 42 
7.3. 
Order of Assessments..................................................................................................... 46 
7.4. 
Restrictions During the Study ........................................................................................ 46 
7.4.1. 
Reproductive Restrictions....................................................................................... 47 
7.4.1.1. 
Women of Non-Childbearing Potential........................................................... 47 
7.4.1.2. 
Women of Childbearing Potential ................................................................... 48 


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Clinical Study Protocol
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7.4.1.3. 
Male Patients ................................................................................................... 48 
7.5. 
Selection of Study Population........................................................................................ 49 
7.5.1. 
Inclusion Criteria .................................................................................................... 49 
7.5.2. 
Exclusion Criteria ................................................................................................... 50 
7.5.3. 
Discontinuation of Investigational Medicinal Product and Withdrawal from the 
Study....................................................................................................................... 52 
7.5.4. 
Premature Termination of the Study....................................................................... 53 
7.5.5. 
Replacement of Patients.......................................................................................... 54 
7.5.6. 
Total Blood Volume ............................................................................................... 54 
8. 
TREATMENTS..................................................................................................................... 55 
8.1. 
Identity of the Investigational Medicinal Products ........................................................ 55 
8.2. 
Supply of Investigational Medicinal Product................................................................. 55 
8.3. 
Storage and Handling Procedures .................................................................................. 55 
8.4. 
Labeling.......................................................................................................................... 56 
8.5. 
Drug Accountability, Dispensing and Destruction ........................................................ 56 
8.6. 
Dose and Treatment Regimens ...................................................................................... 56 
8.7. 
Treatment Compliance ................................................................................................... 57 
8.8. 
Concomitant Medication................................................................................................ 57 
8.8.1. 
Concomitant and Post-study Treatments ................................................................ 57 
8.8.2. 
Prior and Concomitant Medication......................................................................... 58 
8.9. 
Randomization ............................................................................................................... 58 
8.9.1. 
Patient Enrolment and Randomization ................................................................... 58 
8.9.2. 
Procedures for Randomization................................................................................ 59 
8.9.3. 
Procedures for Handling Incorrectly Randomized Patients.................................... 59 
8.10. Blinding.......................................................................................................................... 59 
8.11. Methods for Ensuring Blinding...................................................................................... 59 
8.12. Methods for Unblinding the Study................................................................................. 60 
9. 
MEASUREMENTS AND METHODS OF ASSESSMENTS.............................................. 61 


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9.1. 
Appropriateness of Measurements................................................................................. 61 
9.2. 
Pharmacodynamics......................................................................................................... 61 
9.2.1. 
Sample Collection and Handling ............................................................................ 61 
9.2.2. 
Pharmacodynamic Assays ...................................................................................... 61 
9.3. 
Pharmacokinetics ........................................................................................................... 61 
9.3.1. 
Sample Collection and Handling ............................................................................ 61 
9.3.2. 
Pharmacokinetic Drug Assays ................................................................................ 62 
9.4. 
Safety and Eligibility Measurements ............................................................................. 62 
9.4.1. 
Adverse Events ....................................................................................................... 62 
9.4.2. 
Events of Diabetic Ketoacidosis............................................................................. 62 
9.4.3. 
Vital Signs............................................................................................................... 63 
9.4.4. 
Electrocardiograms ................................................................................................. 63 
9.4.4.1. 
Resting 12-lead Electrocardiogram ................................................................. 63 
9.4.5. 
Physical Examination.............................................................................................. 63 
9.4.6. 
Laboratory Assessments ......................................................................................... 64 
9.4.6.1. 
Hematology ..................................................................................................... 64 
9.4.6.2. 
Clinical Chemistry........................................................................................... 64 
9.4.6.3. 
Urinalysis by Dipstick ..................................................................................... 65 
9.4.6.4. 
Urinalysis for Urine Collection Interval.......................................................... 65 
9.4.6.5. 
Pregnancy Testing ........................................................................................... 65 
9.4.6.6. 
Viral Serology.................................................................................................. 65 
9.4.6.7. 
Drugs of Abuse and Alcohol ........................................................................... 65 
9.4.7. 
Concomitant Medication......................................................................................... 65 
9.5. 
Exploratory Assessments ............................................................................................... 66 
9.5.1. 
Collection of Biomarker Samples........................................................................... 66 
9.5.2. 
Collection of Pharmacogenetic Sample.................................................................. 66 
9.6. 
Procedures for Handling of Biological Samples............................................................ 66 
9.6.1. 
Storage and Destruction of Biological Samples ..................................................... 66 


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9.6.1.1. 
Pharmacokinetic Samples................................................................................ 66 
9.6.1.2. 
Pharmacodynamic Samples............................................................................. 67 
9.6.1.3. 
Pharmacogenetic Samples ............................................................................... 67 
9.6.2. 
Labeling and Shipment of Biohazard Samples....................................................... 68 
9.6.3. 
Chain of Custody of Biological Samples................................................................ 68 
9.6.4. 
Withdrawal of Informed Consent for Donated Biological Samples....................... 68 
10. DATA QUALITY ASSURANCE AND DATA MANAGEMENT..................................... 69 
10.1. Quality Control and Source Data Verification............................................................... 69 
10.2. Audit/Inspections ........................................................................................................... 69 
10.3. Study Monitoring ........................................................................................................... 69 
10.4. Data Collection............................................................................................................... 69 
10.4.1. Case Report Forms and Source Documents............................................................ 70 
10.4.2. Access to Source Documents.................................................................................. 70 
10.5. Data Management .......................................................................................................... 70 
11. STATISTICAL METHODS.................................................................................................. 72 
11.1. Overview ........................................................................................................................ 72 
11.2. General Statistical Methodology.................................................................................... 72 
11.2.1. Missing Data........................................................................................................... 73 
11.3. Study Populations........................................................................................................... 73 
11.3.1. Safety Analysis Set ................................................................................................. 73 
11.3.2. Pharmacodynamic Analysis Set.............................................................................. 73 
11.3.3. Pharmacokinetic Analysis Set................................................................................. 74 
11.3.4. Randomized Set ...................................................................................................... 74 
11.4. Determination of Sample Size........................................................................................ 74 
11.5. Protocol Deviations........................................................................................................ 75 
11.6. Patient Disposition ......................................................................................................... 76 
11.7. Demographic and Baseline Data.................................................................................... 76 
11.8. Prior and Concomitant Medication and Drug Administration....................................... 76 


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11.8.1. Prior and Concomitant Medication......................................................................... 76 
11.8.2. Drug Administration............................................................................................... 77 
11.9. Pharmacodynamic Analysis........................................................................................... 77 
11.9.1. Pharmacodynamic Variables .................................................................................. 77 
11.9.2. Presentation of Pharmacodynamic Data................................................................. 77 
11.9.3. Statistical Analysis of Pharmacodynamic Data ...................................................... 77 
11.10. Pharmacokinetic Analysis.............................................................................................. 79 
11.10.1. Pharmacokinetic Parameters................................................................................... 79 
11.10.2. Derivation of Pharmacokinetic Parameters ............................................................ 79 
11.10.3. Presentation of Pharmacokinetic Data.................................................................... 80 
11.10.4. Statistical Analysis of Pharmacokinetic Data......................................................... 82 
11.11. Analysis of Safety Data.................................................................................................. 82 
11.11.1. Adverse Events ....................................................................................................... 83 
11.11.2. Potential Events of Diabetic Ketoacidosis.............................................................. 85 
11.11.3. Vital Signs............................................................................................................... 85 
11.11.4. Resting 12-lead Electrocardiogram......................................................................... 85 
11.11.5. Physical Examination.............................................................................................. 85 
11.11.6. Laboratory Assessments ......................................................................................... 85 
11.12. Analysis of Exploratory Data......................................................................................... 86 
11.12.1. Fasting Plasma Glucose.......................................................................................... 86 
11.12.2. Urinary Glucose Excretion ..................................................................................... 86 
11.12.3. Hematocrit............................................................................................................... 86 
11.12.4. Pharmacodynamic – Pharmacokinetic Analyses .................................................... 87 
11.12.5. Biomarkers.............................................................................................................. 87 
11.12.6. Pharmacogenetics ................................................................................................... 87 
12. ADVERSE EVENTS ............................................................................................................ 88 
12.1. Definitions...................................................................................................................... 88 
12.1.1. Definition of Adverse Events.................................................................................. 88 


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12.1.2. Definitions of Serious Adverse Event..................................................................... 88 
12.1.3. Other Significant Adverse Events........................................................................... 88 
12.2. Recording of Adverse Events......................................................................................... 89 
12.2.1. Time Period for Collection of Adverse Events....................................................... 89 
12.2.2. Follow-up of Unresolved Adverse Events.............................................................. 89 
12.2.3. Variables ................................................................................................................. 89 
12.2.4. Causality Collection................................................................................................ 90 
12.2.5. Adverse Events Based on Symptoms and Signs..................................................... 90 
12.2.6. Adverse Events Based on Examinations and Tests ................................................ 91 
12.2.7. Hy's Law ................................................................................................................. 91 
12.3. Reporting of Serious Adverse Events ............................................................................ 91 
13. LEGAL AND ADMINISTRATIVE ASPECTS................................................................... 93 
13.1. Archiving of Study Documents...................................................................................... 93 
13.2. Publication of Study Results .......................................................................................... 93 
13.3. Clinical Study Report..................................................................................................... 93 
14. REFERENCE LIST............................................................................................................... 94 
15. APPENDICES....................................................................................................................... 96 
15.1. Additional Safety Information ....................................................................................... 96 
15.2. International Airline Transportation Association 6.2 Guidance Document................... 99 
15.3. Actions Required in Cases of Combined Increase of Aminotransferase and Total 
Bilirubin - Hy’s Law .................................................................................................... 101 
15.4. Actions Required in Cases of a Renal-related or Kidney Stone Treatment-emergent 
Adverse Event or a Serum Creatinine Elevation.......................................................... 105 
16. SIGNATURES .................................................................................................................... 112 
16.1. Declaration of Sponsor or Responsible Medical Expert (Physician)........................... 112 
16.2. Declaration of Sponsor or Responsible Medical Expert (Biostatistician).................... 113 
16.3. Declaration of the Principal Investigator (Baltimore).................................................. 114 
16.4. Declaration of the Principal Investigator (Los Angeles).............................................. 115 


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1.1.
List of Tables
Table 1 
Schedule of Assessments ........................................................................................ 43 
Table 2 
Total Blood Volume ............................................................................................... 54 
Table 3 
Identity of the Investigational Medicinal Products................................................. 55 
1.2.
List of Figures
Figure 1 
Study Flow Chart .................................................................................................... 42 


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2.
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviation or 
Special Term
Explanation 
AE
Adverse event (see definition in Section 12.1.1)
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ANOVA
Analysis of variance
AST
Aspartate aminotransferase
ATP
Adenosine triphosphate
AUC
Area under plasma concentration-time curve from zero to infinity
AUClast
Area under plasma concentration time curve from time zero to the time 
of last measurable concentration
$8&Ĳ
Area under plasma concentration time curve over a dosing interval 
(24 hours)
BDRM
Blind Data Review Meeting
BMI
Body mass index
BP
Blood pressure
bpm
Beats per minute
BUN
Blood urea nitrogen
CI
Confidence interval 
management system
Cmax
Maximum observed plasma concentration
CO2
Carbon dioxide
CrCL
Creatinine Clearance
CRF
Case report form
CRO
Contract research organization
CSP
Clinical Study Protocol
CSR
Clinical Study Report 
CV
Coefficient of variation
CYP
Cytochrome P450
DAE
Adverse event leading to the discontinuation of IMP
DCF
Data clarification form
DGR
Dangerous Goods Regulations
CCI
CCI


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Abbreviation or 
Special Term
Explanation
DILI
Drug Induced Liver Injury
DKA
Diabetic ketoacidosis
DMP
Data management plan
DNA
Deoxyribonucleic acid
DVS
Data validation specification
ECG
Electrocardiogram
EDV
Early discontinuation visit
eGFR
Estimated glomerular filtration rate
FAS
Full Safety Analysis Set
FDA
Food and Drug Administration
FPG
Fasting plasma glucose
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
Gamma glutamyl transpeptidase (transferase)
GMP
Good Manufacturing Practice
Hb
Hemoglobin
HbA1c
Hemoglobin A1c
HBsAg
Hepatitis B surface antigen
HCG
Human beta chorionic gonadotrophin
HCT
Hematocrit
HIV
Human immunodeficiency virus
HL
Hy’s Law
IATA
International Airline Transportation Association
ICF
Informed Consent Form
ICH
International Council for Harmonisation
IMP
Investigational Medicinal Product
IRB
Institutional Review Board
IV
Intravenous
KDIGO
Kidney Disease Improving Global Outcomes
LLOQ
Lower limit of quantification
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume


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Abbreviation or 
Special Term
Explanation
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
ms
milliseconds
n
Number of patients
NC
Not Calculated
ND
Not determined
NR
No result
NQ
Non-quantifiable
OAE
Other significant adverse events
OTC
Over-the-counter
PD
Pharmacodynamics
PDS
Protocol deviation specification (document)
PHL
Potential Hy’s Law
PI
Principal Investigator
PK
Pharmacokinetics
PP
Per Protocol
QP
Qualified Person
R&D
Research and Development
RBC
Red blood cell
RCTC
Rheumatology Common Toxicity Criteria
RNA
Ribonucleic acid
SAE
Serious adverse event (see definition in Section 12.1.2).
SAP
Statistical Analysis Plan
sCr
Serum creatinine
SD
Standard deviation
SGLT2
Sodium-glucose cotransporter 2
SOC
System Organ Class
SOP
Standard operating procedure
sUA
Serum uric acid
SUSAR
Suspected unexpected serious adverse reaction
TCA
Tricyclic anti-depressant
TEAE
Treatment-emergent adverse event
TFLs
Tables, Figures and Listings


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Abbreviation or 
Special Term
Explanation
t½
Apparent terminal half-life
tlast
Time of last measurable concentration
tmax
Time to reach maximum observed plasma concentration
UA
Uric acid
UGT
8ULGLQHƍ-disphopho-glucoronsyltransferase
ULN
Upper limit of normal
ULT
Uric acid-lowering therapy
URAT1
Uric acid transporter 1
USA
United States of America
USPI
United States Package Insert
UUA
Uric acid excretion in urine per hour
WAD
Windows Allowance Document
WBC
White blood cell
XO
Xanthine oxidase
XOI
Xanthine oxidase inhibitor


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3.
ETHICAL AND REGULATORY REQUIREMENTS
3.1.
Ethical Conduct of the Study
The clinical study will be performed in accordance with ethical principles that have their origin 
in the Declaration of Helsinki
and are consistent with International Council for 
Harmonisation (ICH) Good Clinical Practice (GCP) and the AstraZeneca policy on Bioethics and 
Human Biological Samples.
3.2.
Patient Data Protection
The Informed Consent Form (ICF) will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation.
All clinical study findings and documents will be regarded as confidential.  The Principal 
Investigator (PI) and members of his/her research team must not disclose such information 
without prior written approval from the Sponsor.
The anonymity of participating patients must be maintained.  Patients will be specified in outputs
and other documents containing patient data by their patient number, not by name.  Documents 
that identify the patient (e.g., signed ICF) will be maintained in confidence by the PI and 
members of his/her research team.
Study data will be stored in accordance with local and global data protection laws.
3.3.
Ethics and Regulatory Review
The study will be submitted to the national Regulatory Authority, Food and Drug Administration 
(FDA), for review and approval, by PAREXEL in accordance with local regulatory procedures.
The study will be submitted to the Institutional Review Board (IRB) for ethical review and 
approval by the PI in accordance with local procedures.
PAREXEL will provide the IRB and PI with safety updates/reports according to local 
requirements, including Suspected Unexpected Adverse Reactions (SUSARs), where relevant.
AstraZeneca will provide the Regulatory Authority with safety updates/reports according to local 
requirements, including SUSARs, where relevant.


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The PI is also responsible for providing IRB with reports of any serious and unexpected adverse 
drug reactions from any other study conducted with the Investigational Medicinal Product (IMP).
AstraZeneca will provide this information to the PI so he/she can meet these reporting 
requirements.
Compensation will be reasonable and related to the nature and degree of inconvenience and 
discomfort as a result of participation in the clinical study.  Information on how participants will 
be compensated is contained in the ICF.
3.4.
Insurance
The Sponsor has covered this clinical study by means of an insurance of the clinical study 
according to national requirements.  The name and address of the relevant insurance company, 
the certificate of insurance, the policy number and the sum insured are provided in the 
Investigator's Site File.
3.5.
Informed Consent
The patients shall be informed of the nature, significance, implications and risks of the clinical 
study, and informed consent will be freely given and evidenced in writing, dated and signed or
otherwise marked, by the patient as evidence to indicate his/her free informed consent, before the 
start of the clinical study.
The nature of the informed consent will comply with the Declaration of Helsinki, the current 
requirements of GCP (CPMP/ICH/135/95) and local regulation which ever offers the greater 
patient protection.
3.6.
Changes to the Protocol and Informed Consent Document
Study procedures will not be changed without the mutual agreement of the PI and AstraZeneca.
If there are any substantial changes to the Clinical Study Protocol (CSP), then these changes will 
be documented in a CSP amendment and where required in a new version of the CSP.
If a CSP amendment requires a change to the ICF, the IRB should approve the revised ICF 
before the revised form is used.
If local regulations require, any administrative change will be communicated to or approved by 
the IRB.


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4.
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE
Sponsor: 
AstraZeneca AB
151 85 Södertälje
Sweden
Sponsor’s Lead Physician: 
AstraZeneca R&D
Pepparedsleden 1
SE- 431 83 Mölndal 
Sweden
 
 
Sponsor’s Biostatistician:
AstraZeneca Pharmaceuticals
GMD, Biometrics & Information Sciences
One MedImmune Way
Gaithersburg, MD 20878 
United States of America
 
 
Principal Investigators: 
r 
PAREXEL Early Phase Clinical Unit Baltimore
Harbor Hospital 
3001 South Hanover St. 
Baltimore, MD 21225 
United States of America
 
 
PPD
PP
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PPD
PP
D
PP
D
PPD


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PAREXEL Early Phase Clinical Unit-Los Angeles
1560 Chevy Chase Drive, Suite 140 
Glendale, CA 91206 
United States of America
United States of America
 
 
Contract Research Organization:
PAREXEL Early Phase Clinical Unit Baltimore
Harbor Hospital 
3001 South Hanover St. 
Baltimore, MD 21225 
United States of America
 
 
  
PAREXEL Early Phase Clinical Unit-Los Angeles
1560 Chevy Chase Drive, Suite 140 
Glendale, CA 91206 
United States of America
 
 
  
Clinical Laboratory:
Harbor Hospital Laboratory 
3001 South Hanover St. 
Baltimore, MD 21225 
United States of America
Contact:
 
 
  
PP
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PP
D
PP
D
PPD
C
PPD


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GenX Laboratories Inc. 
  
United States of America
  
  
  
 
Analytical Laboratory:
(Pharmacokinetic Sample 
Analysis)
Covance Bioanalytical Services, LLC
United States of America
Contact:
 
 
  
Exploratory samples (Long term 
storage):
Biobank Gothenburg 
AstraZeneca R&D Gothenburg 
SE-431 83 Mölndal 
Sweden
  
PPD
PPD
PPD
PPD
PPD


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Pharmacogenetic Samples:
  
 
 
 
Adverse Event Reporting: 
AstraZeneca Patient Safety Data Entry Site
A list and contact details of Investigators and other key study team members are provided in the 
Project Plan in the electronic Investigator’s Site File.  A list of all participating Investigators will 
be provided in the Clinical Study Report (CSR).
CCI
PPD


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5.
INTRODUCTION
5.1.
Background Information
Purines are essential building blocks in all living organisms as adenosine triphosphate (ATP), the 
cellular carrier of energy, is a purine, and purines and pyrimidines make up deoxyribonucleic 
acid (DNA) and ribonucleic acid (RNA), the bearers of genetic information.  Metabolism of 
endogenous and ingested purines results in production of uric acid (UA). In contrast to many 
lower species, the human body is unable to metabolize UA further, and therefore eliminates urate 
through excretion.  Uric acid is excreted primarily through the kidneys, but UA is also eliminated 
through excretion into the intestines, where UA can be degraded by the uricase activity in the 
intestinal microbiome to carbon dioxide (CO2) and allantoin. The level of urate in the circulation 
is determined by the balance between production and elimination.  At steady state, production 
and elimination are similar [1].  
Uric acid is the protonated form of urate and can also be found in the human body.  At 
SK\VLRORJLFDOS+§RIWKHFLUFXODWLQJXUDWHLVLQWKe form of UA, but in urine the fraction of 
excreted urate present in the form of UA increases with lower urinary pH.
Uric acid has proven and emerging roles in human disease.  Hyperuricemia (elevated levels of 
UA in the circulation) is a prerequisite for development of gout, an inflammatory arthritis caused 
by deposition of monosodium UA crystals in joints.  Gout occurs in patients with serum UA
> 6.8 mg/dL, which is the solubility limit of monosodium UA.  The prevalence of gout increases 
with higher serum UA (sUA) [2].  Gout affects approximately 4% of the adult United States of 
America (USA) population [3]. The prevalence of hyperuricemia is higher than the prevalence 
of gout, as not all subjects with hyperuricemia develop gout.
Hyperuricemia without clinical symptoms (e.g., gouty attack [acute gouty arthritis], gouty 
tophus, renal disorder) is called “asymptomatic hyperuricemia” [4]. In the USA and Europe, 
asymptomatic hyperuricemia is not an approved indication for UA-lowering therapy (ULT).  The 
Japanese and Chinese treatment guidelines propose that ULT should be considered for patients 
ZLWK DV\PSWRPDWLF K\SHUXULFHPLD ZLWK D V8$ OHYHO RI  8.0 mg/dL with complications 
(e.g., urinaU\FDOFXOXVUHQDOGLVHDVHDQGK\SHUWHQVLRQDQG 9.0 mg/dL without complications
[5, 6].
Evidence shows independent associations between elevated sUA and the risk of hypertension, 
myocardial infarction, heart failure, chronic kidney disease, type 2 diabetes and metabolic 
syndrome, including obesity [7, 8, 9, 10, 11]. Gout is associated with an increased risk of all 


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cause death, as well as cardiovascular death [12, 13, 14, 15]. However, the causal relationship 
between elevated sUA and the aforementioned diseases and outcomes remains to be proven.
Pharmacological modification of the levels of UA is possible through multiple mechanisms.  
Inhibition of xanthine oxidase (XO), a key enzyme in the transformation of purines into UA,
lowers sUA by decreasing production.  The prototypical XO inhibitor (XOI) allopurinol, has 
been the cornerstone of the clinical management of gout and conditions associated with 
hyperuricemia for several decades.  More recently, febuxostat, another XOI, has been approved 
for the treatment of patients with gout.  Xanthine oxidase inhibitor therapy is recommended as a 
first-line pharmacologic ULT approach in gout. 
Inhibition of UA transporter 1 (URAT1), a key transporter responsible for reabsorption of UA
from the primary urine in the proximal tubule, lowers sUA by increasing renal excretion.  
Increased renal excretion of UA is mediated by uricosuric agents.  Probenecid is recommended 
either as an alternative or as an addition to XOI, whereas Lesinurad (Zurampic®), is a URAT1 
inhibitor approved by the FDA in 2015 for treatment of gout in combination with a XOI. 
Combination therapy with RDEA3170, a URAT1 inhibitor, and a XOI such as febuxostat targets 
both excretion and production of UA, providing a dual mechanism approach that would 
effectively lower sUA and thereby potentially enables more patients to achieve and maintain 
target treatment goals to control their disease [16, 17, 18] and establish a potential causal relation 
between sUA lowering therapy and chronic kidney and cardiovascular disease.
Initial Phase 1 development of RDEA3170 explored multiple formulations to identify an agent 
with an optimized pharmacokinetic (PK) and food-effect profile.  Initial studies explored 
RDEA3170 given as monotherapy.  Although these studies demonstrated that RDEA3170 
resulted in effective lowering of UA, a higher rate of serum creatinine (sCr) elevations was 
observed with no clear relationship to dose.
Based on an in-depth evaluation of sCr elevations in conjunction with the known mechanism of 
action of RDEA3170, the Sponsor concluded that the likely basis for the increased sCr levels 
following treatment with RDEA3170 was oversaturation of UA in the urine.  Results from 
3 Phase 2a studies (Studies 204, 205 and 206) and a Phase 1b study (Study 107) demonstrated an 
enhanced sUA-lowering effect of RDEA3170 in combination with an XOI, and an improved UA
excretion profile.  This dual-mechanism approach may result in a lower incidence of 
renal-related adverse events (AEs), thereby improving safety.


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5.2.
RDEA3170
RDEA3170 (also known as verinurad) is a potent and specific URAT1 inhibitor.  Uric acid 
transporter 1 is responsible for most of the reabsorption of filtered UA from the renal tubular 
lumen.  By inhibiting URAT1 RDEA3170 increases UA excretion and thereby lowers sUA.
5.2.1.
Pre-Clinical Findings
A series of pre-clinical studies were performed with results supporting clinical development of 
RDEA3170.  Overall, RDEA3170 was well tolerated in the chronic rat and dog studies at high 
multiples of the exposures achieved at the highest doses tested in man.
No additive or new 
toxicity was observed in 13-week combination studies of RDEA3170 and febuxostat or 
allopurinol in rats.
RDEA3170 was not genotoxic based on results from the in vitro and in vivo batteries of
genotoxicity tests. RDEA3170 is not considered a reproductive hazard based on the results of
reproductive toxicology studies and the lack of effects on reproductive organs in the 6- and
9-month studies in rats and dogs, respectively.
Further information on pre-clinical findings is available in the Investigator’s Brochure [19].
5.2.2.
Clinical Studies
RDEA3170 has been studied in healthy volunteers, subjects with gout, asymptomatic 
hyperuricaemia and renally impaired patients.  In total 763 subjects have received RDEA3170 in 
10 Phase 1 and 5 Phase 2 clinical studies (293 healthy subjects, 31 subjects with renal 
impairment, and 439 subjects with gout or asymptomatic hyperuricemia).
The maximum 
duration of exposure was 183 days for RDEA3170 monotherapy and 21 days for RDEA3170 in 
combination with allopurinol or febuxostat.
5.2.2.1.
Safety Results
Healthy Subjects
Safety was assessed in a pooled analysis of the completed Phase 1 studies in healthy subjects.  
Collectively, these studies enrolled 293 male subjects treated at the following RDEA3170 dose 
ranges: 53 received < 5 mg; 131 received 5 to < 10 mg; 131 received 10 to 15 mg, and 
30 received > 15 mg. Overall, 94.5% completed the planned treatment.


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The incidence of AEs was similar among the pooled RDEA3170 groups and pooled placebo
groups.  There were no serious adverse events (SAEs).  Overall, 86 subjects (29.4%) experienced 
AEs.  The most common AE was headache, which occurred in 12 subjects (4.1%).  There was no 
apparent relationship between the incidence of these AEs and RDEA3170 dose.  Three subjects 
withdrew from the study due to AEs: 2 subjects in Study 103 who had received RDEA3170 5 mg
(dehydration and influenza, respectively) and 1 subject in Study 104 who had received 
RDEA3170 15 mg and experienced urticaria.
Subjects with Gout or Asymptomatic Hyperuricemia
In Study 204, subjects received RDEA3170 in combination with febuxostat. No deaths, other 
SAEs or AEs leading to study withdrawal were reported in the study.  Adverse events were 
reported for 21% of pooled subjects receiving RDEA3170 and febuxostat combination treatment, 
and in 4.9% and 15.7% of subjects receiving febuxostat 40 mg and 80 mg doses alone, 
respectively.  No AEs of Grade 4 were reported, and a single Grade 3 AE (hypertriglyceridemia) 
was reported for 1 subject receiving febuxostat 80 mg alone. The only AEs reported in more 
than 1 subject were pain in extremity (3 subjects), and dyspepsia, musculoskeletal pain, and 
headache, (2 subjects each). Of note, a Grade 1 AE of hepatic enzyme increased occurred during 
treatment with febuxostat 40 mg alone and cases of Grade 1 hepatitis and hepatitis acute 
occurred with febuxostat 80 mg alone. No sCr elevations were reported as AEs.
In Study 205, male Japanese subjects received RDEA3170 in combination with febuxostat.  No 
deaths, other SAEs, withdrawals due to AEs or other significant AEs were reported during the 
study.  A total of 6 AEs were reported in 5 subjects: 1 subject in Cohort 1 (vomiting and 
influenza), 2 subjects in Cohort 2 (influenza and myalgia), 1 subject in Cohort 3 (eczema 
eyelids), and 1 subject in Cohort 6 (diarrhea).  All AEs were Rheumatology Common Toxicity 
Criteria (RCTC) Grade 1 or 2 in severity, except for the myalgia (Grade 3), which was 
accompanied by increased creatine kinase and related to physical activity.
Further information on safety findings is available in the Investigator’s Brochure [19].
5.2.2.2.
Clinical Efficacy
Dose-dependent decreases in sUA levels were observed following once daily oral doses of 
RDEA3170 from 5 to 15 mg under fed conditions for 10 days.  Maximum reduction in sUA
levels occurred within 24 hours after the Day 10 dose.  The observed changes in urinary 
excretion and renal handling of UA were consistent with changes in sUA values.


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When RDEA3170 was co-administered with febuxostat or allopurinol in healthy subjects, the 
combination treatment resulted in enhanced sUA lowering compared with either single agent 
administered alone, while the 24-hour urinary UA amounts remained below baseline, indicative 
of a reduced risk of creatinine elevations compared with RDEA3170 monotherapy.
The sUA-lowering efficacy of RDEA3170 in combination with a XOI in patients with gout was 
demonstrated in 3 Phase 2a studies.  In all 3 studies the efficacy was higher when RDEA3170 
was administered in combination with the XOI than for the XOI alone.
Further information on clinical efficacy findings is available in the Investigator’s Brochure [19].
5.2.2.3.
Pharmacokinetics
RDEA3170 undergoes oxidative metabolism by cytochrome P450 (CYP)3A to form an N-oxide 
metabolite (M4) that undergoes sequential metabolism to form an acylglucuronide (M8) by 
XULGLQH ƍ-disphopho-glucoronsyltransferases (UGTs).  Additionally, RDEA3170 can undergo 
direct glucuronidation by UGTs to form the acylglucuronide (M1), which may undergo further 
oxidation by CYP2C8 to form M8. Most of RDEA3170 is eliminated as M1 and M8.
Plasma apparent terminal half-life (t½) of RDEA3170 was approximately 15 hours.
The 
metabolites were formed quickly after absorption of RDEA3170 (median tmax 0.5 to 0.75 hours)
with t½ values of approximately 13 and 18 hours, respectively.
Further information on PK findings is available in the Investigator’s Brochure [19].
5.3.
Febuxostat
Febuxostat is a XOI indicated for the chronic management of hyperuricemia in patients with 
gout.  Febuxostat achieves its therapeutic effect by decreasing sUA.  Febuxostat is not expected to 
inhibit other enzymes involved in purine and pyrimidine synthesis and metabolism at therapeutic 
concentrations.  [20]
5.3.1.
Safety Clinical Trials Experience
A total of 2757 subjects with hyperuricemia and gout were treated with febuxostat 40 mg or 
80 mg daily in clinical studies.  For febuxostat 40 mg, SDWLHQWVZHUHWUHDWHGIRU 6 months.  
For febuxostat 80 mg, 1377 subjects were WUHDWHGIRU 6 months, 674 patients were treated for 
 \HDUDQGSDWLHQWVZHUHWUHDWHGIRU 2 years. [20]


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The most common adverse reaction leading to discontinuation from therapy was liver function 
abnormalities in 1.8% of febuxostat 40 mg, 1.2% of febuxostat 80 mg, and in 0.9% of 
allopurinol-treated subjects.
The most common AEs reported as related to the study drug at a rate of at least 1% in febuxostat 
treatment groups and at least 0.5% greater than placebo were liver function abnormalities, 
nausea, arthralgia and rash.
Further information is available in the highlights of prescribing information - ULORIC 
(febuxostat) [20].
5.3.2.
Pharmacodynamics
In healthy subjects, febuxostat resulted in a dose dependent decrease in 24-hour mean sUA 
concentrations, and an increase in 24-hour mean serum xanthine concentrations.  In addition, 
there was a decrease in the total daily urinary UA excretion.  Also, there was an increase in total 
daily urinary xanthine excretion.  Percent reduction in 24-hour mean sUA concentrations was 
between 40% to 55% at the exposure levels of 40 mg and 80 mg daily doses.  [20]
Further information is available in the highlights of prescribing information - ULORIC 
(febuxostat) [20].
5.3.3.
Pharmacokinetics
In healthy subjects, maximum plasma concentrations (Cmax) and AUC of febuxostat increased 
in a dose proportional manner following single and multiple doses of 10 mg to 120 mg.
Febuxostat has an t½ of approximately 5 to 8 hours.
Maximum plasma concentrations of 
febuxostat occurred between 1 to 1.5 hours post-dose.  [20]
Febuxostat is extensively metabolized by both conjugation via UGT enzymes including 
UGT1A1, UGT1A3, UGT1A9, and UGT2B7 and oxidation via CYP enzymes including 
CYP1A2, 2C8 and 2C9 and non-P450 enzymes.  The relative contribution of each enzyme 
isoform in the metabolism of febuxostat is not clear.  Febuxostat is eliminated by both hepatic 
and renal pathways [20]
Further information is available in the highlights of prescribing information - ULORIC 
(febuxostat) [20].


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5.4.
Dapagliflozin
Dapagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor indicated as an adjunct to 
diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. [21]
5.4.1.
Safety Clinical Trials Experience
The AEs below reflect the data of 2338 patients to exposed to dapagliflozin with a mean 
exposure duration of 21 weeks.  Patients received placebo (N=1393), dapagliflozin 5 mg
(N=1145), or dapagliflozin 10 mg (N=1193) once daily.
Adverse events that were not present occurred more commonly on dapagliflozin than on placebo, 
and occurred in at least 2% of patients treated with either dapagliflozin 5 mg or dapagliflozin
10 mg.  The following AEs occurred in at least 2% of patients treated with either dapagliflozin
5 mg or dapagliflozin 10 mg, female genital mycotic infections, nasopharyngitis, urinary tract 
infections, male genital mycotic infections, nausea, influenza, dyslipidemia, constipation, 
discomfort with urination and pain in extremity.
Further information is available in the highlights of prescribing information - FARXIGA 
(dapagliflozin) [21].
5.4.2.
Pharmacodynamics
Increases in the amount of glucose excreted in the urine were observed in healthy subjects and in 
patients with type 2 diabetes mellitus following the administration of dapagliflozin.  
Dapagliflozin dose of 5 to 10 mg per day in patients with type 2 diabetes mellitus for 12 weeks 
resulted in excretion of approximately 70 g of glucose in the urine per day at Week 12. A near 
maximum glucose excretion was observed at the dapagliflozin daily dose of 20 mg. This urinary 
glucose excretion with dapagliflozin also results in increases in urinary volume.  [21]
Further information is available in the highlights of prescribing information - FARXIGA 
(dapagliflozin) [21].
5.4.3.
Pharmacokinetics
Following oral administration of dapagliflozin, Cmax is usually attained within 2 hours under 
fasting state.  The Cmax and AUC values increase dose proportionally with increase in 
dapagliflozin dose in the therapeutic dose range.  The absolute oral bioavailability of 
dapagliflozin following the administration of a 10 mg dose is 78%.  [21]


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The metabolism of dapagliflozin is primarily mediated by UGT1A9; CYP-mediated metabolism 
is a minor clearance pathway in humans.  Dapagliflozin is extensively metabolized, primarily to 
yield dapagliflozin 3-O-glucuronide, which is an inactive metabolite.  [21] 
Dapagliflozin and related metabolites are primarily eliminated via the renal pathway.  The mean 
plasma t½ for dapagliflozin is approximately 12.9 hours following a single oral dose of 
dapagliflozin 10 mg.  [21] 
5.5.
Study Rationale 
RDEA3170 is a novel URAT1 inhibitor in Phase 2 development. RDEA3170 combined with 
febuxostat has been proven to be a safe and efficacious therapy to lower sUA and manage 
patients with recurrent gout and hyperuricemia (in Japan) in Phase 2 studies.  Inhibition of 
URAT1 results in increased renal excretion of urate. To avoid high peak excretion rates, 
RDEA3170 should be used in combination with a XO-inhibitor, such as febuxostat, as 
RDEA3170 may deliver the most potent UA lowering effect via renal excretion reported for any 
treatment.
Dapagliflozin is a stable, reversible, highly selective and orally active inhibitor of human renal
SGLT2, the major transporter responsible for renal glucose reabsorption in the kidney.  The 
mechanism of action of dapagliflozin results in the direct and insulin-independent elimination of 
glucose by the kidneys.  Results from non-clinical- and clinical studies have shown that 
dapagliflozin can be used to promote urinary excretion of glucose as a safe and effective method 
of reducing blood glucose levels.  Currently, there are multiple oral SGLT2-inhibitors approved 
and indicated for the treatment of type 2 diabetes (dapagliflozin, empagliflozin
and
canagliflozin).  In addition to providing glycemic control, body weight reduction and blood 
pressure lowering, SGLT2-inhibition also results in sUA lowering, potentially due to increased 
renal excretion of urate. 
 the objective of the study is to 
explore whether intensive UA lowering therapy with febuxostat and RDEA3170 can be safely 
combined with dapagliflozin, and if the sUA lowering effects would be additive. 
5.6.
Dose Rationale 
The doses of RDEA3170 and febuxostat selected for this study were chosen as they represent the 
doses achieving maximal sUA reduction in Phase 2 studies in patients with gout.  
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, the febuxostat and RDEA3170 doses and 
formulations used in this study have been previously administered to patients with more advance 
disease than recruited in this study, without raising any safety concerns to date. 
For febuxostat, the United States Package Insert (USPI) recommends a starting dose of 40 mg
once daily while a starting dose of 80 mg is recommended in Europe, and for patients who do not 
achieve a sUA less than 6 mg/dL after 2 weeks an increase to 80 mg and 120 mg is 
recommended in the USA and Europe, respectively.  No dose adjustment is necessary in patients 
with mild or moderate renal impairment (Creatinine Clearance [CrCl] 30 to 89 mL/min).  As this 
study does not aim to achieve a predefined sUA target of < 6 mg/dL, but rather to lower sUA as 
much as possible, a dose of 80 mg from the start of the study is relevant to adequately reduce the 
sUA production and to maintain the proportional contributions of febuxostat and RDEA3170 to 
the overall sUA acid lowering effects. The current study will be performed at 2 Clinical Units
with close monitoring of all study participants through frequent visits, an extensive safety 
laboratory panel, and close monitoring of safety data as it emerge.
For dapagliflozin, the USPI recommends a starting dose of 5 mg once daily while a starting dose 
of 10 mg is recommended in Europe.  The marketed dose 10 mg have been found to be well 
tolerated in subjects with chronic kidney disease 3 (estimated glomerular filtration rate [eGFR] 
30 to 60 mL/min/1.73 m2) [22].
From a PK and pharmacodynamic (PD) perspective, 
dapagliflozin 10 mg is appropriate for use in patients with renal impairment.
5.7.
Choice of Study Population, Risk-Benefit Assessment and Risk Mitigation 
There are no direct benefits for the patients participating in this study.  However, study related 
health assessments are provided without costs for the subjects.  The major risks for patients who 
participate in the study will come from AEs caused by RDEA3170, febuxostat and/or 
dapagliflozin.  In addition, there may be a slight risk of infection or bruising that may occur after 
insertion of an intravenous (IV) cannula for frequent blood sampling.  
 is an approved 
URAT1 inhibitor.  Most common AEs identified in the prescribing information are headache, 
increased blood creatinine and gastroesophageal reflux disease.
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Asymptomatic hyperuricemic subjects (sUA > 6.0 mg/dL) will be included in this study.  It is the 
most suitable population to explore whether there is an additive effect on urinary excretion of 
urate and sUA levels, when dapagliflozin is combined with RDEA3170 and febuxostat.  
Initial Phase 1 development of RDEA3170 explored multiple formulations to identify an agent 
with an optimized PK and food-effect profile.  Initial studies explored RDEA3170 given as 
monotherapy.  Although these studies demonstrated that RDEA3170 resulted in effective 
lowering of UA, a higher rate of sCr elevations was observed with no clear relationship to dose.  
These elevations have usually been transient and reversible, and most have resolved without 
interruption of RDEA3170.
Based on an in depth evaluation of sCr elevations in conjunction with the known mechanism of 
action of RDEA3170, the Sponsor concluded that the likely basis for the increased sCr levels 
following treatment with RDEA3170 was oversaturation of urate in the urine.  Results from 
3 Phase 2a studies (Studies 204, 205 and 206) and a Phase 1b study (Study 107) demonstrated an 
enhanced sUA lowering effect of RDEA3170 in combination with an XOI, and an improved UA 
excretion profile.  This dual mechanism approach may result in a lower incidence of 
renal-related AEs, thereby improving safety.
During the clinical development program, subjects with gout or asymptomatic hyperuricemia 
were included in Study 107 (RDEA3170 in combination with allopurinol), Study 201 
(RDEA3170 monotherapy), Study 203 (RDEA3170 monotherapy in Japanese subjects), 
Study 204 (RDEA3170 in combination with febuxostat) and Study 205 (RDEA3170 in 
combination with febuxostat in Japanese subjects).  
Serum creatinine elevations have occurred in patients with gout treated with RDEA3170 alone.  
Therefore, only subjects with eGFR > 45 mL/minute/1.73 m2 at screening will be included in the 
study.  Renal safety parameter (including assessment of serum and urinary levels of creatinine 
and cystatin-C, blood urea nitrogen [BUN], serum and urinary electrolytes, urinary pH) are 
monitored during the study. Elevations in sCr will be monitored and appropriate actions taken as 
described in Appendix 15.4.
In patients reporting symptoms that may indicate acute urate nephropathy including flank pain, 
nausea, or vomiting, treatment will be immediately discontinued and renal safety parameter will 
be measured and appropriate actions taken as described in Appendix 15.4.  Implementation of a 
hydration scheme is considered an appropriate risk mitigation measure.


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Initiating or increasing the dose of ULT has been shown to induce gout flares in some patients 
with a history of gout.  To protect participating patients from experiencing gout flares, patients 
with a history of gout will be excluded from the study.  Should a patient nevertheless experience 
a gout flare, treatment with colchicine, steroids and/or non-steroidal anti-inflammatory drugs as 
appropriate, and according to the Investigator’s best medical judgment is recommended.
There have been post-marketing reports of ketoacidosis, including diabetic ketoacidosis (DKA),
in patients with type 1 and type 2 diabetes mellitus taking dapagliflozin and other SGLT2
inhibitors, although a causal relationship has not been established. Dapagliflozin is not indicated 
for the treatment of patients with type 1 diabetes mellitus.
Patients treated with dapagliflozin who present with signs and symptoms consistent with
ketoacidosis, including nausea, vomiting, abdominal pain, malaise and shortness of breath,
should be assessed for ketoacidosis, even if blood glucose levels are below 14 mmol/L
(250 mg/dL). 
If ketoacidosis is suspected, discontinuation or temporary interruption of
dapagliflozin should be considered and the patient should be promptly evaluated.
Predisposing factors to ketoacidosis include a low beta-cell function reserve resulting from
pancreatic disorders (e.g., type 1 diabetes, history of pancreatitis, or pancreatic surgery), insulin 
dose reduction, reduced caloric intake or increased insulin requirements due to infections, illness 
or surgery and alcohol abuse. Dapagliflozin should be used with caution in these patients.
A multiple-dose interaction study showed that RDEA3170 did not affect Cmax and AUC of 
febuxostat. 
The predictable risks and disadvantages for the study subjects are acceptable, compared to the 
presumed future importance of the triple therapy, expected to be commonly used in the proposed 
target patient population (chronic kidney disease and/or heart failure).


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6.
STUDY OBJECTIVES
6.1.
Primary Objective
x
To assess the effects of intensive UA lowering therapy with RDEA3170, febuxostat and
dapagliflozin on urinary excretion of UA. 
6.1.1.
Primary Objective Outcome Measure:
x
Peak UA excretion during the first 8 hours (maximum UA excreted as measured in mg, in an 
interval out of the first 8 hours) on Day 7 of treatment (Day 1 is the first day of treatment).
6.2.
Secondary Objectives
x
To assess the effects of intensive UA lowering therapy with RDEA3170, febuxostat and
dapagliflozin on sUA levels.
x
To assess the PK of RDEA3170 and its main metabolites (M1 and M8), febuxostat and 
dapagliflozin in this patient population. 
x
To assess the renal and general safety and tolerability of intensive UA lowering therapy with 
RDEA3170, febuxostat and dapagliflozin. 
6.2.1.
Secondary Objective Outcome Measures:
x
Serum UA levels after 7 days of treatment. 
x
RDEA3170, M1, M8, febuxostat and dapagliflozin plasma concentrations and PK 
parameters.
x
Changes in clinical laboratory parameters, including assessment of serum and urinary levels 
of creatinine and cystatin-C, BUN, serum and urinary electrolytes, urinary pH.  Changes in 
vital signs.  Rates of AEs and SAEs. 
6.3.
Exploratory Objectives 
x
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x
.
6.3.1.
Exploratory Objectives Outcome Measures:
x
Refer to Section 11.9.1 for details on PD variables, Section 11.10.1 for details PK parameters, 
Section 9.4 for details safety variables and Section 11.12 for details on exploratory outcomes. 
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7.
OVERALL DESIGN AND PLAN OF THE STUDY
7.1.
Overall Study Design
This is a randomized, placebo controlled, double-blind, 2-way crossover study to assess the 
effect of intensive UA lowering therapy with RDEA3170, febuxostat and dapagliflozin on 
urinary excretion of UA, in asymptomatic hyperuricemic patients.  Thirty-six, asymptomatic 
hyperuricemic patients aged 18 to 65 years (inclusive) will be enrolled into this study at 2 study 
centers.  Twenty-four patients have been enrolled and completed the study to date.
Due to 
inadequate urine sampling, it was decided to include 12 additional patients to ensure an adequate 
sample size (at least 20 evaluable patients) to evaluate the effects of intensive UA lowering with 
RDEA3170, febuxostat and dapagliflozin on urinary excretion of UA. Each patient will receive 
the 2 treatments listed below for 7 consecutive days (1 treatment per treatment period).
x
Treatment A:
9 mg RDEA3170 + 80 mg febuxostat + 10 mg dapagliflozin
x
Treatment B:
9 mg RDEA3170 + 80 mg febuxostat + placebo
The study will comprise of:
x
A screening period of maximum 28 days;
x
Two treatment periods during which patients will be resident in the Clinical Unit from
Day -2 to Day 1 and from Day 6 to Day 8; and
x
A Follow-up Visit within 14 to 28 days after the first administration of IMP in Treatment 
Period 2.
Before any study specific assessments are performed, potential patients must provide informed 
consent.  Patients that provided informed consent will attend the Screening Visits within 28 days 
before receiving the first dose of IMP.  Patients that are meet all of the inclusion criteria 
(Section 7.5.1) and none of the exclusion criteria (Section 7.5.2), will return to the Clinical Unit 
on Day -2 of Treatment Period 1 and will be randomized (1:1) to 1 of 2 treatment sequences (AB 
or BA) before the start of urine collection on Day -1 of Treatment Period 1.
For each treatment period, baseline measurements will be performed. Patients receive the IMP 
for 7 consecutive days (Day 1 to Day 7).  Patients will be residential in the Clinical Unit from 
Day -2 to Day 1.  On Day 1, after all dosing and all assessments have been performed, patients
will receive instruction to administer the IMP at home once daily in the morning from Day 2 to 
Day 6 and the IMP will be dispensed for home dosing.  Patients will return to the Clinical Unit 
on Day 6 and will be residential in the Clinical Unit from Day 6 to Day 8.


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Treatment Period 1 and Treatment Period 2 will be separated by a washout period of 7 to 
21 days.
Patients will return to the Clinical Unit for a Follow-up Visit, 14 to 28 days after Day 1 of 
Treatment Period 2.
See Table 1 for details on assessment that will be performed during the treatment periods.
7.1.1.
End of Study
The end of study is defined as the last patient’s last visit to the Clinical Unit.
7.1.2.
Interim Analyses
No interim analyses will be performed in this study.
7.1.3.
Expected Duration of the Study
Each patient will be involved in the study for 10 to 11 weeks.
7.2.
Study Flow Chart and Schedule of Assessments
The flow of events is illustrated in Figure 1 for all treatments, depending on the patient’s 
assigned randomization (refer to Section 8.9.2).
Figure 1
Study Flow Chart
 
Dapa: Dapagliflozin; fbx: Febuxostat; pbo: placebo
The Schedule of Assessments displaying assessments/tasks and time points is presented in
Table 1.


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Table 1
Schedule of Assessments
Screening
Treatment Period 1
Washout
(7 to 21
days) 
Treatment Period 2
Follow-up
Visit /
EDV
Visit
1
2
3
4
5
6
Study Day
-28
-2
-1
1
2-5
6
7
8
-2 a
-1
1
2- 5
6 a
7
8
23 a
Visit Window (days)
0 to 28
±0
±0
±0
±0
0-7
Written informed consent
X
Demographics 
X
Medical/surgical history
X
Inclusion/exclusion criteria
X
X
Urinary drug/blood alcohol 
screen
X
X
X
Complete physical 
examination b
X
X
Height and BMI
X
Serology
X
Pregnancy tests
(women only)
X
(Serum)
X
(Urine)
X
(Urine)
X
(Urine)
FSH (post-menopausal women 
only)
X
Randomization 
X
Study Residency:
Admission to Clinical Unit
X
X
X
X
Discharge from Clinical Unit
X
X
X
X
Non-residential visit
X
X
RDEA3170, Febuxostat, 
Dapagliflozin Administration 
Treatment administered at 
Clinical Unit
X c
X d
X c
X d
Controlled meals and fluid 
intake e
X
X
X
X
X
X
X
X
X
X
Treatment dispensed
X
X
Treatment administered at home
X f
X f
X f
X f
Treatment returned
X
X


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Screening
Treatment Period 1
Washout
(7 to 21
days) 
Treatment Period 2
Follow-up
Visit /
EDV
Visit
1
2
3
4
5
6
Study Day
-28
-2
-1
1
2-5
6
7
8
-2 a
-1
1
2- 5
6 a
7
8
23 a
Visit Window (days)
0 to 28
±0
±0
±0
±0
0-7
Safety and tolerability:
Adverse event review (AEs and 
SAEs)
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication 
X
X
X
X
X
X
Vital signs (BP and pulse)
X
X
X
X
X
X
12-lead ECG
X
X
X
X
Blood samples for hematology, 
clinical chemistry g
X 
X 
X
(only 
FPG)
X 
X 
X
(only 
FPG)
X 
X 
Urine analysis (dipstick and spot 
urine collection)
X 
X 
eGFR
X
Brief physical h examination
X
X
X
X
Weight
X
X
X
X
X
X
Pharmacodynamics
Timed urine sample collection
including hourly samples at 
specific study day i, j
X i
X j
X i
X j
Blood samples for sUA
X k
X k
X l
X k
X l
X k
Pharmacokinetics
Blood samples m for PK analysis
X
X
Exploratory
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AE: Adverse event; BMI: Body Mass Index; BP: Blood pressure; ECG: Electrocardiogram; EDV: Early discontinuation Visit; eGFR: Estimated glomerular filtration 
rate; FPG: Fasting plasma glucose; FSH: Follicle stimulating hormone; IMP: Investigational Medicinal Product; PK: Pharmacokinetic; SAE: Serious adverse event; 
sUA: Serum uric acid;
a)
Visit 4 admission cannot occur earlier than 5 days nor later than 19 days post Visit 3 discharge (minimum of 7 days where study drug is not administered).  The 
relative timing of Visit 4 to Visit 5 (admission for Visit 5 should occur 5 days post Visit 4 discharge) and Visit 6 (15 to 22 days after Visit 4 discharge) must 
remain the same irrespective of when Visit 4 is performed.
b)
A complete physical examination should include general appearance, respiratory, cardiovascular, abdomen, skin, head, and neck (including ears, eyes, nose and 
throat), lymph nodes, thyroid, musculoskeletal and neurological systems.
c)
First dose on site, then once daily at home until next visit, including dosing at home the morning of admission day for next visit (Day 6).
d)
Treatment administered at Clinical Unit.
e)
On urine collection days, (Day -1 and Day 7) 400 mL water will be consumed by the patients within 15 minutes after IMP administration (for Day -1, clock 
time of planned dose administration for dosing days), followed by 200 mL water every 2 hours until 12 hours after IMP administration (for Day -1, clock time 
of planned dose administration for dosing days).  On Days -2, -1, 1, 6 and 7, patients will receive standardized meals, and will be encouraged to consume the 
entire meal.  Mealtimes and other activities will be synchronized for all patients and food and liquid intake specified and monitored. On Day -1, Day 1 and 
Day 7 of each treatment period, patients will be fasted for 10 hours before dosing (for Day -1, clock time of planned dose administration for dosing days) until 
4 hours after dosing, and patients will receive standardized meals thereafter. After discharge on Day 1 and Day 8, the food and liquid intake of the patients will 
be ad libitum. On Days -2 and 6 identical standardized lunch and dinner meals will be provided.
f)
Treatment administered at home in the morning.
g)
Fasting samples, collected before breakfast (food) and before dose (when applicable).
h)
A brief physical examination should include general appearance, skin, abdomen, cardiovascular system and respiratory; and any organ systems pertinent to the 
patient’s signs, symptoms or AEs.
i)
Baseline collection of urine consists of hourly collections from -24 to -12 hours (inclusive, counted from the time of dosing on Day 1 where 0 hours is time of 
dosing) at the following sampling intervals: -24 to -23 hours, -23 to -22 hours, -22 to -21 hours, -21 to -20 hours, -20 to -19 hours, -19 to -18 hours, -18 
to -17 hours, -17 to -16 hours, -16 to -15 hours, -15 to -14 hours, -14 to -13 hours, -13 to -12 hours, followed by a single 12-hour collection from -12 to 0 hours.
j)
Directly following the dose of study treatment on Day 7, hourly collection of urine is performed every hour from 0 to 12 hours (inclusive), at the following 
post-dose sampling intervals (0 to 1 hour, 1 to 2 hours, 2 to 3 hours, 3 to 4 hours, 4 to 5 hours, 5 to 6 hours, 6 to 7 hour, 7 to 8 hours, 8 to 9 hours 9 to 10 hours,
10 to 11 hours, 11 to 12 hours).  These sampling intervals will be followed by a single pooled collection from 12 to 24 hours.  Mealtimes and other activities 
should be synchronized for all patients and food and liquid intake specified and monitored.
k)
A single sUA assessment (matched by time of day, e.g. always in the morning, and after a 10 hour overnight fast).  This does not apply to the screening sUA. 
The screening sUA can be repeated once during the screening period.
l)
Time-points for sUA to match the pharmacokinetic time-points (see the bullet m), detailing PK time-points).
m) Time points for plasma collection for pharmacokinetics: Pre-dose and 15 minutes, 30 minutes, 1 hour, 1.5, 2, 3, 4, 8, 12 and 24 hours post-dose.


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7.3.
Order of Assessments
It is important that PD and PK sampling occurs as close as possible to scheduled time.  To
achieve this, other assessments scheduled at the same time may be initiated before the time point.
The sequence at a time point is:
1.
Electrocardiograms (ECGs).
2.
Vital signs (systolic and diastolic BP and pulse).
3.
Blood samples for sUA (will be drawn at the specified time point).
4.
Pharmacokinetic blood sampling (will be drawn at the specified time point).
7.4.
Restrictions During the Study
The following restrictions apply for the specified times during the study period:
1.
On urine collection days, (Day -1 and Day 7) 400 mL of water will be consumed by the 
patients within 15 minutes after IMP administration (for Day -1, clock time of planned dose 
administration for dosing days), followed by 200 mL water every 2 hours until 12 hours after 
IMP administration (for Day -1, clock time of planned dose administration for dosing days).  
On Days -2, -1, 1, 6 and 7, patients will receive standardized meals, and will be encouraged 
to consume the entire meal.  Mealtimes and other activities will be synchronized for all 
patients and food and liquid intake specified and monitored.  On Day -1, Day 1 and Day 7 of 
each treatment period, patients will be fasted for 10 hours before dosing (for Day -1, clock 
time of planned dose administration for dosing days) until 4 hours after dosing, and will 
receive standardized meals thereafter until discharge.  On Day -2 and Day 6 patients will 
receive identical standardized meals from the time they arrive at the site. See Section 8.6.
2.
Patients should not engage in any strenuous activity from 72 hours before check-in until after 
their final Follow-up Visit.
3.
Before each treatment period, patients should abstain from alcohol for 72 hours before 
admission to the Clinical Unit until after their last PD/PK sampling visit.  Patients should 
also abstain from alcohol for 72 hours before their final Follow-up Visit.
4.
Before each treatment period, patients should abstain from caffeine-containing foods and 
beverages for 24 hours before admission to the Clinical Unit until the last dose of IMP in 
each treatment period.


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5.
Patients should abstain from grapefruit or grapefruit juice, Seville oranges, quinine (e.g., 
tonic water) from 7 days before admission to the Clinical Unit on Day -2 until after their 
Follow-up Visit.
6.
During admission periods, patients will receive a standard diet, which excludes all alcohol 
and grapefruit-containing products.  No additional food or beverages must be consumed 
while in the Clinical Unit
7.
During the patients’ outpatient periods, patients should abstain from consuming high-energy 
drinks (e.g., red bull), and food containing poppy seeds and any Over-the-Counter (OTC)
medication or herbal preparations until after their final Follow-up Visit has been completed.  
Patients should also limit their caffeine intake to equivalent of 3 cups of coffee per day 
(1 cup = 12 oz soda, 6 oz coffee or 8 oz tea).  Patients should consume no more than 2 units 
of alcohol per day and completely abstain from alcohol from 72 hours before each admission 
to the Clinical Unit.
8.
Patients will be required to abstain from blood or plasma donation until 3 months after the 
final medical examination at the Follow-up Visit.
9.
Patients must not smoke for 1 hour before any vital sign or ECG assessments.  Smoking is 
prohibited while patients are confined to the Clinical Unit.
10. For medication restrictions, please refer to Section 8.8.
7.4.1.
Reproductive Restrictions
7.4.1.1.
Women of Non-Childbearing Potential
Women of non-childbearing potential are defined as female patients who are permanently 
surgically sterilized or post-menopausal.
Permanent sterilization includes hysterectomy and/or bilateral oophorectomy and/or bilateral 
salpingectomy but excludes bilateral tubal ligation.
Females are considered post-menopausal if they have had amenorrhea for at least 12 months or 
more following cessation of all exogenous hormonal treatments and follicle-stimulating hormone 
(FSH) levels are in the post-menopausal range (FSH levels is > 40 mIU/mL). If there is any 
uncertainty, this must be discussed between the Investigator and the Medical Monitor.


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7.4.1.2.
Women of Childbearing Potential
Women of childbearing potential who are sexually active must agree to use, with their partner, 
an approved method of highly effective contraception from the time of IMP administration until 
3 months after the study Follow-up Visit. 
The following are considered highly effective 
methods:
x
Surgical sterilization1 (i.e., bilateral tubal ligation for females; vasectomy for male partners).
x
Placement of an intrauterine device1 or intrauterine hormone releasing system1.
x
Hormonal contraception associated with inhibition of ovulation (injectable1, implantable1,
patch and oral).
1
These methods are considered to have low user dependency
In addition,
a barrier method must also be used i.e.,
condom (with spermicidal 
foam/gel/film/cream/suppository or fat-
or oil-containing lubricants); or occlusive cap 
(diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository.
Alternatively, true abstinence is acceptable when it is in line with the patient’s preferred and 
usual lifestyle. 
Pregnancy Testing
Women of childbearing potential can be included only after a negative highly sensitive serum 
pregnancy test.  Additionally, urine pregnancy testing will be done as per the Schedule of 
Assessments, see Table 1.
7.4.1.3.
Male Patients
Restrictions for Male Patients
RDEA3170 had no effects on fertility or embryo-fetal development in rats at doses up to 
300 mg/kg/day, and did not affect embryo-fetal development in rabbits at doses up to 
30 mg/kg/day.
Male patients participating in this study are not required to apply contraception.
Pregnancy
Patients will be instructed that if their partner becomes pregnant during the study this should be 
reported to the PI.  The PI should also be notified of pregnancy occurring during the study but 


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confirmed after completion of the study.  In the event that a patient’s partner is subsequently 
found to be pregnant after the patient is included in the study, then consent will be sought from 
the partner and if granted any pregnancy will be followed and the status of mother and/or child 
will be reported to the Sponsor after delivery.
A pregnancy notification form and follow-up will be completed.
7.5.
Selection of Study Population
The PI should keep a patient screening log of all potential patients who consented and were 
subjected to screening procedures.
Patients who fail to meet the inclusion criteria or meet any exclusion criterion should not, under 
any circumstances, be randomized into the study.  There can be no exceptions to this rule.
This study will be conducted in male and female patients.  The study may not necessarily be 
balanced regarding gender.  The study was not formally powered to detect differences between 
genders for the primary endpoint.  It is not planned to perform sub-analyses on gender.
7.5.1.
Inclusion Criteria
For inclusion in the study, patients should fulfill the following criteria:
1.
Provision of signed and dated, written informed consent before any study specific 
procedures.
2.
Male and female asymptomatic hyperuricemic patients aged 18 to 65 years at the Screening 
Visit with suitable veins for cannulation or repeated venipuncture.
3.
Male and female patients with a sUA > 6.0 mg/dL at the Screening Visit. The screening sUA 
can be repeated once during the screening period.
4.
Females must have a negative pregnancy test at the Screening Visit and Day -2 of each 
treatment period, must not be lactating and must be:
4.1. of non-childbearing potential, confirmed at the Screening Visit by fulfilling one of the 
following criteria
4.1.1. Post-menopausal defined as amenorrhea for at least 12 months or more following 
cessation of all exogenous hormonal treatments and FSH levels in the 
post-menopausal range (FSH levels > 40 mIU/mL). If there is any uncertainty, 
inclusion must be discussed between the Investigator and the Medical Monitor.


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4.1.2. Documentation of irreversible surgical sterilization by hysterectomy, bilateral 
oophorectomy or bilateral salpingectomy but not tubal ligation.
4.2. OR if of childbearing potential must be willing to use an acceptable method of 
contraception to avoid pregnancy for the entire study period, as described in 
Section 7.4.1.2.
5.
Have a body mass index (BMI) between 18 and 35 kg/m2 inclusive and weigh at least 50 kg 
and no more than 150 kg inclusive.
6.
Provision of signed, written and dated informed consent for optional genetic/biomarker 
research.  If a patient declines to participate in the genetic component of the study, there will 
be no penalty or loss of benefit to the patient.  The patient will not be excluded from other 
aspects of the study described in this CSP.
7.5.2.
Exclusion Criteria
Patients will not enter the study if any of the following exclusion criteria are fulfilled:
1.
History of any clinically significant disease or disorder which, in the opinion of the 
Investigator, may either put the patient at risk because of participation in the study, or 
influence the results or the patient’s ability to participate in the study.
2.
History or presence of gastrointestinal, hepatic or renal disease or any other condition known 
to interfere with absorption, distribution, metabolism or excretion of drugs.
3.
Any clinically significant illness, medical/surgical procedure or trauma within 4 weeks of the 
first administration of IMP.
4.
eGFR* < 45 mL/minute/1.73 m2 at Screening (blood sample obtained at Screening Visit).
*According to the re-expressed abbreviated (four-variable) Modification of Diet in Renal 
Disease (MDRD) Study equation, using central laboratory measurements of serum creatinine 
(sCr). [eGFR (mL/min/1.73 m2) = 175 x (standardized sCr)-1.154 x (Age)-0.203 x (0.742 if 
female) x (1.212 if Black)] [Note: sCr reported in mg/dL ]
5.
Diagnosed with type 2 diabetes mellitus with either hemoglobin A1c (HbA1c) > 8% or doses 
of oral antidiabetic drugs changed within 4 weeks before the Screening Visit.
6.
History of diabetic ketoacidosis or hyperosmolar non-ketotic coma.
7.
History of gout.


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8.
Patient with any condition which, in the judgment of the Investigator, may render the patient 
unable to complete the study or which may pose a significant risk to the patient.
9.
Ongoing treatment with an SGLT2-inhibitor, a URAT1-inhibitor, and/or an XOI.
10. Dose of losartan, fenofibrate or guaifenesin changed within 2 weeks of first admission to the 
Clinical Unit (Day -2 of Treatment Period 1) or further dose titration expected after first 
admission to the Clinical Unit (Day -2 of Treatment Period 1).
11. Any clinically significant abnormalities in clinical chemistry, hematology or urinalysis 
results, at the Screening Visit and/or first admission to the Clinical Unit as judged by the 
Investigator.
Note: Screening and Day -2 tests may be repeated, at the discretion of the Investigator, if 
abnormal.
12. Any clinically significant abnormal findings in vital signs at the Screening Visit and/or first 
admission to the Clinical Unit, as judged by the Investigator.
Note: Screening and Day -2 tests may be repeated, at the discretion of the Investigator, if 
abnormal.
13. Any clinically significant abnormalities on 12-lead ECG at the Screening Visit and/or first 
admission to the Clinical Unit, as judged by the Investigator.
Note: Screening and Day -2 tests may be repeated, at the discretion of the Investigator, if 
abnormal.
14. Any positive result on screening for serum hepatitis B surface antigen, hepatitis C antibody, 
and human immunodeficiency virus (HIV) antibody.
15. Known or suspected history of drug abuse, as judged by the Investigator.
16. Has received another new chemical entity (defined as a compound that has not been 
approved for marketing) within 30 days before the Screening Visit.
Note: patients consented and screened, but not randomized in this study or a previous study, 
are not excluded.
17. Plasma donation within 1 month of the Screening Visit or any blood donation/loss more than 
400 mL during the 6 weeks before the Screening Visit.
18. History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged by 
the Investigator or history of hypersensitivity to drugs with a similar chemical structure or 
class to RDEA3170, febuxostat or dapagliflozin.


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19. Suspected history of alcohol or drug abuse or excessive intake of alcohol, as judged by the 
PI, or positive screen for drugs of abuse or alcohol at the Screening Visit or Day – 2 of each 
treatment period.
20. Use of drugs with enzyme-inducing properties such as St John’s Wort within 3 weeks before
the first administration of IMP.
21. Use of any prescribed or non-prescribed medication including antacids, analgesics, herbal 
remedies, megadose vitamins (intake of 20 to 600 times the recommended daily dose) and 
minerals during the 2 weeks before the first administration of IMP or longer if the medication 
has a long half-life.
Note: The use of paracetamol/acetaminophen, hormone replacement therapy, systemic 
contraceptives, corticosteroid cream and prescription medication for chronic illness that has 
been approved by the PI will be allowed.
22. Involvement of any AstraZeneca, PAREXEL or study site employee or their close relatives.
23. Patients who have previously received RDEA3170.
24. Judgment by the Investigator that the patient should not participate in the study if they have 
any ongoing or recent (i.e., during the screening period) minor medical complaints that may 
interfere with the interpretation of study data or are considered unlikely to comply with study 
procedures, restrictions and requirements.
25. Vulnerable patients, e.g., kept in detention, protected adults under guardianship, trusteeship
or committed to an institution by governmental or juridical order.
In addition, the following is considered a criterion for the exclusion from the optional genetic 
component of the study:
26. Non-leukocyte depleted whole blood transfusion within 120 days of the date of the genetic 
sample collection or previous bone marrow transplant.
7.5.3.
Discontinuation of Investigational Medicinal Product and Withdrawal from the 
Study
Patients may be discontinued from IMP in the following situations:
x
Patient decision.  The Patient is at any time free to discontinue treatment, without prejudice 
to further treatment.
x
Severe non-compliance to the CSP.


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x
Any significant and clinically relevant changes in the safety parameters (e.g., ECG, BP, pulse 
rate, laboratory assessments and AEs) making the continuation of IMP administration 
unjustified.
x
Study specific withdrawal criteria: If a patient reports symptoms, which are considered 
unacceptable by the patient or the Investigator, he/she will be withdrawn from the study.  In 
particular:

Any other severe or SAE that is judged as possibly related to the IMP by the Investigator.

Any case of Potential Hy’s Law (PHL) according to Appendix 15.3.

Study treatment will be temporarily stopped if a patient has elevated creatinine and 
cystatin-C levels greater than 1.5 times the pre-treatment value and retest of the creatinine 
and cystatin-C will be performed as soon as possible (see Appendix 15.4).

In patients who report symptoms that may indicate acute UA nephropathy including flank
pain, nausea, or vomiting, treatment may need to be temporarily stopped or permanently 
discontinued.  Appendix 15.4 contains guidelines on management of such patients.

Pregnancy.
The appropriate AE form in the case report form (CRF) is to be completed.
7.5.4.
Premature Termination of the Study
The study may be terminated prematurely if:
x
The PI and the Sponsor assess that the number and/or severity of AEs justify discontinuation 
of the study.  For instance, when there is at least 1 case of fatal SAE or 2 cases of other 
SAEs, in both situations considered related to the IMP by the PI and the Sponsor.
x
The Sponsor considers the applied doses of the study drug to be no longer relevant.
x
The Sponsor decides to discontinue the study.
x
Data not known before become available and raise concern about the safety of IMP so that 
continuation would pose potential risks to the patients.
Premature termination of the study must be mutually agreed upon by the PI and the Sponsor and 
must be documented.  However, study results will be reported according to the requirements 
outlined in this CSP as far as applicable.


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7.5.5.
Replacement of Patients 
Patients who are withdrawn from the study due to AEs or changes in safety parameters will not 
be replaced unless a specific sample size is to be met for statistical purposes and if the Sponsor’s 
responsible physician and the PI agree it is safe to do so.  Patients who withdraw or are 
withdrawn from the study for other reasons may be replaced following discussion with the 
Sponsor. 
7.5.6.
Total Blood Volume
The approximate total amount of blood to be collected from each patient in this study, excluding 
repeat samples, is summarized in Table 2.
Table 2 
Total Blood Volume 
Assessments
Sample Volume (mL)
Number of Samples
Total Blood Volume (mL)
Clinical Laboratory
Hematology
2
6
12
Clinical chemistry a
5
6
30
Serology
3.5
1
3.5
Fasting plasma glucose
4
8
32
Pharmacodynamics:
Serum uric acid
3.5
26
91
Pharmacokinetics:
RDEA3170 + metabolites
3
22
66
Febuxostat 
2
22
44
Dapagliflozin
2
22
44
Exploratory:
a)
Pregnancy and follicle stimulating hormone assessments will be performed on the sample collected for 
clinical chemistry at the same time point.
b)
Excluding repeat laboratory investigations.
Repeat blood samples may be collected for safety reasons.  The maximum volume to be drawn 
from each patient must not exceed 500 mL. 
CCI


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8.
TREATMENTS
8.1.
Identity of the Investigational Medicinal Products
Details on the identity of the IMPs are presented in Table 3.
Table 3
Identity of the Investigational Medicinal Products
Investigational product
Dosage form and strength
Provider
RDEA3170
9 mg capsules for oral 
administration
AstraZeneca
Febuxostat
80 mg tablet for oral administration
PAREXEL
Dapagliflozin
10 mg tablets for oral 
administration
AstraZeneca
Dapagliflozin matched placebo
Placebo
AstraZeneca
Details of the batch numbers will be included in the trial master file and the final CSR.
8.2.
Supply of Investigational Medicinal Product
RDEA3170 and dapagliflozin will be supplied by AstraZeneca and provided in bulk labeled
according to the master study specific labels.  Commercial Febuxostat will be supplied by 
PAREXEL. The IMP will be re-packaged into patient specific containers by PAREXEL, as 
applicable.
A release document signed by the pharmacy or designee at the Clinical Unit will be placed in the 
appropriate section of the Trial Master File to document labeling and dispensing of the study 
drug to the patient.
8.3.
Storage and Handling Procedures
Separate instructions for preparation and handling of the IMP will be provided by AstraZeneca.
All IMPs will be stored in a secure facility, details of storage conditions will be provided on the 
label of the IMP.
The AstraZeneca will be permitted upon request to audit the supplies, storage, dispensing 
procedures and records provided that the blind of the study is not compromised.


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8.4.
Labeling
Labels will be prepared in accordance with local regulatory guidelines.
The IMP labels will fulfill Good Manufacturing Practice (GMP) Annex 13 requirements and 
medical device directive for labeling.
Refer to the Drug Manual for more detail on subject 
specific labeling.
8.5.
Drug Accountability, Dispensing and Destruction
The open-label RDEA3170 and febuxostat and the blinded dapagliflozin will be dispensed at 
Visit 2 (Day 1 Treatment Period 1). At Visit 3 (Day 6 Treatment Period 1) all IMPs will be 
returned for drug accountability. The bottles of RDEA3170 and febuxostat will be kept at site 
and re-dispensed to the patients at Visit 4 (Day 1 Treatment Period 2). The blinded dapagliflozin 
10 mg or placebo will be replaced by the other alternative labeled with the same randomization 
code. At Visit 5 (Day 6 Treatment Period 2) all IMPs will be returned for drug accountability.
The IMP provided for this clinical study will be used only as directed in the CSP.
In accordance with GCP, the Investigational Site will account for all supplies of RDEA3170, 
febuxostat, dapagliflozin and placebo.  Details of receipt, storage, assembly/dispensing and 
return will be recorded.
All unused supplies of RDEA3170, febuxostat, dapagliflozin and placebo will either be 
destroyed by PAREXEL or returned at the end of the study in accordance with instruction by the 
Sponsor. Refer to the Drug Manual for more details. 
8.6.
Dose and Treatment Regimens
Patients will receive 9 mg RDEA3170 plus 80 mg febuxostat once daily in combination with 
either placebo or dapagliflozin 10 mg once daily for 7 consecutive days.
Clinical Unit Dosing
Patients will be residential in the Unit from Day -2 to Day 1, and from Day 6 to Day 8.
On Days -2, -1, 1, 6 and 7, patients will receive standardized meals, and will be encouraged to 
consume the entire meal.  Mealtimes and other activities will be synchronized for all patients and 
food and liquid intake specified and monitored as described in the Schedule of Assessments 
(Table 1) and Section 7.4.


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On Day -1, Day 1 and Day 7 of each treatment period, patients will be fasted for 10 hours before 
dosing (for Day -1, clock time of planned dose administration for dosing days) until 4 hours after 
dosing, and will receive standardized meals thereafter.  On Day 1 and Day 7, patients will 
receive the IMPs in the morning with 240 mL water, after an overnight fast of at least 10 hours.  
A standard meal will be given 4 hours after dosing. 
On urine collection days, (Day -1 and Day 7) 400 mL water will be consumed by the patients 
within 15 minutes after IMP administration (for Day -1, clock time of planned dose 
administration for dosing days), followed by 200 mL water every 2 hours until 12 hours after
IMP administration (for Day -1, clock time of planned dose administration for dosing days).  
Patients will consume 400 mL water within 15 minutes after IMP administration, followed by 
200 mL water every 2 hours until 12 hours after IMP administration.   
Home Dosing 
Patients will take the IMPs at home on Days 2 to Day 6.
During home dosing, patients will be instructed to take the IMPs with water and to stay 
adequately hydrated and pause dosing in the event of dehydration, such as occurs with 
gastroenteritis.
Other restrictions, are described in Section 7.4. 
8.7.
Treatment Compliance
Dosing will take place at the PAREXEL Early Phase Clinical Unit and at the patient’s homes.
The administration of all IMPs will be recorded in 
Compliance will be assured by direct supervision and witnessing of study drug administration
when administration is performed at the Clinical Unit.  After IMP administration, a check of the 
patient’s mouth and hands will be performed. 
Compliance will be assured during at home dosing by drug accountability.
8.8.
Concomitant Medication
8.8.1.
Concomitant and Post-study Treatments
Apart from paracetamol/acetaminophen, hormone replacement therapy, systemic contraceptives, 
corticosteroid cream and prescription medication for chronic illness that has been approved by 
the PI, no concomitant medication or therapy will be allowed. 
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The patients should be instructed that no other medication is allowed, including herbal remedies, 
vitamin supplements and OTC products, without the consent of the PI. 
Medication, which is considered necessary for the patient’s safety and well-being, may be given 
at the discretion of the PI during the residential period. 
When any medication is required, it should be prescribed by the PI.  Following consultation with 
AstraZeneca Lead Physician, the PI should determine whether the patient should continue in the 
study.  Administration of concomitant medications that may influence the measurement of the 
PD and/or PK endpoints may be documented as a protocol deviation after consultation of the PI
with AstraZeneca Lead Physician.
8.8.2.
Prior and Concomitant Medication 
Prior medications are those that started and stopped before the first dose of IMP; all medications 
taken after first dosing are considered as concomitant (including medications that started before 
dosing and continued after).  Prior medication started within 3 months before the first dose of 
IMP will be recorded also in the concomitant medication module of 
. 
8.9.
Randomization 
8.9.1.
Patient Enrolment and Randomization 
The PI will ensure:
x
Signed informed consent is obtained from each potential patient before any study specific 
procedures are performed. 
x
Each potential patient is assigned a unique enrolment number at screening upon signing the 
Informed Consent. 
x
The eligibility of each patient is in accordance with the inclusion and exclusion criteria.
x
Each eligible patient is assigned a unique randomization code. 
Randomization codes will be assigned strictly sequentially as patients become eligible for 
randomization (codes to be used without leading zero[s]).
When using unique enrolment number, the specific format must be followed (i.e., reduced 
enrolment number, e.g., “
” [for Baltimore] and “
” [for Los Angeles] for 
outputs).  The site number for Baltimore is 
 and the site number for Los Angeles is 
. 
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If a patient withdraws his/her participation in the study, then his/her enrolment/randomization 
code cannot be reused.  If a replacement is mandated, replacement patients will receive a new 
randomization number and will be allocated to the same treatment sequence as the replaced 
patient.
8.9.2.
Procedures for Randomization 
Upon completion of the randomization requirements specifications form, the randomization will 
be produced by PAREXEL according to the AstraZeneca randomization system (
). 
Twenty-four patients were randomized equally (1:1 ratio) into 1 of 2 treatment sequences (AB, 
BA) to ensure 20 evaluable patients.  An additional set of replacement random numbers were
generated within AZRand on a like for like treatment sequence basis.
Due to inadequate urine sampling, it was decided to include 12 additional patients to obtain valid 
assessment of the primary endpoint for at least 20 evaluable patients.
An additional 12 patients will be randomized to allow for at least 7 additional completers. With 
24 completers available for the interim analysis, this will provide for a total sample size of 
36 evaluable patients. A separate randomization list will be created for these additional patients.
8.9.3.
Procedures for Handling Incorrectly Randomized Patients 
Patients who fail to meet the inclusion criteria or meet any exclusion criterion should not, under 
any circumstances, be randomized into the study.  There can be no exceptions to this rule. 
Where a patient, who does not meet the selection criteria, is randomized in error and this is 
identified before dosing, the patient should be withdrawn from the study.  If a patient is 
withdrawn before dosing, they will be replaced.
If a patient, who does not meet the selection criteria and has been dosed before the error is 
identified; the patient should be withdrawn and advised to continue safety assessments to ensure 
their safety.  The PI will inform the AstraZeneca Lead Physician of the error and a joint decision
made as to whether the patient should be replaced. 
8.10.
Blinding
8.11.
Methods for Ensuring Blinding
This study is double-blind with regard to treatment (dapagliflozin or placebo) in each treatment 
period.  
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Dapagliflozin and placebo will be matched for formulation, appearance and amount.  Patients
randomized to placebo received the same number of tablets as patients on active drug. 
The randomization list should be kept in a secure location until the database lock or equivalently, 
clean file is declared.
The pharmacokineticist will remain blinded during the study conduct, unless otherwise required 
based on study findings.
The pharmacokineticist will be unblinded to perform the final PK analyses after all patients have 
completed the study, final bioanalytical results are available and all required study data are 
considered clean.  This may occur before database lock.
The following personnel will have access to the randomization list:
x
The AstraZeneca personnel carrying out the labeling and packaging of patient specific 
treatments.
x
The pharmacy personnel preparing study drug at the site.
x
The personnel performing the bioanalyses of the plasma/urine samples.
The randomization list should be kept in a secure location until the end of the study.
8.12.
Methods for Unblinding the Study
Individual treatment codes, indicating the treatment randomization for each randomized patient,
will be available to the PI and the pharmacist.
In most of the studies using blinding, the treatment code should not be broken except in medical 
emergencies when the appropriate management of the patient requires knowledge of the 
treatment randomization.  The PI documents and reports the action to AstraZeneca, without 
revealing the treatment given to patient to the AstraZeneca staff.  
In the event of a medical emergency when management of a patient’s condition requires 
knowledge of the trial medication, the treatment received may be revealed by personnel
authorized by the PI.  If possible, such emergencies are to be discussed with AstraZeneca before
disclosure of the treatment allocation.  Reasons for breaking a code will be clearly explained and 
justified in the patient’s CRF.  The date on which the code was broken together with the identity 
of the person responsible will also be documented.


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9.
MEASUREMENTS AND METHODS OF ASSESSMENTS
9.1.
Appropriateness of Measurements
Standard measures to assess PD, PK, safety and tolerability apply during the study.  For the 
doses of RDEA3170, febuxostat and dapagliflozin planned to be given during this study, no 
safety issues are expected.
For timing of assessments, refer to Table 1.
9.2.
Pharmacodynamics
9.2.1.
Sample Collection and Handling
Urine samples for the determination of urinary excretion of UA will be collected for each 
treatment period as specified in the Schedule of Assessments (Table 1).
Blood samples for the determination of sUA levels will be collected for each treatment period as 
specified in the Schedule of Assessments (Table 1).
Samples will be collected, handled, labeled, stored and shipped as detailed in the Laboratory 
Manual.
9.2.2.
Pharmacodynamic Assays
Blood samples for determination of sUA in serum and urine samples for the determination of UA 
in urine will be analyzed by safety laboratory, using a validated assay.
9.3.
Pharmacokinetics
9.3.1.
Sample Collection and Handling
Blood samples for the determination of plasma concentrations of RDEA3170 (and its metabolites 
M1 and M8), febuxostat and dapagliflozin will be collected for each treatment period as 
specified in the Schedule of Assessments (Table 1).
Samples will be collected, handled, labeled, stored and shipped as detailed in the Laboratory 
Manual.  Plasma samples will be analyzed for RDEA3170 (and its metabolites M1 and M8), 
febuxostat and dapagliflozin using a validated assay.


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9.3.2.
Pharmacokinetic Drug Assays
Blood samples for determination of RDEA3170 (and its metabolites M1 and M8), febuxostat and 
dapagliflozin concentrations in plasma will be analyzed by Covance on behalf AstraZeneca 
Research and Development (R&D), using a validated assay.
Full details of the analytical method and analyses performed used will be described in a separate 
Bioanalytical Report.
Additional analyses may be conducted on the biological samples to further investigate the 
presence and/or identity of drug metabolites.
9.4.
Safety and Eligibility Measurements
Safety and tolerability variables will include:
x
Adverse events
x
Events of diabetic ketoacidosis
x
Vital signs (systolic and diastolic BP, pulse rate)
x
Electrocardiogram(s)
x
Physical examination
x
Weight
x
Laboratory assessments (hematology, clinical chemistry and urinalysis).
Viral serology and drugs of abuse and alcohol will be assessed for eligibility.  Follicle 
stimulating hormone (post-menopausal females only), pregnancy testing (females only) and use 
of concomitant medication will also be assessed and reported.
9.4.1.
Adverse Events
Refer to Section 12.2.3.
9.4.2.
Events of Diabetic Ketoacidosis
Patients will be monitored for signs and symptoms consistent with ketoacidosis, including 
nausea, vomiting, abdominal pain, malaise and shortness of breath.  Patients with these signs and 
symptoms will be should be assessed for ketoacidosis, even if blood glucose levels are below 
14 mmol/L (250 mg/dL).


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9.4.3.
Vital Signs 
The following variables will be collected after the patient has rested in the supine position for at 
least 5 minutes:
x
Systolic BP (mmHg)
x
Diastolic BP (mmHg)
x
Pulse rate (bpm) 
The measurement of vital signs will be carried out according to the relevant PAREXEL standard 
operating procedures (SOPs). 
9.4.4.
Electrocardiograms 
9.4.4.1.
Resting 12-lead Electrocardiogram 
At the time points specified in the Schedule of Assessments (Table 1), a 10-second 12-lead ECG 
will be obtained after 10 minutes supine rest) using 
. 
The Investigator will judge the overall interpretation as normal or abnormal and this evaluation 
will be reported in 
.  If abnormal, it will be further documented as to whether or not the 
abnormality is clinically significant by the Investigator.  For all abnormalities (regardless of 
clinical significance), the specific type and nature of the abnormality will be documented in 
ClinBase.  Clinically significant findings should also be documented on the AE page of the CRF 
if applicable.
The Investigator may add extra 12-lead resting ECG safety assessments if there are any abnormal 
findings or if the Investigator considers it is required for any other safety reason.  These 
assessments should be entered as an unscheduled assessment. 
All ECG readings will be digitally stored as source documents.
9.4.5.
Physical Examination 
Full
The complete physical examinations will include an assessment of the general appearance, 
respiratory, cardiovascular, abdomen, skin, head, and neck (including ears, eyes, nose and 
throat), lymph nodes, thyroid, musculoskeletal and neurological systems.
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Brief (Abbreviated)
The brief physical examinations will include an assessment of the general appearance, skin, 
abdomen, cardiovascular system and respiratory; and any organ systems pertinent to the patient’s 
signs, symptoms or AEs.
9.4.6.
Laboratory Assessments
9.4.6.1.
Hematology
Hematology 
White blood cell (WBC) count
Neutrophils absolute count 
Red blood cell (RBC) count
Lymphocytes absolute count 
Hemoglobin (Hb)
Monocytes absolute count 
Hematocrit (HCT)
Eosinophils absolute count 
Mean corpuscular volume (MCV)
Basophils absolute count 
Mean corpuscular hemoglobin (MCH)
Platelets
Mean corpuscular hemoglobin concentration (MCHC)
Reticulocytes absolute count 
Hemoglobin A1c (HbA1c) (Screening Visit only)
9.4.6.2.
Clinical Chemistry
Serum Biochemistry
Sodium
Alkaline phosphatase (ALP)
Potassium
Alanine aminotransferase (ALT)
Blood Urea Nitrogen (BUN)
Aspartate aminotransferase (AST)
Creatinine
Gamma glutamyl transpeptidase (GGT)
Albumin
Total Bilirubin
Calcium
Unconjugated bilirubin
Phosphate
Cystatin-C
Uric acid
eGFR a
Estimated Creatinine Clearance (CrCl)
Plasma Biochemistry
Glucose (fasting) b
a)
Screening Visit only (Visit 1)
b)
Plasma glucose after at least 4 hours fasting.


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9.4.6.3.
Urinalysis by Dipstick
Urinalysis
Glucose
Protein
Blood
Microscopy (if dipstick is positive for protein or blood): RBC, WBC, Casts (Cellular, Granular, Hyaline)
9.4.6.4.
Urinalysis for Urine Collection Interval
Urinalysis
Uric acid
Creatinine
Glucose
Cystatin-C
Sodium
pH
9.4.6.5.
Pregnancy Testing
Pregnancy test (females only)
Human beta chorionic gonadotrophin (HCG)
Follicle-stimulating hormone (FSH) (Screening Visit Only)
9.4.6.6.
Viral Serology
Viral Serology
Human immunodeficiency virus (HIV) I and II
Hepatitis C Virus antibody
Hepatitis B surface antigen (HBsAg)
9.4.6.7.
Drugs of Abuse and Alcohol
Drugs of Abuse and Alcohol
Amphetamine/Ecstasy
Benzodiazepines
Ethanol
Methadone Metabolites
Cannabinoids
Barbiturates
Cocaine
Phencyclidine
Opiates 
Tricyclic anti-depressants (TCA)
Drugs of abuse screen will be done via a urine sample.  Alcohol screen will be done via a serum 
sample.
9.4.7.
Concomitant Medication
Refer to Section 8.7.


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9.5.
Exploratory Assessments
9.5.1.
Collection of Biomarker Samples 
Blood and urine samples for biomarkers, bio-banking and metabolomics will be collected for 
each treatment period as specified in the Schedule of Assessments (Table 1).
Samples will be collected, handled, labeled, stored and shipped as detailed in the Laboratory 
Manual.
9.5.2.
Collection of Pharmacogenetic Sample
Patients will be offered the possibility to participate in optional genetic exploratory research.  
After signing a separate consent for optional genetic research, a blood sample will be collected in 
accordance with the inclusion criteria and the Schedule of Assessments, see Table 1. 
If for any reason the blood sample is not drawn on Day 1 of Treatment Period 1 according to the 
Schedule of Assessments, it may be taken at any time up until the last study visit.  Although the 
genotype is a stable parameter, early sample collection is preferred to avoid introducing bias 
through excluding patients who may withdraw due to an AE, such patients would be important to 
include in any genetic analysis.  Only 1 sample should be collected per patient for genetic 
research during the study. 
A record of the date the patient consented to the genetic research and the date and time of the 
blood sample collection will be recorded in 
.  Samples will be collected, handled, 
labeled, stored and shipped as detailed in the Laboratory Manual.
9.6.
Procedures for Handling of Biological Samples
9.6.1.
Storage and Destruction of Biological Samples
Biologic samples will be retained for a maximum of 15 years following the last patient’s last 
visit in the study.
9.6.1.1.
Pharmacokinetic Samples 
Pharmacokinetic samples will be disposed of after the Bioanalytical Report finalization or 
6 months after issuance of the draft Bioanalytical Report (whichever is earlier), unless requested 
for future analyses.
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Pharmacokinetic samples may be disposed of or destroyed and anonymized by pooling.  
Additional analyses may be conducted on the anonymized, pooled PK samples to further 
evaluate and validate the analytical method.  Any results from such analyses may be reported 
separately from the CSR.
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis of 
the test samples.  The results from the evaluation will not be reported in the CSR but separately 
in a Bioanalytical Report.
Any residual or back-up PK samples may be used for exploratory safety, metabolite and/or 
biomarker research and may be stored for up to 15 years (in this case, residual back-up PK 
samples will be shipped to an AstraZeneca designated BioBank).
9.6.1.2.
Pharmacodynamic Samples 
Pharmacodynamic samples will be retained for a maximum of 15 years following the last 
patient’s last visit in the study.  The results from future analysis will not be reported in the CSR. 
9.6.1.3.
Pharmacogenetic Samples
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.
9.6.2.
Labeling and Shipment of Biohazard Samples
Samples will be labeled and shipped in accordance with the Laboratory Manual and the 
Biological Substance, Category B regulations (materials containing or suspected to contain 
infectious substances that do not meet Category A criteria) (for International Airline 
Transportation Association [IATA] guidance, see Appendix 15.2 of this CSP).
Any samples identified as Infectious Category A materials will not be shipped and no further 
samples will be taken from the patient unless agreed with AstraZeneca and appropriate labeling,
shipment and containment provisions are approved. 
9.6.3.
Chain of Custody of Biological Samples
A full chain of custody will be maintained for all samples throughout their life cycle.
The PI will ensure full traceability of collected biological samples from the patients while in 
storage at the Clinical Unit until shipment and will keep documentation of receipt of arrival. 
The sample receiver will keep full traceability of samples while in storage and during use, until 
used, disposed of, or until further shipment or disposal (where appropriate) and will keep 
documentation of receipt of arrival.
Samples retained for further use will be registered in the AstraZeneca bio-bank system during the 
entire life cycle.
9.6.4.
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 if not already analyzed and the action documented. 
As collection of donated biological samples is an integral part of the study then the patient is 
withdrawn from further study participation.  If the patient withdraws consent for the genetic 
component of the study, then they may continue in the study. 
AstraZeneca ensures the central laboratory(ies) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed, the action 
documented and the signed document returned to the study site. 
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10.
DATA QUALITY ASSURANCE AND DATA MANAGEMENT
10.1.
Quality Control and Source Data Verification 
Source data verification will be conducted with due regard to patient confidentiality. 
The Clinical Unit will allow the study monitor and Sponsor representative direct access to all 
study documents, medical files and source documents to enable verification of the study data, 
while maintaining the anonymity of the patient and confidentiality of the data.
Internal quality control will be performed at all stages of the study by the Clinical Unit.
10.2.
Audit/Inspections
The Clinical Unit facilities and all study data/documentation may be audited/inspected by 
independent auditor/inspector/any representatives of regulatory authorities.  The PI must allow 
the applicable persons access to all relevant facilities and data/documents.  The PI must be 
available to discuss any findings/issues. 
If an audit was performed, the audit certificate will be included in the CSR. 
10.3.
Study Monitoring
The conduct of the study will be monitored by an independent PAREXEL monitor or a 
subcontracted monitor to ensure compliance with applicable regulatory requirements and GCP.  
The summary of the documentation of the monitoring visits will form part of the study 
documentation and will be archived as such. 
10.4.
Data Collection 
The 
 system is an electronic source data capturing and information management system.  
The system combines all aspects of source data capturing with process control and clinical study 
management.  All clinical and laboratory data, except those which are paper-based or provided 
by external vendor, will be collected in 
  Only paper-based data will be subject to data 
entry.  For electronic source data, no data entry will be performed. 
The responsible study monitor will check data at the monitoring visits to the Clinical Unit.  The 
PI will ensure that the data collected are accurate, complete and legible.  Data will be monitored 
within 
 by the study monitor before being exported.  Any changes made during 
monitoring will be documented with a full audit trail within 
.
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10.4.1.
Case Report Forms and Source Documents
All data obtained using paper collection methods during the clinical study will be recorded in 
.  All source documents from which 
 entries are derived should be placed in 
the patient’s personal records.
The original 
 entries for each patient will be checked against source documents by the 
study monitor.  Instances of missing or uninterpretable data will be discussed with the PI for 
resolution. 
10.4.2.
Access to Source Documents
During the clinical study, a study monitor will make Clinical Unit visits to review protocol 
compliance, compare 
 entries and individual patient’s personal records, assess IMP 
accountability and ensure that the clinical study is being conducted according to pertinent 
regulatory requirements.  
 entries will be verified against source documents.  The 
review of medical records will be handled confidentially to ensure patient anonymity.
Checking of the 
 entries for completeness and clarity and verifying with source 
documents, will be required to monitor the clinical study for compliance with GCP and other 
regulations.  Moreover, regulatory authorities of certain countries, IRBs may wish to carry out 
source data inspections on-site, and the Sponsor’s clinical quality assurance group may wish to 
carry out audits.  Direct access to source data will be required for these inspections and audits; 
they will be carried out giving due consideration to data protection and patient confidentiality.  
The PI assures the Sponsor of the necessary support at all times.
10.5.
Data Management 
PAREXEL will utilize standardized and validated procedures and systems to collect, process and 
file the clinical data of this study.  Any system used will be compliant with FDA 21 CFR Part 11 
requirements.
Since this is a multi-site study, for the purposes of data management processing all data obtained 
during the clinical study will be recorded in 
The original 
 entries for each subject will be checked against 
 and any 
additional paper source documents as necessary, by the study monitor.  Instances of missing or 
uninterpretable data will be discussed with the Investigator for resolution. 
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After the data has been monitored by the responsible study monitor all data received will be 
reviewed, logged and filed.
A data management plan (DMP) will be prepared to describe the processes and data-flow within 
the clinical study.  Timelines, versions for the computer systems and the coding will be defined 
in the DMP, and if applicable, Sponsor specific requests will also be documented within.  The 
DMP will be finalized before first dose where possible but before database lock.
A data validation specification (DVS) will be created to outline the validation checks to be 
performed during the study.  The DVS must be finalized before data validation.
Corrections resulting from these validation checks will be confirmed as response to query.  This 
process will be repeated until no further discrepancies are found.  The data will then be declared 
as clean.  Applicable documentation will be stored in the study files.
Only trained study staff will have access to the clinical database and every change in data will 
have a full audit trail.


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11.
STATISTICAL METHODS
11.1.
Overview
The statistical methodology below describes the statistical analysis as it is foreseen when the 
study is being planned.
If circumstances should arise during the study rendering the analysis inappropriate, or if in the 
meantime improved methods of analysis should become known, different analyses may be 
performed.  A separate Statistical Analysis Plan (SAP) will be written for the study.  Any 
deviations from the statistical methodology defined in the SAP, reasons for such deviations and 
all alternative/additional statistical analyses that may be performed will be described in the CSR.
The verification and review of all statistical modeling assumptions will be documented 
appropriately.
11.2.
General Statistical Methodology
All original and derived parameters as well as demographic and disposition data will be listed 
and described using summary statistics.  All safety data (scheduled and unscheduled) will be 
presented in the data listings.
Demographic and baseline data will be summarized for all randomized patients.
Pharmacodynamic and PK data will be summarized by treatment.  Safety and tolerability data 
will be summarized by treatment, if applicable.
Frequency counts (number of patients [n] and percentages) will be made for each qualitative 
variable.  Descriptive statistics (n, mean, standard deviation [SD], median, minimum and 
maximum) will be calculated for each quantitative variable (unless otherwise stated).  
'HVFULSWLYHVWDWLVWLFVZLOORQO\EHSUHVHQWHGLIQ 3.
The following rules will apply to any repeated safety assessments occurring within each 
treatment period:
x
If the repeated measurement of a specific parameter occurs before IMP administration 
(Day 1), then the last obtained value before dosing will be used in the descriptive statistics 
and in the calculation of changes from baseline;
x
If the repeated measurement of a specific parameter occurs after IMP administration (Day 1), 
then the first (non-missing) value after dosing will be used in descriptive statistics and in the 
calculation of changes from baseline.


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The planned sequence for measurement of multiple assessments at the same time point is 
described in Section 7.3. 
For safety assessments performed at the Screening Visit and the Follow-up Visit, the following 
rules will apply for any repeated assessments:
x
If the repeated assessment occurs at the Screening Visit the last available value will be used 
in the summary statistics;
x
If the repeated assessment occurs at the Follow-up Visit, the first non-missing assessment 
will be used in the summary statistics.
All statistical analyses and production of tables, figures and listings will be performed using 
 or later. 
11.2.1.
Missing Data
Missing dates and times in the AE data will be handled as described in Section 11.11.1.
Concentrations that are non-quantifiable (NQ) in the PK data will be handled as described in 
Section 11.10.2.
There will be no imputations of other missing data.  All patients will be included into the safety 
analyses as far as the data permit.
11.3.
Study Populations 
11.3.1.
Safety Analysis Set
The safety analysis set will include all patients who received at least 1 dose of IMP and for 
whom any safety post-dose data are available.
Unless otherwise stated the safety analysis set will be used for the presentation of all 
demographic and disposition data, as well as all safety analyses.  Exposure to IMP will also be 
presented using the safety analysis set.
11.3.2.
Pharmacodynamic Analysis Set 
Analysis of the primary variable, maximum UA excretion in urine per hour (UUA), as well as 
the secondary variable sUA at 7 days will be done using the Full Safety Analysis Set (FAS) 
comprising of all patients randomized.  Any sensitivity analysis will be considered using the Per 
Protocol (PP) Set as sensitivity analysis.  The PP Set will be defined as all patients in the FAS 
without major protocol deviations (to be defined before database lock).
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11.3.3.
Pharmacokinetic Analysis Set
The PK analysis set for each cohort will consist of all patients in the safety analysis set for whom 
at least 1 of the primary PK parameters can be calculated for at least 1 analyte (RDEA3170, 
Febuxostat or dapagliflozin), and who have no major protocol deviations thought to impact on 
analysis of the PK data.
Patients may be excluded from the PK analysis set as a result of the following:
x
Data from patients who experienced vomiting during the study may be deleted from 
summary statistics and statistical analysis if vomiting occurred at or before median tmax
A patient may be excluded from the analysis only for the specific treatment period in which the 
AE occurred.
The exclusion of any patients or time points from the calculation of the PK parameters will be 
documented by the PK Scientist including the reason(s) for exclusion.
The available concentration data and PK parameter data for any patients excluded from the PK 
analysis set will be listed only.  Concentration data for patients excluded from the PK analysis 
set will be presented in the individual figures of concentration versus time plots.
11.3.4.
Randomized Set
The Randomized Set will consist of all patients randomized into the study.
11.4.
Determination of Sample Size
Basis for this sample size calculation is the study RDEA3170-204.  Baseline (as well as Day 7) 
UUA data are highly skewed and hence log-transformation is applied. 
Based on the RDEA3170-204 study, we assume that the within patient SD for the between 
treatment difference in UUA (comparing within patient changes on log-scale from baseline to 
day 7 for the respective treatments) is 0.32. 
A study with 10 patients completing each sequence of treatments (dapagliflozin-placebo or 
placebo-dapagliflozin) will then (under the assumed SD above) estimate the true, unknown, 
mean ratio for dapagliflozin/placebo with a precision of 16.6% as half-width of the 95% 
confidence interval (CI).
Thus, 24 patients in total were randomized to ensure 20 (2*10) patients complete the study
(12 randomized patients per sequence). 


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Twenty patients completing their treatment sequence, is based on previous experience of studies 
investigating relative bioavailability in presence of concomitant treatments, seen as a suitable 
sample size.  As based on previous experience of studies investigating relative bioavailability in 
presence of concomitant treatments, 12 patients completing each treatment sequence is 
considered a suitable sample size.
Interim Analysis of Sample Size and Power of the Statistical Test
During the Blind Data Review Meeting (BDRM), the unblinded data were reviewed and 
patients from site 
 were identified as invalid for purposes of analysis of the primary 
endpoint. 
Based on these results, it was decided to enroll an additional 12 patients to ensure an adequate 
sample size to evaluate the effects of intensive UA lowering with RDEA3170, febuxostat and 
dapagliflozin on urinary excretion of UA. This will allow for 36 evaluable patients overall; of 
these it is expected that at least 20 patients will provide evaluable data for the primary endpoint. 
11.5.
Protocol Deviations 
Protocol deviations are considered any deviation from the CSP relating to a patient, and include 
the following: 
x
Inclusion/exclusion criteria deviations
x
Dosing deviations (e.g., incorrect treatment received, patient was not fasted as per the 
protocol requirements before and after dosing) 
x
Time window deviations for safety and/or PD and/or PK assessments
x
Patients receiving prohibited concomitant medications 
x
Other procedural and study conduct deviations recorded by the Clinical Unit on a protocol 
deviation log 
The criteria for the assessment and reporting of protocol deviations will be stipulated in a 
separate study specific protocol deviation specification (PDS) document.  This will include a 
Windows Allowance Document (WAD), which stipulates tolerance windows for safety, PD and 
PK assessments.  Measurements performed within these tolerance windows will not be 
considered as protocol deviations and will not be reported. 
All protocol deviations will be discussed at the data review meeting before database hard lock in 
order to define the analysis sets for the study.
C
CI
PPD


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Important protocol deviations will be listed by patient.
Protocol deviations will be handled in accordance with PAREXEL SOPs.
For handling of protocol amendments, see Section 3.6.
11.6.
Patient Disposition
A randomization listing will be presented and include the following: each patient’s 
randomization number, the patient’s full enrolment number, the treatment sequence to which the 
patient has been randomized and the country where the location of the study center is located.
Patients and/or data excluded from the PD/PK analysis set will be listed including the reason for 
exclusion.  Patient disposition will be summarized and will include the following information: 
number of patients randomized and dosed, number and percentage of patients completing the 
study and the number and percentage of patients who were withdrawn (including reasons for 
withdrawal).  Disposition data will be presented based on all patients randomized.
Patient discontinuations will be listed including the date of study exit, duration of treatment and 
reason for discontinuation.  A listing of informed consent response will also be presented.
11.7.
Demographic and Baseline Data
Demographic variables (age, gender, race, ethnicity, height, weight and BMI) will be listed by 
patient.  Demographic characteristics (age, gender, race and ethnicity) and patient characteristics 
(height, weight and BMI) will be summarized separately for all randomized patients.  The 
denominator for percentages will be the number of randomized patients.
Medical history data will be listed by patient
including visit, description of the 
disease/procedure, Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class 
(SOC), MedDRA Preferred Term, start date and stop date (or ongoing if applicable).
A summary of the number and percentage of patients who had relevant medical histories will be 
presented by treatment sequence and for all patients for the medical history Preferred Term.
11.8.
Prior and Concomitant Medication and Drug Administration
11.8.1.
Prior and Concomitant Medication
Prior medications are those that started and stopped before the first dose of IMP; all medications 
taken after first dosing are considered as concomitant (including medications that started before


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dosing and continued after). Prior medication started within 3 months before the first dose of 
IMP will be recorded also in the concomitant medication module of 
.  
Prior and concomitant medication will be listed by patient and will include the following 
information: reported name, Preferred Term, the route of administration, dose, frequency, start 
date/time, duration and indication.  Prior and concomitant medication will be coded according to 
the Sponsor’s drug dictionary. 
11.8.2.
Drug Administration
Drug administration dates and times will be listed for each patient and treatment period.
11.9.
Pharmacodynamic Analysis 
11.9.1.
Pharmacodynamic Variables 
The following PD variables will be assessed. 
Primary Variable
x
Uric acid excretion in urine per hour 
Peak UA excretion during the first 8 hours maximum UA excreted as measured in mg, in an 
interval out of the first 8 hours on Day 7 (after 7 days of treatment).
Secondary Variable 
x
Serum UA
Serum UA levels on Day 7 (after 7 days of treatment).
11.9.2.
Presentation of Pharmacodynamic Data 
A listing of PD blood sample and urine collection times, as well as derived sampling time 
deviations will be provided.  Serum and urine UA concentrations will be summarized by 
treatment using appropriate descriptive statistics.  Where possible, the following descriptive 
statistics will be presented: n, geometric mean, geometric CV, arithmetic mean, arithmetic SD,
median, minimum and maximum. 
11.9.3.
Statistical Analysis of Pharmacodynamic Data 
Due to the explorative nature of this study, no adjustment for multiple testing of primary variable 
and secondary variables will be done. 
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Analysis of the primary variable will be done on log-transformed values, looking at changes at 
day 7 of treatment (Day 7) from maximum baseline (Day -1) excretion. A mixed effects 
Analysis of Variance (ANOVA) model, correcting for treatment (dapagliflozin/placebo) and 
sequence (dapagliflozin-placebo or placebo-dapagliflozin) as fixed effects as well as patient
within sequence as random effect, will be used.
Results will be presented as geometric mean ratios from baseline within treatment with 95% CIs,
based on Student’s t-distribution. A geometric mean ratio for change from baseline between 
treatments with 95% CI will also be constructed, using Student’s t-distribution. 
Analysis of the secondary variable sUA will be conducted in an equivalent way as UUA, using 
log-transformed values and change from baseline (Day -1) to Day 7.
A mixed effect model 
correcting for the same fixed and random effects as for UUA will be employed. Results will be 
presented in the same way as the results for UUA. No adjustment for multiplicity will be done 
for secondary variables, due to the explorative nature of the study.
Effects on kidney function (secondary objective, variables: Estimated glomerular filtration rate 
cystatin-C, creatinine) will be assessed in the same way as UUA and sUA.  Log-transformation 
of data will be done when needed for application of statistical models based on normal theory.
A geometric mean ratio for the change from baseline response will be calculated by taking the 
anti-logarithm of the difference between treatment means.  A 95% CI for each treatment ratio 
will be obtained by taking the anti-logarithm of the 95% CI endpoints for each mean difference.
Analysis of the secondary variable sUA will be conducted using a similar approach as described 
above for the analysis of UUA, using log-transformed values and change from baseline (Day -1)
to Day 7
In these analyses, an adjustment for multiple comparisons will not be considered.
For all ANOVA models described above the geometric mean ratios, their 95% CI, along with the 
ratios of individual patient values will be plotted to visualize the treatment comparisons.


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11.10. Pharmacokinetic Analysis 
11.10.1.
Pharmacokinetic Parameters
Where possible, the following PK parameters will be calculated for RDEA3170, M1, M8 
febuxostat and dapagliflozin using plasma concentrations.
Primary PK parameters
$8&Ĳ
Area under plasma concentration time curve over a dosing interval 
(24 hours)
AUClast
Area under plasma concentration time curve from time zero to the 
time of last measurable concentration
Cmax
Maximum observed plasma concentration
Secondary PK parameters
tmax
Time to reach maximum observed plasma concentration
tlast
Time of last measurable concentration
Additional PK parameters may be determined where appropriate.
11.10.2.
Derivation of Pharmacokinetic Parameters
The PK analyses of the plasma concentration data for RDEA3170, M1, M8 febuxostat and 
dapagliflozin will be performed by Covance, on behalf of Clinical Pharmacokinetic Alliance, 
AstraZeneca R&D.
Pharmacokinetic parameters will be derived using non-compartmental methods with 
 
.  All descriptive and 
inferential statistical computations will be performed using 
. 
Pharmacokinetic analysis will, where possible, be carried out using actual times recorded in the 
raw data.  If actual times are missing, nominal times will be used.
Plasma concentrations which are NQ before the first quantifiable concentration will be set to a 
value of zero.  After the first quantifiable concentration, any NQ plasma concentrations will be 
set to missing for all concentration profiles.  Where 2 or more consecutive concentrations are NQ 
at the end of a profile, the profile will be deemed to have terminated and therefore any further 
quantifiable concentrations will be set to missing for the calculation of the PK parameters unless 
it is considered to be a true characteristic of the profile of the drug.
CCI
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If an entire concentration-time profile is NQ, the profile will be excluded from the PK analysis.
Cmax and tmax will be obtained directly from the individual concentration-time profiles.
$8&ĲDQG$8&ODst will be calculated using the linear trapezoidal method when concentrations 
are increasing and the logarithmic trapezoidal method when concentrations are decreasing.
The minimum requirement for the calculation of $8&Ĳ and AUClast will be the inclusion of at 
least 3 consecutive plasma concentrations above the lower limit of quantification (LLOQ), with 
at least 1 of these concentrations following Cmax.
11.10.3.
Presentation of Pharmacokinetic Data
A listing of PK blood sample collection times, as well as derived sampling time deviations will 
be provided.  Plasma concentrations and PK parameters will be summarized by treatment and 
analyte using appropriate descriptive statistics.  Where possible, the following descriptive 
statistics will be presented: n, geometric mean, geometric CV, geometric +SD, geometric –SD 
arithmetic mean, arithmetic SD, median, minimum and maximum.  For tmax and tlast, only n, 
median, minimum and maximum will be presented.
The geometric mean is calculated as the exponential of the arithmetic mean calculated using 
log-transformed data.
The CV% is calculated as
where s is the SD of the log-transformed data.
The geometric ±SD (geometric +SD and geometric –SD) is calculated as exp[μ ± s] For
concentration data will be presented using the same number of significant figures as the data 
received from the bioanalytical laboratory; for PK parameters, the listings will be presented 
according to the following rules:
x
Cmax – will be presented to the same number of significant figures as received from the 
bioanalytical laboratory.
x
tmax and tlast – will be presented as received in the data, usually to 2 decimal places.
x
$8&Ĳ and AUClast - will be presented to 3 significant figures.
For PK concentration data, all descriptive statistics will be presented to 4 significant figures 
except for the minimum and maximum which will be presented to 3 significant figures.
For PK parameters data, the descriptive statistics will be presented according to the following 
rules:




1
exp
100
2 

s


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x
Cmax, $8&Ĳ, AUClast – all descriptive statistics will be presented to 4 significant figures 
with the exception of the minimum and maximum which will be presented to 3 significant 
figures.
x
tmax, tlast – all descriptive statistics will be presented as received in the data, usually to 2
decimal places.
Individual plasma concentrations below the LLOQ of the bioanalytical assay will be listed as NQ 
(not quantifiable) with the LLOQ defined in the Tables, Figures and Listings (TFLs), as 
applicable.  For calculation of descriptive statistics, plasma concentrations that are NQ or if there 
are missing values (e.g., no result [NR]) will be handled as follows:
Where there is NR, these will be set to missing.
x
At a time point where less than or equal to 50% of the values are NQ, all NQ values will be 
set to the LLOQ, and all descriptive statistics will be calculated.
x
At a time point where more than half of the values are NQ, the mean, SD, geometric mean,
geometric +SD, geometric –SD and CV% will be set to Not Calculated (NC).  The maximum
value will be reported from the individual data, and the minimum and median will be set to 
NQ.
x
If all values are NQ at a time point, no descriptive statistics will be calculated for that time
point.  Not calculated “NC” will be written in the field for SD, geometric +SD, geometric –
SD and CV% and NQ will be written in fields for mean, geometric mean, minimum, median 
and maximum.
x
The number of NQ values (n below LLOQ) will be reported for each time point.
Three observations > LLOQ are required as a minimum for a plasma concentration or PK 
parameter to be summarized. Two values are presented as a minimum and maximum with the 
other summary statistics as NC.
Data from patients excluded from the PK analysis set will be included in the data listings, but not 
in the descriptive statistics or in the inferential statistics.
Individual plasma concentrations versus actual time will be plotted in linear and 
semi-logarithmic scale with all treatments overlaid on the same plot and separate plots for each 
patient and each analyte.
Combined individual plasma concentration versus actual times will be plotted in linear and 
semi-logarithmic scale.  Separate plots for each treatment and each analyte.


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Geometric mean plasma concentration (±SD) versus nominal sampling time will be plotted in 
linear and semi-logarithmic (no SD presented) scale with all treatments overlaid on the same 
figure and separate figure for each analyte.
For mean plots, NQ values will be handled as described for the summary tabulations; for 
individual plots, plasma concentrations which are NQ before the first quantifiable concentration 
will be set to a value of zero (linear plots only).  After the first quantifiable concentration, any 
NQ plasma concentrations will be regarded as missing.  All plots will be based on the PK 
analysis set, with the exception of individual plots by patient which will be based on the safety 
analysis set.
11.10.4.
Statistical Analysis of Pharmacokinetic Data
Pharmacokinetic variables (AUCW, AUClast, Cmax, tmax, tlast) and plasma concentrations of 
RDEA3170, M1, M8, febuxostat and dapagliflozin will be analyzed using the PK set as defined 
above.  Plasma concentrations of RDEA3170, M1, M8, febuxostat and dapagliflozin will be 
presented descriptively by IMP, study day/treatment and time point, using both summary tables 
and figures as well as individual plots of plasma concentration vs. time and day per IMP.  
Derived pharmacokinetic parameters will be presented descriptively by IMP and study 
day/treatment. 
To assess the potential drug-drug interaction of RDEA3170 and febuxostat given with and 
without dapagliflozin, the natural log-transformed PK parameters $8&Ĳ, AUClats and Cmax of 
RDEA3170, M1, M8 and febuxostat will be separately analyzed using a mixed effects ANOVA
model, fitting a fixed effect for treatment and random effect for patient.  The point estimate and 
90% CI for the difference between treatments (RDEA3170 + febuxostat + dapagliflozin and 
RDEA3170 + febuxostat) will be constructed.  The point estimate and adjusted 90% CIs will 
then be exponentially back transformed to provide point and CI estimates for the ratio of interest 
(RDEA3170 + febuxostat + dapagliflozin and RDEA3170 + febuxostat).  Additionally, for each 
treatment, back transformed geometric means together with 95% CIs for $8&Ĳ, AUClast and 
Cmax, for RDEA3170, M1 and M8 will be estimated and presented.
For all ANOVA models described above the geometric mean ratios, their 95% CI, along with the 
ratios of individual patient values will be plotted to visualize the treatment comparisons.
11.11. Analysis of Safety Data
Safety data (scheduled and unscheduled) will be presented in the data listings.  Continuous 
variables will be summarized using descriptive statistics (n, mean, SD, minimum, median, 


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maximum) by treatment.  Categorical variables will be summarized in frequency tables 
(frequency and proportion) by treatment. The analysis of the safety variables will be based on 
the safety analysis set.
Adverse events will be summarized by Preferred Term and SOC using MedDRA vocabulary.  
Furthermore, listings of SAEs and AEs that led to withdrawal will be made and the number of 
patients who had any AEs, SAEs, AEs that led to withdrawal, and AEs with severe intensity will 
be summarized.  Adverse events that occur before dosing will be reported separately.
Tabulations and listings of data for vital signs, clinical laboratory tests and ECGs, will be 
presented.  Any new or aggravated clinically relevant abnormal medical physical examination 
finding compared to the baseline assessment will be reported as an AE.  Data will be 
summarized for the observed values at each scheduled assessment, together with the 
corresponding changes (and/or percentage change) from the baseline when baseline is defined.  
Clinical laboratory data will be reported in the units provided by the clinical laboratory and in 
Système International units in the CSR.
Out-of-range values for safety laboratory, vital signs and ECG will be flagged in individual 
listings as well as summarized descriptively using agreed standard reference ranges and/or 
extended reference ranges (e.g., AZ, program or laboratory ranges).
11.11.1.
Adverse Events
All AEs will be coded using MedDRA vocabulary, and will be listed for each patient.  A 
treatment-emergent adverse event (TEAE) is defined as an AE with onset (start date/time) after 
the first dose of IMP in Treatment period 1.
Adverse events will be assigned to a treatment based on the start date/time of the AE in relation 
to dosing in that period; for tabulation purposes the AE will then be assigned to the treatment 
received in the respective treatment period as follows:
x
Screening: all AEs with start date/time before dosing in Treatment period 1.
x
Treatment period 1: AEs with start date/time at the time of or after dosing in Treatment 
period 1 until the time of dosing in Treatment period 2.
x
Treatment period 2: AEs with start date/time at the time of or after dosing in Treatment 
period 2 until the Follow-up Visit.
Adverse events with missing start dates/times will be handled as follows:


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x
If the start date is completely missing but the end date is known and shows that the AE ended 
on or after the first dose date, then the start date will be imputed as the first day of dosing; if 
the end date is known and shows that the AE ended before the first dose date, then the 
screening date will be used for the start date.  If the end date is non-informative (i.e., is 
missing or does not contain enough information), the start date will be imputed as the first 
date of dosing;
x
If only the start day is missing the day will be imputed as the first day on which a dose was 
given in that month unless the end date is known and shows that the AE ended before a dose 
was given in that month; in which case the date will be imputed as 01.  If the end date is 
non-informative (i.e., is missing or does not contain enough information), the start date will 
be imputed as the first date of dosing in the known month.  If the month is not a dosing 
month the date will be imputed as 01;
x
If the start day and month are missing the date will be imputed as the first day of dosing in 
the known year unless the end date is known and shows that the AE ended before a dose was 
given in that year; in which case the start day and month will be imputed as 01Jan or with the 
date of screening if this is later.  If the end date is non-informative (i.e., is missing or does 
not contain enough information), the start date will be imputed as the first date of dosing in 
the known year.  If the year is not a year of dosing, then the date will be imputed as 01Jan or 
with the date of screening if this is later.
x
Missing times will be imputed as 00:00 h or with the time of dosing for events starting on a 
dosing day.
Adverse events will be summarized by treatment (where treatments will be pooled across 
treatment periods) and overall for all patients, including tabulations by causality and severity 
(mild, moderate and severe).  All tabulations will be presented by SOC and Preferred Term.  
Furthermore, separate listings of SAEs, AEs that led to discontinuation (DAEs) and AEs that led 
to death will be presented.
The following information will be included in the listings: verbatim term, SOC, Preferred Term
and lowest level term, start date/time, end date/time, time from last dose, causality, action taken, 
whether the AE was classified as serious and the outcome.
All tabulations will include the number and percentage of patients.
In addition, a separate 
tabulation will be presented showing the number of events by treatment and Preferred Term.


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Lastly, an overview of all AEs will be presented, separately for the number and percentage of 
patients and the number of events.  This will include categories for any AE, AEs with outcome 
of death and SAEs.
11.11.2.
Potential Events of Diabetic Ketoacidosis 
All potential events of DKA will be recorded in 
 and submitted to an independent DKA 
Adjudication Committee.  The DKA Committee T2DM will assess available information on each 
potential DKA event and will classify the event in accordance with the definitions in the DKA 
Adjudication Charter T2DM. 
The DKA Adjudication Committee will be kept blinded to the study drug treatment received by 
each patient with a potential DKA event in the clinical study.  A separate DKA Adjudication 
Manual will define and describe the procedures for the collection of DKA information, handling, 
adjudication criteria and reporting of these events/cases.
11.11.3.
Vital Signs 
The results of the vital signs measurements will be listed by patient and time point including the 
date/time of the assessment, changes from baseline and repeat/unscheduled measurements.  The 
baseline for vital signs measurements will be the pre-dose assessment on Day 1 in each treatment 
period.  Descriptive statistics will be presented by treatment and time point for both observed 
values and changes from baseline.
11.11.4.
Resting 12-lead Electrocardiogram
12-Lead ECG results will be listed for each patient.
11.11.5.
Physical Examination 
The baseline/screening results of the physical examination will be documented in medical history 
for each patient. 
Any new or aggravated clinically relevant abnormal medical physical examination finding 
compared to the baseline assessment will be reported as an AE.
Body weight will be listed by patient and time point. 
11.11.6.
Laboratory Assessments
Hematology and clinical chemistry values will be listed by patient and time point including 
changes from baseline and repeat/unscheduled measurements.  Summary tabulations including 
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observed absolute values and changes from baseline will be presented by time point for the 
safety analysis set.  The baseline for the measurements will be the pre-dose Day 1 assessment 
performed before dosing in Treatment Period 1.  Shift tables will also be presented. 
The listings will include the following information: test name, date of measurement, reference 
range, result and flags for any measurements that are outside the reference range (e.g., 
AstraZeneca, program or laboratory ranges).  Clinical laboratory data will be reported in System 
International units in the CSR. 
Additional listings will be presented for the following:
x
Urinalysis (macroscopic and microscopic, if applicable)
x
Pregnancy testing (including FSH)
x
The results of viral serology and the drugs of abuse and alcohol screen will not be listed in 
the CSR.
11.12. Analysis of Exploratory Data 
   
   
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12.
ADVERSE EVENTS
12.1.
Definitions
12.1.1.
Definition of Adverse Events
An AEs is the development of an undesirable medical condition or the deterioration of a 
pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product.
An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., 
tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, 
ECG).
In clinical studies, an AE can include an undesirable medical condition occurring at any time 
after the patient has signed informed consent, including run-in or washout periods, even if no 
specific treatment has been administered.
The term AE is used generally to include any AE whether serious or non-serious.
12.1.2.
Definitions of Serious Adverse Event
A SAE is an AE occurring during any study phase (i.e., run-in, treatment, washout, follow-up), 
that fulfills one or more of the following criteria:
x
Results in death.
x
Is immediately life-threatening.
x
Requires in-patient hospitalization or prolongation of existing hospitalization.
x
Results in persistent or significant disability or incapacity or substantial disruption of the 
ability to conduct normal life functions.
x
Is a congenital abnormality or birth defect.
x
Is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above.
For further guidance on the definition of a SAE, see Appendix 15.1 of this CSP.
12.1.3.
Other Significant Adverse Events
During the evaluation of the AE data, an AstraZeneca medically qualified expert will review the 
list of AEs that were not reported as SAEs or where relevant AEs leading to discontinuation of 


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IMP (DAEs) and withdrawal from the study.  Based on the expert’s judgment, significant AEs of 
particular clinical importance may, after consultation with the Global Safety Physician, be 
considered Other significant adverse events (OAEs) and reported as such in the CSR.  A similar 
review of other data from laboratory tests, vital signs, ECGs and other safety assessments will be 
performed for identification of OAEs.
Examples of these are marked hematological and other laboratory abnormalities, and certain 
events that lead to intervention (other than those already classified as serious), dose reduction or 
significant additional treatment.
12.2.
Recording of Adverse Events
12.2.1.
Time Period for Collection of Adverse Events
Adverse events will be collected from the start of randomization throughout the treatment period 
up to and including the Follow-up Visit.
Serious adverse events will be recorded from the time of informed consent.
12.2.2.
Follow-up of Unresolved Adverse Events
Any AEs that are unresolved at the patient’s last visit in the study are followed up by the 
Investigator for as long as medically indicated, but without further recording in the ClinBase.
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.
12.2.3.
Variables
The following variables will be collected for each AE:
x
Adverse event diagnosis/description
x
The date and time when the AE started and stopped
x
Intensity
x
Whether the AE is serious or not
x
Principle Investigator causality rating against the IMP (yes or no)
x
Action taken with regard to IMP
x
Adverse event caused patient’s withdrawal from study (yes or no)


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x
Outcome 
Additional variables will be collected for all SAEs including treatment given for the event. 
The following intensity ratings will be used:
1.
Mild (awareness of sign or symptom, but easily tolerated) 
2.
Moderate (discomfort sufficient to cause interference with normal activities)
3.
Severe (incapacitating, with inability to perform normal activities)
Severity is a measure of intensity whereas seriousness is defined by the criteria in Section 12.1.2. 
An AE of severe intensity need not necessarily be considered serious.  For example, nausea that 
persists for several hours may be considered severe nausea, but not a SAE.  On the other hand, a
stroke that results in only a limited degree of disability may be considered a mild stroke but 
would be an SAE. 
12.2.4.
Causality Collection
The Investigator will assess causal relationship between IMP and each AEs, 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 IMP?”
For SAEs, causal relationship will also be assessed for other medication, any additional drug and 
study procedures.  Note that for SAEs that could be associated with any study procedure the 
causal relationship is implied as “yes”.
A guide to the interpretation of the causality question is found in Appendix 15.1 of this CSP. 
12.2.5.
Adverse Events Based on Symptoms and Signs 
All AEs spontaneously reported by the patient or reported in response to the open question from 
the study personnel: “Have you had any health problems since you were last asked?”, or 
revealed by observation will be collected and recorded in the 
. 
When collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list 
of signs and symptoms. 
However, if a diagnosis is known and there are other signs or symptoms that are not generally 
part of the diagnosis, the diagnosis and each sign or symptom will be recorded separately. 
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12.2.6.
Adverse Events Based on Examinations and Tests
The results from protocol-mandated laboratory tests, vital signs, ECGs and other safety 
assessments will be summarized in the CSR. 
Deterioration as compared to baseline in protocol-mandated laboratory values, vital signs, ECGs 
and other safety assessments should therefore only be reported as AEs if they fulfill any of the 
SAE criteria.
If deterioration in a laboratory value or vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result or vital sign 
will be considered as additional information. 
Wherever possible the reporting Investigator should use the clinical, rather than the laboratory 
term (e.g., anemia versus low hemoglobin value). 
In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s).
Any new or aggravated clinically relevant abnormal medical finding at a physical examination as 
compared with the baseline assessment will be reported as an AE.
12.2.7.
Hy's Law
Cases where a patient shows elevations in liver biochemistry may require further evaluation and 
RFFXUUHQFHVRI$67RU$/7 3 x upper limit of normal (ULN) WRJHWKHUZLWKWRWDOELOLUXELQ 2 x 
ULN may need to be reported as SAEs. Please refer to Appendix 15.3 for further instruction on 
cases of increases in liver biochemistry and evaluation of Hy’s Law. 
12.3.
Reporting of Serious Adverse Events
All SAEs will be reported, whether or not considered causally related to the IMP, or to the study 
procedure(s). All SAEs will be recorded in the 
. 
If any SAE occurs in the course of the study, then the PI or other site personnel will inform 
appropriate AstraZeneca representatives immediately, or no later than 24 hours of when he or 
she becomes aware of it.
The designated AstraZeneca representative will work with the PI or other site personnel to 
ensure that all the necessary information is provided to the AstraZeneca patient safety data entry 
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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 will be undertaken immediately.
The PI or other site personnel will inform AstraZeneca representatives of any follow-up
information on a previously reported SAE immediately, or no later than 24 hours of when he or 
she becomes aware of it.


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13.
LEGAL AND ADMINISTRATIVE ASPECTS
13.1.
Archiving of Study Documents
All source documents generated in connection with the study will be retained in the limited 
access file storage area, respecting the privacy and confidentiality of all records that could 
identify the patients.  Direct access is allowed only for authorized people for monitoring and 
auditing purposes.  Source documents will be handled, stored and archived according to in house 
procedures.
The Investigator's Site File will be archived by the contract research organization (CRO) for 
15 years after completion of the study.
13.2.
Publication of Study Results
All of the study information and data collected during the study are confidential and the property 
of AstraZeneca. After completion of the study, the PI may prepare a joint publication with 
AstraZeneca. The PI must undertake not to submit any part of the individual data from this CSP
for publication without prior consent of AstraZeneca at a mutually agreed time.
13.3.
Clinical Study Report
An integrated CSR will be prepared in accordance with the standards of the ICH guideline for 
structure and content of clinical study reports (ICH E3).  Copies of the CSR will be provided to 
the IRB and the national Regulatory Authority in accordance with regulatory requirements and 
PAREXEL SOPs.  In the event of premature termination of the study or other conditions 
specified in ICH E3, an abbreviated CSR may be prepared.


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14.
REFERENCE LIST
1.
Hyndman D, Liu S, Miner JN. Urate handling in the human body. Curr Rheumatol Rep 
2016;18(6):34.
2.
Choi HK, Mount DB, Reginato AM. Pathogenesis of gout. Ann. Intern Med 
2005;143(7):499-516.
3.
Hamburger M, Baraf HS, Adamson TC 3rd, Basile J, Bass L, Cole B, et al. 2011 
Recommendations for the diagnosis and management of gout and hyperuricemia. Postgrad 
Med 2011;123(6 Suppl 1):3-36.
4.
Campion EW, Glynn RJ, DeLabry LO. Asymptomatic hyperuricemia: risks and 
consequences in the Normative Aging Study. Am J Med 1987;82(3):421-426.
5.
Yamanaka H, Japanese Society of Gout. Japanese guideline for the management of 
hyperuricemia and gout: second edition. Nucleos Nucleot Nucl 2011;30(12):1018-1029.
6.
Chinese Rheumatology Association. Primary gout diagnosis and treatment guideline. Chin J 
Rheumatol 2011;15(6):410-413.
7.
Nakayama S, Atsumi R, Takakusa H, Kobayashi Y, Nagai Y, Nakai D, et al. A zone 
classification system for risk assessment of idiosyncratic drug toxicity using daily dose and 
covalent binding. Drug Metab Dispos 2009;37(9):1970-1977.
8.
Grayson PC, Kim SY, LaValley M, Choi HK. Hyperuricemia and incident hypertension: a 
systematic review and meta-analysis. Arthritis Care Res (Hoboken) 2011;63(1):102-110.
9.
Kodama S, Saito K, Yachi Y, Asumi M, Sugawara A, Totsuka K, et al. Association between 
serum uric acid and development of type 2 diabetes. Diabetes Care 2009;32(9):1737-1742.
10. Leyva F, Anker SD, Godsland IF, Teixeira M, Hellewell PG, Kox WJ, et al. Uric acid in 
chronic heart failure: a marker of chronic inflammation. Eur Heart J 1998;19(12):1814-1822.
11. Anker SD, Doehner W, Rauchhaus M, Sharma R, Francis D, Knosalla C, et al. Uric acid and 
survival in chronic heart failure: validation and application in metabolic, functional, and
hemodynamic staging. Circulation 2003;107(15):1991-1997.
12. Ioachimescu AG, Brennan DM, Hoar BM, Hazen SL, Hoogwerf BJ. Serum uric acid is an 
independent predictor of all-cause mortality in patients at high risk of cardiovascular disease: 
a preventive cardiology information system (PreCIS) database cohort study. Arthritis Rheum 
2008;58(2):623-630.


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13. Kim SY, De Vera MA, Choi HK. Gout and mortality. Clin Exp Rheumatol 2008;26(5)(suppl 
51):S115-S119.
14. Niizeki T, Takeishi Y, Arimoto T, Okuyama H, Nozaki N, Hirono O, et al. Hyperuricemia 
associated with high cardiac event rates in the elderly with chronic heart failure. J Cardiol 
2006;47(5):219-228.
15. Jankowska EA, Ponikowska B, Majda J, Zymlinski R, Trzaska M, Reczuch K, et al.
Hyperuricaemia predicts poor outcome in patients with mild to moderate chronic heart 
failure. Int J Cardiol 2007;115(2):151-155.
16. Richette P, Doherty M, Pascual E, et al. Updated EULAR evidence-based recommendations 
for the management of gout [EULAR abstract SAT0531]. Ann Rheum Dis. 2014;73(suppl 2).
17. Zhang W, Doherty M, Bardin T, Pascual E, Barskova V, Conaghan P, et al. EULAR 
evidence based recommendations for gout, Part II: management: report of a task force of the 
EULAR Standing Committee for International Clinical Studies Including Therapeutics 
(ESCISIT). Ann Rheum Dis 2006;65(10):1312-1324.
18. Jordan KM, Cameron JS, Snaith M, Zhang, W, Doherty M, Secki J, et al. British Society for 
Rheumatology and British Health Professionals in Rheumatology guideline for the 
management of gout. Rheumatology (Oxford) 2007;46(8):1372-1374.
19. Investigator’s Brochure, RDEA3170, Edition 1, 16 March 2017.
20. Highlights of Prescribing Information - ULORIC (febuxostat) tablet for oral use Initial U.S. 
Approval: 2009. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021856lbl.pdf
21. Highlights of Prescribing Information - FARXIGA (dapagliflozin) tablets, for oral use Initial 
U.S. Approval: 2014. https://www.azpicentral.com/farxiga/pi_farxiga.pdf#page=1
22. Kohan D., Fioretto P., Tang W., List J. (2014) Long-term study of patients with type 2 
diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood 
pressure but does not improve glycemic control. Kidney Int 85: 962–971
23. FDA Guidance for Industry ‘Drug-induced liver injury: Premarketing clinical evaluation’.  
July 2009.  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance
s/UCM174090.pdf


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15.
APPENDICES
15.1.
Additional Safety Information
Further Guidance on the Definition of a Serious Adverse Event
Life-threatening
‘Life-threatening’ means that the patient was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the patient’s 
death.  ‘Life-threatening’ does not mean that had an AE occurred in a more severe form it might 
have caused death (e.g., hepatitis that resolved without hepatic failure).
Hospitalization
Outpatient treatment in an emergency room is not in itself a SAE, although the reasons for it may 
be (e.g., bronchospasm, laryngeal edema).  Hospital admissions and/or surgical operations 
planned before or during a study are not considered AEs if the illness or disease existed before 
the patient was enrolled in the study, provided that it did not deteriorate in an unexpected way 
during the study.
Important Medical Event or Medical Intervention
Medical and scientific judgment should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life-threatening or result in 
death, hospitalization, disability or incapacity but may jeopardize the patient or may require 
medical intervention to prevent 1 or more outcomes listed in the definition of serious.  These 
should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgment must be used.
Examples of such events are:
x
Angioedema not severe enough to require intubation but requiring intravenous 
hydrocortisone treatment.
x
Hepatotoxicity caused by paracetamol/acetaminophen overdose requiring treatment with
N-acetyl cysteine.
x
Intensive treatment in an emergency room or at home for allergic bronchospasm.


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x
Blood dyscrasias (e.g., neutropenia or anemia requiring blood transfusion) or convulsions 
that do not result in hospitalization.
x
Development of drug dependency or drug abuse.
A Guide to Interpreting the Causality Question
The following factors should be considered when deciding if there is a “reasonable possibility” 
that an AE may have been caused by the IMP.
x
Time Course/Exposure to suspect drug:
Has the patient actually received the suspect drug?  Did the AE occur in a reasonable 
temporal relationship to the administration of the suspect drug?
x
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?
x
Dechallenge experience:
Did the AE resolve or improve on stopping or reducing the dose of the suspect drug?
x
No alternative cause:
The AE cannot be reasonably explained by other etiology such as the underlying disease, 
other drugs, other host or environmental factors.
x
Rechallenge experience:
Did the AE reoccur if the suspected drug was reintroduced after having been stopped?
Note: AstraZeneca would not normally recommend or support a rechallenge.
x
Laboratory tests:
A specific laboratory investigation (if performed) has confirmed the relationship?
In difficult cases, other factors could be considered such as:
x
Is this a recognized feature of overdose of the drug?
x
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.


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The causality assessment is performed based on the available data including enough information 
to make an informed judgment.  With limited or insufficient information in the case, it is likely 
that the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of effect 
should be classified as no reasonable possibility.
 


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15.2.
International Airline Transportation Association 6.2 Guidance Document
Labeling and Shipment of Biohazard Samples
International Airline Transportation Association classifies bio hazardous agents into 
3 categories (http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.htm). 
For transport purposes, the classification of infectious substances according to risk groups was 
removed from the Dangerous Goods Regulations (DGR) in the 46th edition (2005).  Infectious 
substances are now classified either as Category A, Category B or Exempt.  There is no direct 
relationship between Risk Groups and Categories A and B.
Category A Infectious Substances are infectious substances in a form that, when exposure to it 
occurs, is capable of causing permanent disability, life-threatening or fatal disease in otherwise 
healthy humans or animals.  Category A pathogens are for example, Ebola and Lassa Fever 
viruses.  Category A pathogens:
x
Are to be packed and shipped in accordance with IATA Instruction 602.
Category B Infectious Substances are infectious substances that do not meet the criteria for 
inclusion in Category A.  Category B pathogens are for example, hepatitis A, B, C, D and E 
viruses and HIV types 1 and 2.  They are assigned the following UN number and proper shipping 
name:
x
UN 3373 – Biological Substance, Category B
x
Are to be packed in accordance with UN3373 and IATA Instruction 650.
Exempt refers to all other materials with minimal risk of containing pathogens.
x
Clinical trial samples will fall into Category B or Exempt under IATA regulations.
x
Clinical trial samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging.
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.htm)
x
Biological samples transported in dry ice require additional dangerous goods specification 
for the dry ice content.
x
International Airline Transportation Association compliant courier and packaging materials 
should be used for packing and transportation.  Packing should be done by an IATA certified 
person, as applicable.


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x
Samples routinely transported by road or rail are patient to local regulations which require 
that they are also packed and transported in a safe and appropriate way to contain any risk of 
infection or contamination by using approved couriers and packaging/containment materials 
at all times.
The IATA 650 biological sample containment standards are encouraged 
wherever possible when road or rail transport is used.
 


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15.3.
Actions Required in Cases of Combined Increase of Aminotransferase and Total 
Bilirubin - Hy’s Law
Guidance used: FDA Guidance for Industry ‘Drug-induced liver injury: Premarketing clinical 
evaluation’. July 2009
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
CM174090.pdf
Introduction
During the study, the PI will remain vigilant for increases in liver clinical chemistry.  The PI is 
responsible for determining whether a patient meets PHL criteria at any point during the study.
The PI participates, together with AstraZeneca clinical project representatives, in review and 
assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria are met.  The 
HL criteria are met if there is no alternative explanation for the elevations in liver clinical 
chemistry other than Drug Induced Liver Injury (DILI) caused by the IMP.
The PI is responsible for recording data pertaining to PHL/HL cases and for reporting AE and 
SAE according to the outcome of the review and assessment in line with standard safety 
reporting processes.
Definitions
Potential Hy’s Law
x
$VSDUWDWHDPLQRWUDQVIHUDVH$67RUDODQLQHDPLQRWUDQVIHUDVH$/7 3 x ULN and total 
ELOLUXELQ 7%/  2 x ULN at any point during the study irrespective of an increase in 
Alkaline phosphatase (ALP).
x
The elevations do not have to occur at the same time or within a specified time frame.
Hy’s Law
x
$67RU$/7 x ULN and 7%/ x ULN, where no other reason, other than the IMP, 
can be found to explain the combination of increases, e.g., elevated ALP indicating 
cholestasis, viral hepatitis, another drug.
x
The elevations do not have to occur at the same time or within a specified time frame.


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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:
x
$/7 x ULN
x
$67 x ULN
x
7%/ x ULN
The PI will review without delay each new laboratory report and if the identification criteria are 
met will:
x
Notify the AstraZeneca representative
x
Determine whether the patient meets PHL criteria (see definition above) by reviewing 
laboratory reports from all previous visits
x
Promptly enter the laboratory data into the laboratory CRF
Follow-Up
Potential Hy’s Law Criteria not Met
If the patient does not meet PHL criteria the PI will:
x
Inform the AstraZeneca representative that the patient has not met PHL criteria.
x
Perform follow-up on subsequent laboratory results according to the guidance provided in the 
CSP.
Potential Hy’s Law Criteria Met
If the patient does meet PHL criteria the PI will:
x
Notify the AstraZeneca representative who will then inform the central study team.
The study physician contacts the PI, to provide guidance, discuss and agree an approach for the 
study patients’ follow-up and the continuous review of data.
Subsequent to this contact the PI will:
x
Monitor the patient until liver clinical chemistry variables and appropriate clinical symptoms 
and signs return to normal or baseline levels, or as long as medically indicated.


AstraZeneca
Clinical Study Protocol
Study Code: D5495C00001
Revised According to Protocol Amendment No. 3
Drug Substance: RDEA3170, Febuxostat, Dapagliflozin
CONFIDENTIAL
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Page 103 of 115
10 May 2018
x
Investigate the etiology of the event and perform diagnostic investigations as discussed with 
the study physician.
x
Complete the 3 Liver CRF Modules as information becomes available.
If at any time (in consultation with the study physician) the PHL case meets serious criteria, 
report it as an SAE using standard reporting procedures.
Review and Assessment of Potential Hy’s Law Cases
The instructions in this section should be followed for all cases where PHL criteria were met.
No later than 3 weeks after the clinical chemistry abnormality was initially detected, the study 
physician contacts the PI in order to review available data and agree on whether there is an 
alternative explanation for meeting PHL criteria other than DILI caused by the IMP.  The 
AstraZeneca Medical Science Director and Global Safety Physician will also be involved in this 
review together with other patient matter experts as appropriate.
According to the outcome of the review and assessment, the PI will follow the instructions 
below.
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE:
x
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF.
x
If the alternative explanation is an AE/SAE, record the AE/SAE in the CRF accordingly and 
follow the AZ standard processes.
If it is agreed that there is no explanation that would clarify the ALT or AST and TBL elevations 
other than IMP causality:
x
Report an SAE (report term ‘Hy’s Law’) according to AstraZeneca standard processes. 

The ‘Medically Important’ serious criterion should be used if no other serious criteria 
apply.

As there is no alternative explanation for the HL case, a causality assessment of ‘related’ 
should be assigned.


AstraZeneca
Clinical Study Protocol
Study Code: D5495C00001
Revised According to Protocol Amendment No. 3
Drug Substance: RDEA3170, Febuxostat, Dapagliflozin
CONFIDENTIAL
Final 1.0
Page 104 of 115
10 May 2018
If, there is an unavoidable delay, of over 3 weeks, in obtaining the information necessary to 
assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made:
x
Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and causality 
assessment as per above.
x
Continue follow-up and review according to agreed plan.  Once the necessary supplementary 
information is obtained, repeat the review and assessment to determine whether HL criteria 
are met.  Update the SAE report according to the outcome of the review.
 


AstraZeneca
Clinical Study Protocol
Study Code: D5495C00001
Revised According to Protocol Amendment No. 3
Drug Substance: RDEA3170, Febuxostat, Dapagliflozin
CONFIDENTIAL
Final 1.0
Page 105 of 115
10 May 2018
15.4.
Actions Required in Cases of a Renal-related or Kidney Stone Treatment-emergent 
Adverse Event or a Serum Creatinine Elevation 
During the course of the study, the Investigator will remain vigilant for symptoms or signs of 
renal-related events, kidney stone events or changes in renal function. 
Signs and Symptoms Suggestive of Renal Injury or Kidney Stone
If after initiation of study medication a patient experiences signs or symptoms suggestive of acute
renal injury (e.g., reduced urinary output, generally feeling unwell, fatigue, nausea, vomiting,
metallic taste, or loss of appetite) or nephrolithiasis (e.g., flank pain or hematuria), the patient
should be evaluated by a physician and an assessment of serum creatinine, blood urea nitrogen, 
and urinalysis should be performed via central laboratory testing (preferred) and/or local
laboratory testing, as appropriate, for determination of renal function. Any abnormal results
should be treated as medically appropriate by the treating physician.
A careful review of any
AEs and evaluation for potential contributing factors should occur.
All symptoms, testing and
results will be documented in source documents and 
 
Renal Function
Renal function will be assessed during the course of the study at pre-specified times by
measuring serum creatinine and calculating the estimated CrCl.
All results will be documented 
in source documents and 
  Laboratory values that meet the criteria for alert (as
described in the following paragraphs) will be sent to Investigators by the central laboratory.
Any clinically significant serum creatinine abnormality should be reported as an AE. 
The
Investigator will need to determine if randomized study medication is to continue or be 
interrupted and the decision must be documented in source documents.  As described in the
following paragraphs, if a serum creatinine elevation is  3.0 x baseline serum creatinine, if
absolute serum creatinine value is  4.0 mg/dL, or if estimated CrCl value is < 25 mL/min at any
time during the study, then randomized study medication must be permanently discontinued.
Serum Creatinine
Serum creatinine values will be measured at pre-specified and unscheduled visits throughout the 
study and analyzed relative to the baseline serum creatinine.  Elevations in serum creatinine will 
be defined by the Kidney Disease Improving Global Outcomes (KDIGO) Guidelines on Acute 
Kidney Injury and the Acute Kidney Injury Network (Ricci et al 2011).  Any serum creatinine 
elevations that are identified based on this definition will be flagged as alert values and sent to 
the Investigators for clinical assessment.  If a serum creatinine value meeting the criteria 
CCI
CCI


AstraZeneca
Clinical Study Protocol
Study Code: D5495C00001
Revised According to Protocol Amendment No. 3
Drug Substance: RDEA3170, Febuxostat, Dapagliflozin
CONFIDENTIAL
Final 1.0
Page 106 of 115
10 May 2018
described in this section is identified, the patient should return to the study site for further 
evaluation to determine the etiology for the serum creatinine elevation.  The treating physician 
should determine if any intervention is required and if any AEs should be reported.  Any 
potential factors contributing to the serum creatinine elevation should be reported.  Additional 
testing of serum creatinine should be performed.  Investigators should consider temporarily 
stopping concomitant therapies that are known to increase serum creatinine or impact renal 
function as medically appropriate.
Any patient who has a serum creatinine elevation should be monitored as follows:
1.
6HUXPFUHDWLQLQHHOHYDWLRQV 1.5 to < 2.0 x baseline.
)RU D VHUXP FUHDWLQLQH HOHYDWLRQ  1.5 to < 2.0 x baseline serum creatinine value, the 
Investigator will be notified and the patient will return to the study site for further evaluation.  
The randomized study medication may be temporarily interrupted at the Investigator’s 
discretion, and retest of the serum creatinine should be performed as soon as possible.

If the retested serum creatinine value is resolved to  1.2 x baseline serum creatinine
value, the patient should be followed per the schedule defined by the protocol and be
re-evaluated at the next study visit.
Any interrupted randomized study medication may
be resumed after resolution of the serum creatinine elevation.

If the retested serum creatinine value is > 1.2 x baseline serum creatinine value, additional
retests of serum creatinine and a decision to continue or interrupt randomized study
medication should be conducted weekly until resolution to  1.2 x baseline value.
Any
interrupted randomized study medication may be resumed after resolution of the serum
creatinine elevation.

If randomized study medication was not interrupted, and 3 consecutive retests have serum
creatinine values > 1.2 x baseline, randomized study medication must be permanently
discontinued.
The patient will be encouraged to remain in the study and follow the
protocol schedule.
Consult Figure 1 Panel A (page 108) for a flow chart diagram.
2.
6HUXP FUHDWLQLQH HOHYDWLRQV  2.0 to < 3.0 x EDVHOLQH RU DQ DEVROXWH YDOXH  3.0 mg/dL.
,I D VHUXP FUHDWLQLQH HOHYDWLRQ LV  2.0 to < 3.0 x baseline serum creatinine value or an 
DEVROXWH VHUXP FUHDWLQLQH YDOXH RI  3.0 mg/dL, randomized study medication must be 
temporarily interrupted, and retest of the serum creatinine should be performed as soon as 
possible.


AstraZeneca
Clinical Study Protocol
Study Code: D5495C00001
Revised According to Protocol Amendment No. 3
Drug Substance: RDEA3170, Febuxostat, Dapagliflozin
CONFIDENTIAL
Final 1.0
Page 107 of 115
10 May 2018

If the retested serum creatinine YDOXH LV UHVROYHG WR  1.2 x baseline serum creatinine 
value, randomized study medication may be restarted at the Investigator’s discretion and 
monitoring of the serum creatinine should return to the protocol defined schedule.

If the retested serum creatinine value is > 1.2 x baseline serum creatinine value, 
additional retests of serum creatinine should be performed weekly until resolution to 
 1.2 x EDVHOLQH 2QFH WKH VHUXP FUHDWLQLQHHOHYDWLRQLVUHVROYHGWR 1.2 x baseline, 
randomized study medication may be resumed at the Investigator’s discretion and 
monitoring of the serum creatinine should return to the protocol defined schedule.

If the results of 3 consecutive retests of serum creatinine are > 1.2 x baseline serum
creatinine value, randomized study medication must be permanently discontinued.
The
patient will be encouraged to remain in the study and follow the protocol schedule.
Consult Figure 1 Panel B (page 109) for a flow chart diagram.
3.
Serum creatinine elevations  3.0 x baseline or an absolute value  4.0 mg/dL
If a serum creatinine elevation is  3.0 x baseline serum creatinine value or an absolute serum
creatinine value of  4.0 mg/dL, randomized study medication must be permanently
discontinued.
A retest of the serum creatinine should be performed as soon as possible, and
repeat testing should be performed weekly until resolution to  1.2 x baseline value.
Randomized study medication may not be restarted.
The patient will be encouraged to
remain in the study and follow the protocol schedule.
Consult Figure 1 Panel C (page 110) for a flow chart diagram.
4.
Patient’s 
Last 
Study 
Visit 
and 
Post-Follow-Up 
Assessments.
,IDWWKHSDWLHQW¶VODVWVWXG\YLVLWWKHVHUXPFUHDWLQLQHYDOXHLV 0.3 mg/dL above baseline 
serum creatinine value, the patient is required to return to the site in 1 month for 
post-follow- up repeat assessments.

If the retested serum creatinine value is within < 0.3 mg/dL above baseline serum 
creatinine value, no further follow-up is required.

,I WKH UHWHVWHG VHUXP FUHDWLQLQH YDOXH LV  0.3 mg/dL above baseline serum creatinine 
value, repeat testing of serum creatinine should be performed monthly until the value is 
< 0.3 mg/dL above baseline serum creatinine value or until 3 monthly assessments after 
their last study visit have taken place, whichever occurs first.
Consult Figure 1 Panel D (page 110) for a flow chart diagram.


AstraZeneca
Clinical Study Protocol
Study Code: D5495C00001
Revised According to Protocol Amendment No. 3
Drug Substance: RDEA3170, Febuxostat, Dapagliflozin
CONFIDENTIAL
Final 1.0
Page 108 of 115
10 May 2018
5.
Other Considerations
3DWLHQWV ZKR KDYH D VHUXP FUHDWLQLQH YDOXH RI  1.5 x baseline should be encouraged to 
remain adequately hydrated.


AstraZeneca
Clinical Study Protocol
Study Code: D5495C00001
Revised According to Protocol Amendment No. 3
Drug Substance: RDEA3170, Febuxostat, Dapagliflozin
CONFIDENTIAL
Final 1.0
Page 109 of 115
10 May 2018


AstraZeneca
Clinical Study Protocol
Study Code: D5495C00001
Revised According to Protocol Amendment No. 3
Drug Substance: RDEA3170, Febuxostat, Dapagliflozin
CONFIDENTIAL
Final 1.0
Page 110 of 115
10 May 2018
 


AstraZeneca
Clinical Study Protocol
Study Code: D5495C00001
Revised According to Protocol Amendment No. 3
Drug Substance: RDEA3170, Febuxostat, Dapagliflozin
CONFIDENTIAL
Final 1.0
Page 111 of 115
10 May 2018
Estimated Creatinine Clearance
If a patient has an estimated CrCl value of < 25 mL/min at any time during the study, randomized
study medication must be permanently discontinued.
If a patient has a baseline estimated CrCl value RI 45 mL/min that decreases to < 30 mL/min,
randomized study medication must be temporarily interrupted and a retest of CrCl should be
performed as soon as possible.

If the repeated test confirms the CrCl value of < 30 mL/min, the patient will permanently
discontinue randomized study medication.

If the repeated test of CrCl shows a value of > 30 mL/min, randomized study medication
may be restarted with continued routine monitoring.
If a patient has a baseline estimated CrCl value of < 45 mL/min that decreases to < 30 mL/min, a
retest of the CrCl should be performed as soon as possible.

If the repeated test confirms the CrCl value of < 30 mL/min, a decision regarding
continuation of study medication should be discussed with the Sponsor’s Medical
Monitor.

If the repeated test of CrCl shows a value of > 30 mL/min, the patient should be followed
per the schedule defined by the protocol and be re- evaluated at the next study visit.
Other Changes
If a patient develops kidney stones (as confirmed and documented by imaging or passage of
kidney stone) at any time during the study, the patient will discontinue randomized study
medication and be encouraged to remain in the study for continued safety assessments.
If a
kidney stone is passed, it should be collected and submitted to pathology for a kidney stone
analysis.
References
Ricci Z, Cruz DN, Ronco C. Classification and staging of acute kidney injury: beyond the RIFLE
and AKIN criteria. Nat Rev Nephrol 2011;7(4):201-208.


PPD
PPD


PPD
PPD


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PPD

SAP_000.pdf: 
PAREXEL International 
Statistical Analysis Plan 
 
AstraZeneca AB 
Protocol D5495C00001 
 
Version 1.0 
16 July 2018 
 
 
Page 1 of 154 
 
STATISTICAL ANALYSIS PLAN AMENDMENT 
 
 
 
 
 
Protocol D5495C00001 
 
 
 
Quantifying Uric Acid Excretion with RDEA3170, 
Febuxostat and Dapagliflozin 
 
PAREXEL Study Number 
 
 
 
 
Version: 1.0 
 
                         Date 16 July 2018 
 
 
 
 
 
 
 
 
 
 
 
 
&&,


33'


33'


PAREXEL International 
Statistical Analysis Plan 
 
AstraZeneca AB 
Protocol D5495C00001 
 
Version 1.0 
16 July 2018 
 
 
Page 4 of 154 
 
TABLE OF CONTENTS 
TABLE OF CONTENTS ................................................................................................................ 4 
1. 
STATISTICAL ANALYSIS PLAN ................................................................................ 10 
2. 
STUDY OBJECTIVES AND HYPOTHESES ............................................................... 10 
2.1 
PRIMARY OBJECTIVES .............................................................................................. 10 
2.2 
SECONDARY OBJECTIVES ........................................................................................ 10 
2.3 
EXPLORATORY  OBJECTIVES .................................................................................. 10 
2.4 
PRIMARY OUTCOME MEASURES ............................................................................ 11 
2.5 
SECONDARY OUTCOME MEASURES ...................................................................... 11 
2.6 
EXPLORATORY OUTCOME MEASURES ................................................................. 11 
3. 
STUDY DESIGN ............................................................................................................ 11 
3.1 
STUDY POPULATION .................................................................................................. 12 
3.2 
STATISTICAL BASIS FOR SAMPLE SIZE ................................................................. 13 
3.3 
RANDOMIZATION ....................................................................................................... 13 
3.4 
BLINDING ...................................................................................................................... 13 
3.5 
DOSE ADMINISTRATION ........................................................................................... 14 
3.6 
TREATMENT COMPLIANCE ...................................................................................... 14 
3.7 
INTERIM ANALYSIS .................................................................................................... 14 
4. 
STUDY ANALYSIS VARIABLES ................................................................................ 15 
4.1 
DEMOGRAPHIC AND BACKGROUND VARIABLES .............................................. 15 
4.2 
SAFETY VARIABLES ................................................................................................... 15 
4.2.1 
ADVERSE EVENTS ...................................................................................................... 15 
4.3 
POTENTIAL EVENTS OF DIABETIC KETOACIDOSIS ........................................... 15 
4.3.1 
CLINICAL LABORATORY TESTS ............................................................................. 15 
4.3.2 
VITAL SIGNS ................................................................................................................. 18 
4.3.3 
ELECTROCARDIOGRAMS .......................................................................................... 18 
4.3.4 
PHYSICAL EXAMINATION ........................................................................................ 18 
4.3.5 
PRIOR AND CONCOMITANT MEDICATIONS ......................................................... 18 
4.4 
PHARMACOKINETICS ................................................................................................ 18 
4.4.1 
PHARMACOKINETIC PARAMETER CALCULATION METHODS ........................ 19 
4.5 
PHARMACODYNAMIC DATA ................................................................................... 20 
4.6 
EFFICACY VARIABLES .............................................................................................. 21 
4.7 
ANALYSIS POPULATIONS ......................................................................................... 21 
4.7.1 
SAFETY ANALYSIS SET ............................................................................................. 21 


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Protocol D5495C00001 
 
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4.7.2 
PHARMACOKINETIC ANALYSIS SET ...................................................................... 21 
4.7.3 
PHARMACODYNAMIC ANALYSIS SET ................................................................... 21 
4.7.4 
RANDOMIZED SET ...................................................................................................... 22 
5. 
STATISTICAL REPORTING ........................................................................................ 22 
5.1 
GENERAL CONSIDERATIONS FOR DATA PRESENTATIONS ............................. 22 
6. 
SUBJECT AND TREATMENT INFORMATION......................................................... 23 
6.1 
RANDOMIZATION SCHEME AND CODES .............................................................. 23 
6.2 
DISCONTINUED SUBJECTS ....................................................................................... 23 
6.3 
SUBJECT DISPOSITION ............................................................................................... 24 
6.4 
PROTOCOL DEVIATIONS ........................................................................................... 24 
6.5 
SUBJECT AND DATA EXCLUSIONS ......................................................................... 24 
6.6 
DEMOGRAPHIC DATA ................................................................................................ 24 
6.7 
INFORMED CONSENT RESPONSE ............................................................................ 24 
6.8 
MEDICAL HISTORY ..................................................................................................... 24 
6.9 
PREGNANCY TEST RESULTS .................................................................................... 25 
6.10 
MEDICATION ON ENTRY AND DURING THE STUDY.......................................... 25 
6.11 
DOSE ADMINISTRATION ........................................................................................... 25 
6.12 
MEAL ADMINISTRATION .......................................................................................... 25 
7. 
PHARMACOKINETIC CONCENTRATIONS AND PARAMETERS ........................ 25 
7.1 
HANDLING 
OF 
VALUES 
BELOW 
THE 
LIMIT 
OF 
QUANTIFICATION (BLQ) ............................................................................................ 27 
7.2 
PK PLASMA CONCENTRATIONS .............................................................................. 27 
7.3 
PK PARAMETERS ......................................................................................................... 28 
7.4 
GRAPHICAL PRESENTATION OF PK DATA ........................................................... 28 
7.5 
STATISTICAL ANALYSIS OF PHARMACOKINETIC DRUG-DRUG 
INTERACTION .............................................................................................................. 28 
7.6 
MULTIPLICITY ............................................................................................................. 29 
8. 
PHARMACODYNAMIC RESULTS ............................................................................. 29 
8.1 
PRIMARY PD VARIABLES ......................................................................................... 29 
8.2 
SECONDARY PHARMACODYNAMIC VARIABLES ............................................... 30 
8.3 
STATISTICAL ANALYSIS OF PHARMACODYNAMIC VARIABLES ................... 31 
8.3.1 
ANALYSIS OF PRIMARY PD VARIABLE ................................................................. 31 
8.3.2 
ANALYSIS OF SECONDARY PD VARIABLES ........................................................ 32 
8.3.3 
ANALYSIS OF EXPLORATORY PD VARIABLES ................................................... 32 
8.3.4 
VISUALIZING THE PHARMACODYNAMIC RESULTS .......................................... 32 


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Protocol D5495C00001 
 
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16 July 2018 
 
 
Page 6 of 154 
 
8.3.5 
ANALYSIS OF URINARY PD VARIABLES OVER A 24 HOUR 
INTERVAL ..................................................................................................................... 33 
9. 
SAFETY ANALYSIS ..................................................................................................... 33 
9.1 
ADVERSE EVENTS ...................................................................................................... 33 
9.2 
DIABETIC KETOACIDOSIS (DKA) ............................................................................ 36 
9.3 
CLINICAL SAFETY LABORATORY TESTS (HEMATOLOGY, 
CHEMISTRY, URINALYSIS) ....................................................................................... 36 
9.3.1 
HEMATOLOGY AND CHEMISTRY ........................................................................... 36 
9.3.2 
URINALYSIS ................................................................................................................. 36 
9.4 
VITAL SIGNS ................................................................................................................. 37 
9.5 
12-LEAD SAFETY ECG ................................................................................................ 37 
9.6 
PHYSICAL EXAMINATION ........................................................................................ 37 
10. 
REPORTING OUTPUT .................................................................................................. 37 
11. 
TABLES .......................................................................................................................... 39 
12. 
FIGURES ......................................................................................................................... 41 
13. 
LISTINGS........................................................................................................................ 44 
14. 
TABLE SHELLS ............................................................................................................. 47 
15. 
LISTING SHELLS .......................................................................................................... 82 
 
 
 


PAREXEL International 
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Protocol D5495C00001 
 
Version 1.0 
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Page 7 of 154 
 
Abbreviations and Definitions 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANOVA 
Analysis of Variance 
AST 
Aspartate Aminotransferase 
ATP 
Adenosine triphosphate 
AUC 
Area under plasma concentration-time curve from zero to infinity 
AUClast 
Area under plasma concentration time curve from time zero to the time of 
last measurable concentration 
AUCĲ 
Area under plasma concentration time curve over a dosing interval 
(24 hours) 
 
 
BMI 
Body Mass Index 
bpm 
Beats per minute 
BUN 
Blood urea nitrogen 
CI 
Confidence Interval 
 
 
 
CS 
Clinically significant 
Cmax 
Maximum observed plasma concentration 
CO2 
Carbon dioxide 
CrCL 
Creatinine Clearance 
CV 
Coefficient of Variation 
DDI 
Drug-Drug Interaction 
DKA 
Diabetic Ketoacidosis 
ECG 
Electrocardiogram 
eGFR 
Estimated glomerular filtration rate 
 
FAS 
Full Safety Analysis Set 
FPG 
Fasting plasma glucose 
FSH 
Follicle-stimulating hormone 
GGT 
Gamma glutamyl transpeptidase (transferase) 
Hb 
Hemoglobin 
HbA1c 
Hemoglobin A1c 
HBsAg 
Hepatitis B surface antigen 
&&,
&&,


PAREXEL International 
Statistical Analysis Plan 
 
AstraZeneca AB 
Protocol D5495C00001 
 
Version 1.0 
16 July 2018 
 
 
Page 8 of 154 
 
 
HCG 
Human beta chorionic gonadotrophin 
HCT 
Hematocrit 
HIV 
Human immunodeficiency virus 
IV 
Intravenous 
IMP 
Investigational Medicinal Product 
LLOQ 
Lower limit of quantification 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
ms 
milliseconds 
n 
Number of subjects 
NC 
Not Calculated 
NCS 
Not Clinically Significant 
ND 
Not determined 
NR 
No result 
NQ 
Non-quantifiable 
PD 
Pharmacodynamics 
PDS 
Protocol deviation specification (document) 
PK 
Pharmacokinetics 
QTcB 
QT Interval Corrected by Bazett’s Formula 
QTcF 
QT Interval Corrected by Fridericia’s Formula 
RBC 
Red blood cell 
SAE 
Serious adverse event  
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SOC 
System Organ Class 
sUA 
Serum uric acid 
TEAE 
Treatment-Emergent Adverse Event 


PAREXEL International 
Statistical Analysis Plan 
 
AstraZeneca AB 
Protocol D5495C00001 
 
Version 1.0 
16 July 2018 
 
 
Page 9 of 154 
 
t1/2 
Apparent terminal half-life 
tlast 
Time of last measurable concentration 
tmax 
Time to reach maximum observed plasma concentration 
UA 
Uric acid 
WBC 
White blood cell 
WHO-DD 
World Health Organization Drug Dictionary 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


PAREXEL International 
Statistical Analysis Plan 
 
AstraZeneca AB 
Protocol D5495C00001 
 
Version 1.0 
16 July 2018 
 
 
Page 10 of 154 
 
 
1. 
Statistical Analysis Plan 
This Statistical Analysis Plan (SAP) is based on the final protocol D5495C00001 
Version 1.0 dated 05 September 2017 and incorporates protocol amendment #1 dated 
02 October 2017 and protocol amendment #2 dated 02 May 2018. The SAP provides 
details on the planned statistical methodology for analysis of the study data.  The SAP 
also outlines the statistical programming specifications for the tables, listings and 
figures.  It describes the safety, pharmacodynamic (PD) variables, and the 
pharmacokinetic (PK) variables; as well as the anticipated data transformations and 
manipulations, and other details of the analyses not provided in the study protocol.  
This SAP covers the planned analysis of all data collected electronically in 
 
and provided by external vendors. 
2. 
Study Objectives and Hypotheses 
2.1 
Primary Objectives 
To assess the effects of intensive UA lowering therapy with RDEA3170, febuxostat 
and dapagliflozin on urinary excretion of UA. 
2.2 
Secondary Objectives 
x To assess the effects of intensive UA lowering therapy with RDEA3170, 
febuxostat and dapagliflozin on sUA levels. 
x To assess the PK of RDEA3170 and its main metabolites (M1 and M8), 
febuxostat and dapagliflozin in this patient population. 
x To assess the renal and general safety and tolerability of intensive UA lowering 
therapy with RDEA3170, febuxostat and dapagliflozin. 
2.3 
Exploratory  Objectives 
x 
 
 
 
 
 
 
 
 
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&&,


PAREXEL International 
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AstraZeneca AB 
Protocol D5495C00001 
 
Version 1.0 
16 July 2018 
 
 
Page 11 of 154 
 
x 
 
 
2.4 
Primary Outcome Measures 
Peak UA excretion during the first 8 hours (maximum amount excreted in an interval 
out of the first 8 hours) on Day 7 of treatment (Day 1 is the first day of treatment). 
2.5 
Secondary Outcome Measures 
x Serum uric acid levels after 7 days of treatment. 
x RDEA3170, M1, M8, febuxostat and dapagliflozin plasma concentrations and 
PK parameters. 
x Changes in clinical laboratory parameters, including assessment of serum and 
urinary levels of creatinine and cystatin-C, BUN, serum and urinary 
electrolytes, urinary pH. Changes in vital signs. Rates of AEs and SAEs. 
2.6 
Exploratory Outcome Measures 
x 
 
 
 
 
 
 
 
 
3. 
Study Design 
This is a randomized, placebo controlled, double-blind, 2-way crossover study to 
assess the effect of intensive UA lowering therapy with RDEA3170, febuxostat and 
dapagliflozin on urinary excretion of UA, in asymptomatic hyperuricemic patients. 
Twenty-four asymptomatic hyperuricemic patients aged 18 to 65 years (inclusive) 
will be enrolled into this study at 2 study centers. Each patient will receive the 2 
treatments listed below for 7 consecutive days (1 treatment per treatment period). 
 
 
 
 
&&,
&&,


PAREXEL International 
Statistical Analysis Plan 
 
AstraZeneca AB 
Protocol D5495C00001 
 
Version 1.0 
16 July 2018 
 
 
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x 
Treatment A: 9 mg RDEA3170 + 80 mg febuxostat + 10 mg dapagliflozin 
 
x 
Treatment B: 9 mg RDEA3170 + 80 mg febuxostat + placebo  
 
The study consists of a screening period of maximum 28 days. As well as: 
x Two treatment periods during which patients will be resident in the Clinical 
Unit from Day -2 to Day 1 and from Day 6 to Day 8; and 
x A Follow-up Visit within 14 to 28 days after the first administration of IMP in 
Treatment Period 2. 
Before any study specific assessments are performed, potential patients must 
provide informed consent. Patients that provided informed consent will attend the 
Screening Visits within 28 days before receiving the first dose of IMP. Patients that 
are meet all of the inclusion criteria and none of the exclusion criteria, will return to 
the Clinical Unit on Day -2 of Treatment Period 1 and will be randomized (1:1) to 1 
of 2 treatment sequences (AB or BA) before the start of urine collection on Day -1 
of Treatment Period 1. 
For each treatment period, baseline measurements will be performed. Patients 
receive the IMP for 7 consecutive days (Day 1 to Day 7). Patients will be residential 
in the Clinical Unit from Day -2 to Day 1. On Day 1, after all dosing and all 
assessments have been performed, patients will receive instruction to administer the 
IMP at home once daily in the morning from Day 2 to Day 6 and the IMP will be 
dispensed for home dosing. Patients will return to the Clinical Unit on Day 6 and 
will be residential in the Clinical Unit from Day 6 to Day 8. 
Treatment Period 1 and Treatment Period 2 will be separated by a washout 
period of 7 to 21 days. Patients will return to the Clinical Unit for a Follow-up 
Visit, 14 to 28 days after Day 1 of Treatment Period 2. 
The end of study is defined as the last patient’s last visit to the Clinical Unit. 
3.1 
Study Population 
The study population will consist of 20 to 24 male and female patients. 
All enrolled patients must meet all of the inclusion criteria and none of the exclusion 
criteria outlined in the study protocol. Any patient who fails to meet the inclusion 


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criteria or meet any exclusion criterion should not, under any circumstances, be 
randomized into the study. There can be no exceptions to this rule. 
3.2 
Statistical Basis for Sample Size 
Detailed information regarding the formal calculation of sample size can be 
found in the study protocol section 11.4. 
 
3.3 
Randomization 
Upon completion of the randomization requirements specifications form, the 
randomization will be produced by PAREXEL according to the AstraZeneca 
randomization system (AZRand). For this study, a total of 24 patient identifiers will 
be randomly assigned to the treatment sequence(s): AB, BA, with 12 patients 
assigned per sequence. An additional set of replacement random numbers will be 
generated within AZRand on a like for like treatment sequence basis.  
 
Randomization codes will be assigned strictly sequentially as patients become 
eligible for randomization (codes to be used without leading zero[s]). When using 
unique enrolment number, the specific format must be followed (i.e., reduced 
enrolment number, e.g., 
” [for Baltimore] and 
” [for Los 
Angeles] for outputs). The site number for Baltimore is 
 and the site number 
for Los Angeles is 
. 
 
If a patient withdraws his/her participation in the study, then his/her 
enrolment/randomization code cannot be reused. If a replacement is mandated, 
replacement patients will receive a new randomization number and will be 
allocated to the same treatment sequence as the replaced patient. 
3.4 
Blinding 
This study is double-blind with regard to treatment (dapagliflozin or placebo) in each 
treatment period. 
 
Dapagliflozin and placebo will be matched for formulation, appearance and amount. 
Patients randomized to placebo received the same number of tablets as patients on 
active drug. 
 
 
 
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3.5 
Dose Administration 
Patients will receive 9 mg RDEA3170 plus 80 mg febuxostat once daily in 
combination with either placebo or dapagliflozin 10 mg once daily for 7 consecutive 
days. 
Clinical Unit Dosing 
Patients will be residential in the Unit from Day -2 to Day 1, and from Day 6 to Day 
8. 
On Days -2, -1, 1, 6 and 7, patients will receive standardized meals, and will be 
encouraged to consume the entire meal. 
On Day -1, Day 1 and Day 7 of each treatment period, patients will be fasted for 10 
hours before dosing (for Day -1, clock time of planned dose administration for 
dosing days) until 4 hours after dosing, and will receive standardized meals 
thereafter. On Day 1 and Day 7, patients will receive the IMPs in the morning with 
240 mL water, after an overnight fast of at least 10 hours. A standard meal will be 
given 4 hours after dosing.  
Home Dosing 
Patients will self-administer the IMPs at home on a daily basis, from Day 2 to Day 6. 
3.6 
Treatment compliance 
Dosing will take place at the PAREXEL Early Phase Clinical Unit and at the patient’s 
homes. The administration of all IMPs will be recorded in 
. 
Compliance will be assured by direct supervision and witnessing of study drug 
administration when administration is performed at the Clinical Unit. After IMP 
administration, a check of the patient’s mouth and hands will be performed. 
Compliance will be assured during at home dosing by drug accountability. 
 
3.7 
Interim Analysis 
Not applicable 
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4. 
Study Analysis Variables 
4.1 
Demographic and Background Variables 
The following demographic and anthropometric information will be recorded: 
x Date of informed consent 
x Medical/surgical history  
x Urine drug, blood alcohol 
x Age calculated as (date of informed consent – date of birth)/365.25 
x Gender 
x Ethnic origin 
x Race 
x Height (cm) 
x Body weight (kg) 
x Body mass index (BMI) (kg/m2) 
x eGFR 
4.2 
Safety Variables 
4.2.1 Adverse Events 
The Adverse events will be collected from the start of randomization throughout the 
treatment period up to and including the Follow-up Visit. 
Serious adverse events will be recorded from the time of informed consent. 
4.3 
Potential Events of Diabetic Ketoacidosis 
All potential events of DKA will be recorded in 
 and submitted to an 
independent DKA Adjudication Committee.  The DKA Committee T2DM will assess 
available information on each potential DKA event and will classify the event in 
accordance with the definitions in the DKA Adjudication Charter T2DM. 
4.3.1 Clinical Laboratory Tests 
Laboratory safety tests for hematology and chemistry will be performed at Screening, 
Period 1 (Day-2, Day 7), Period 2 (Day -2, Day 7), and at Follow-up.  
The following safety laboratory parameters will be measured: 
Hematology 
 
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x White blood cell (WBC) count 
x Red blood cell (RBC) count  
x Hemoglobin (Hb) 
 
x Hematocrit (HCT) (c)  
x Mean corpuscular volume (MCV) 
 
x Mean corpuscular hemoglobin (MCH) 
 
x Mean corpuscular hemoglobin concentration (MCHC) 
 
x Neutrophils absolute count 
x Lymphocytes absolute count 
x Monocytes absolute count 
x Eosinophils absolute count 
x Basophils absolute count 
x Platelets 
x Reticulocytes absolute count 
x Hemoglobin A1c (HbA1c) (Screening Visit only) 
 
Clinical Chemistry  
 
x Alkaline phosphatase (ALP) 
x Alanine aminotransferase (ALT) 
x Aspartate aminotransferase (AST) 
x Gamma glutamyl transpeptidase (GGT) 
x Potassium 
 
x Blood Urea Nitrogen (BUN)  
x Creatinine(c)  
x Albumin 
 
x Calcium 
 
x Phosphate 
 
x Uric acid(c) 
 
x Total Bilirubin 
x Unconjugated bilirubin 
x Cystatin-C(c) 
x Sodium 
x Estimated Creatinine Clearance (CrCl) 
x eGFR(a) 
x Glucose (Fasting)(b)(c) 
 
Notes:  
(a) eGFR collected at screening visit only (Visit 1) 
(b) Plasma glucose after at least 4 hours fasting (Day -1 of each period) 
 
 
 
 
 


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Urinalysis by dipstick 
x Glucose 
x Protein 
x Blood 
x Microscopy (if dipstick is positive for protein or blood): RBC, WBC, Casts 
(Cellular, Granular, Hyaline) 
 
Urinalysis for urine collection interval(c) 
x Uric Acid 
x Creatinine 
x Glucose 
 
x Sodium 
x pH 
x Cystatin-C 
 
Pregnancy Test (females only) 
x Human beta chorionic gonadotrophin (HCG) 
x Follical-stimulating hormone (FSH) – Screening visit. 
 
 
Vital Serology 
x Human immunodeficiency virus (HIV) I and II 
x Hepatitis C Virus antibody  
x Hepatitis B surface antigen (HBsAg) 
 
Drugs of Abuse 
x Amphetamine/Ectasy 
x Benzodiazepines 
x Ethanol 
 
x Cannabinoids  
x Cocaine 
 
x Opiates 
x Tricyclic anti-depressants (TCA) 
x Methadone Metabolites 
x Barbiturates 
x Phencyclidine 
 
Note: Laboratory results indicated (c) will be listed, summarized, and analyzed as part 
of the PD panel, as described in section 8 below. 
 
 
 


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4.3.2 Vital Signs 
Vital signs will be collected at Screening, Period 1 (Day -2, Day 7), Period 2 (Day -
2, Day 7), and at Follow-up. 
 
The following variables will be collected after the patient has rested in the supine 
position for at least 5 minutes: 
 
x 
Systolic BP (mmHg) 
x 
Diastolic BP (mmHg) 
x 
Pulse rate (bpm) 
 
4.3.3 Electrocardiograms 
 
Standard 12-lead ECGs will be collected at Screening, Day-2 of each period, and at 
Follow-up. 
 
The ECG will be evaluated by the Investigator as ‘Normal’, ‘Abnormal, NCS’ or 
‘Abnormal, CS’. 
4.3.4 Physical Examination 
Complete physical examinations will be performed at Screening and Follow-up. 
 
A brief physical examination will be performed at Day -1 and Day 7 of each period.  
 
Subject body weight will be assessed at Screening, Day -1 and Day 7 of each period 
and at Follow-up.  
4.3.5 Prior and Concomitant Medications 
Prior medications are those that started and stopped before the first dose of IMP; all 
medications taken after first dosing are considered as concomitant (including 
medications that started before dosing and continued after). Prior medication started 
within 3 months before the first dose of IMP will be recorded also in the 
concomitant medication module of 
. 
4.4 
Pharmacokinetics 
Plasma pharmacokinetic samples will be collected at Pre-dose and 15 minutes, 30 
minutes, 1 hour, 1.5, 2, 3, 4, 8, 12 and 24 hours post-dose. 
 
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The PK analyses of the plasma concentration data for RDEA3170, febuxostat, 
dapagliflozin, M1, and M8 will be performed by Covance, on behalf of Clinical 
Pharmacokinetic Alliance, AstraZeneca R&D. 
Where possible, the following plasma PK parameters will be calculated for 
RDEA3170, febuxostat, dapagliflozin, M1, and M8 using plasma concentrations. 
 
AUCĲ 
Area under plasma concentration time curve over a dosing 
interval (24 hours) 
AUClast 
Area under plasma concentration time curve from time zero to the 
time of last measurable concentration 
Cmax 
Maximum observed plasma concentration 
tmax 
Time to reach maximum observed plasma concentration 
tlast 
Time of last measurable concentration 
 
4.4.1 Pharmacokinetic Parameter Calculation Methods 
Pharmacokinetic parameters will be derived using non-compartmental methods with 
    
Pharmacokinetic analysis will, where possible, be carried out using actual times 
recorded in the raw data.  If actual times are missing, nominal times will be used. 
 
Plasma concentrations which are NQ before the first quantifiable concentration will 
be set to a value of zero.  After the first quantifiable concentration, any NQ plasma 
concentrations will be set to missing for all concentration profiles.  Where 2 or more 
consecutive concentrations are NQ at the end of a profile, the profile will be deemed 
to have terminated and therefore any further quantifiable concentrations will be set to 
missing for the calculation of the PK parameters unless it is considered to be a true 
characteristic of the profile of the drug. 
 
If an entire concentration-time profile is NQ, the profile will be excluded from the PK 
analysis. 
 
Cmax and tmax will be obtained directly from the individual concentration-time 
profiles. 
 
AUCĲ and AUClast will be calculated using the linear trapezoidal method when 
concentrations are increasing and the logarithmic trapezoidal method when 
concentrations are decreasing. 
 
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The minimum requirement for the calculation of AUCĲ and AUClast will be the 
inclusion of at least 3 consecutive plasma concentrations above the lower limit of 
quantification (LLOQ), with at least 1 of these concentrations following Cmax. 
4.5 
Pharmacodynamic Data 
The following PD data will be collected:  
 
Time Urine Sample Collections 
 
The times of urine sample collection will occur at Day -1 and 7 of each period. 
Day -1 baseline collection of urine consists of hourly collections from -24 to -12 
hours (inclusive, counted from the time of dosing on Day 1 where 0 hours is time of 
dosing) at the following sampling intervals: -24 to -23 hours, -23 to -22 hours, -22 to -
21 hours, -21 to -20 hours, -20 to -19 hours, -19 to -18 hours, -18 to -17 hours, -17 to -
16 hours, -16 to -15 hours, -15 to -14 hours, -14 to -13 hours, -13 to -12 hours, 
followed by a single 12-hour collection from -12 to 0 hours. 
 
Directly following the dose of study treatment on Day 7, hourly collection of urine is 
performed every hour from 0 to 12 hours (inclusive), at the following post-dose 
sampling intervals (0 to 1 hour, 1 to 2 hours, 2 to 3 hours, 3 to 4 hours, 4 to 5 hours, 5 
to 6 hours, 6 to 7 hour, 7 to 8 hours, 8 to 9 hours 9 to 10 hours, 10 to 11 hours, 11 to 
12 hours). These sampling intervals will be followed by a single pooled collection 
from 12 to 24 hours. 
 
Time matched PD Urine Samples for Each Period 
Day -1 
Day 7 
-24 to -23 hours  
0 to 1 hour  
-23 to -22 hours 
1 to 2 hours 
-22 to -21 hours 
2 to 3 hours 
-21 to -20 hours 
3 to 4 hours 
-20 to -19 hours 
4 to 5 hours 
-19 to -18 hours 
5 to 6 hours 
-18 to -17 hours 
6 to 7 hours 
-17 to -16 hours 
7 to 8 hours 
-16 to -15 hours 
8 to 9 hours  
-15 to -14 hours 
9 to 10 hours 
-14 to -13 hours 
10 to 11 hours  
-13 to -12 hours 
11 to 12 hours 
-12 to 0 hours* 
12 to 24 hours** 
*single 12-hour collection 
**Single Pooled Collection 
 


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Blood Samples for Serum Uric Acid 
 
A single sUA assessment (matched by time of day, e.g. always in the morning, and 
after a 10 hour overnight fast) will be taken at screening, Day -1 of each period and at 
the follow-up visit. The screening sUA can be repeated once during the screening 
period. 
 
In each period day 7 blood samples for serum UA will match the PK sample times: 
pre-dose and 15 minutes, 30 minutes, 1 hour, 1.5, 2, 3, 4, 8, 12 and 24 hours post-
dose. This will allow for 26 possible blood samples for PD serum UA. 
 
4.6 
Efficacy Variables 
Not applicable 
4.7 
Analysis Populations 
4.7.1 Safety Analysis Set 
The safety analysis set will include all patients who received at least 1 dose of IMP 
and for whom any safety post-dose data are available 
4.7.2 Pharmacokinetic Analysis Set 
The PK analysis set will consist of all patients in the safety analysis set for whom at 
least 1 of the primary PK parameters can be calculated for at least 1 analyte  
(RDEA3170, M1, M8, Febuxostat or dapagliflozin), and who have no major 
protocol deviations thought to impact on analysis of the PK data. 
 
Patients may be excluded from the PK analysis set as a result of the following: 
 
x 
Data from patients who experienced vomiting during the PK samples collection 
day may be excluded from summary statistics and statistical analysis if 
vomiting occurred at or before the median tmax for each respective analyte. 
 
A patient may be excluded from the analysis only for the specific treatment period 
in which the AE occurred. 
4.7.3 Pharmacodynamic Analysis Set 
Analysis of the primary variable, maximum uric acid excretion in urine per hour, as 
well as the secondary variable serum UA at 7 days will be done using the full Safety 
Analysis Set as defined in section 4.7.1 above. Any sensitivity analysis will be 


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considered using the Per Protocol (PP) Set. The PP Set will be defined as all patients 
in the randomized set without major protocol deviations (to be defined before 
database lock). 
4.7.4 Randomized Set 
The Randomized Set will consist of all patients randomized into the study. 
5. 
STATISTICAL REPORTING 
For the purposes of this SAP IMP will include any of the study drugs: 
RDEA3170, febuxostat, dapagliflozin, or placebo. 
5.1 
General Considerations for Data Presentations 
Data for all enrolled subjects will be presented in the data listings.     
 
A subject who is enrolled but does not receive IMP will be included in those data 
listings for which they have data but will be excluded from all data summaries. Data 
summaries will only include those subjects that receive IMP.  
 
For those listings or data summaries where baseline and change from baseline 
measurements will be presented, unless stated otherwise the last observed 
measurement prior to the first dose of IMP in a given treatment period will be 
considered the baseline measurement for all post-dose assessments in that treatment 
period.  
 
All pre- and post-dose assessments, including unscheduled assessments and repeats, 
will be included in the data listings. For unscheduled (repeat) assessments collected 
pre-dose, the last assessment taken for a time point will be used in the data summaries 
(summary tables, figures, and statistical analysis); for all post-dose time points, the 
original assessment for any given time point will be used in the data summaries 
(summary tables, figures, and statistical analysis). 
 
Data summaries of continuous variables will be summarized using descriptive 
statistics including: number of observations (n), mean (arithmetic and/or geometric), 
median, standard deviation (SD), minimum, and maximum. Frequencies and 
percentages will be used for summarizing discrete (categorical) data. In summaries for 
safety the denominator for all percent’s will be the number of subjects in a given 
treatment.  
 
Data that are reported as missing will be excluded from all descriptive and non-
descriptive data analysis. There will be no imputation of data.  Observations that 
might be considered spurious (extreme relative to the majority of the data) will not be 


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altered or removed from any presentation of the data, including the calculation of 
summary statistics (means, medians, etc.), unless approved by the sponsor.  
 
For data listings, all raw data will be reported/displayed exactly as provided. For 
summaries of quantitative safety data, the minimum and maximum value will be 
reported exactly as the raw data are reported; measures of central tendency (means, 
medians) will be reported to one more decimal place than the raw data; measures of 
variance (SD) will be reported to two more decimal places than the raw data.   
Methods for summarizing PK data are described in Section 7 of this SAP. 
 
Listings will include all subjects and will be sorted by subject identifier (enrolment 
number) and time point (where applicable). All listings will include the site number 
identifier, the subject identifier, and the subject’s treatment sequence. All derived data 
used in a data summary or statistical analysis will be listed.  In all data presentations 
treatment will be defined by the 2 categories: 
 
x 
Treatment A: 9 mg RDEA3170 + 80 mg febuxostat + 10 mg dapagliflozin 
x 
Treatment B: 9 mg RDEA3170 + 80 mg febuxostat + placebo  
 
 
 SOFTWARE  
 
All statistical analyses will be performed using 
 
(
 Institute Inc., Cary, North Carolina, United States of America [USA]) 
Version 9.2 or higher. The PK analysis will be performed using 
 
 
 (Certara, L.P., 9666 Olive Blvd, Suite 
425, St. Louis MO 63132). 
6. 
Subject and Treatment Information 
6.1 
Randomization Scheme and Codes 
A listing of randomization codes will be provided including the subject identifier, the 
randomization number, as well as the treatment associated with each period that 
defines each subject’s treatment sequence.  
6.2 
Discontinued Subjects 
All subjects who discontinued early from the study will be listed including the date of 
study exit, duration of treatment, and the reason for early discontinuation.  
  
&
&
&
&
,
&
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6.3 
Subject Disposition 
The number of subjects randomized and the frequency and percentage of subjects who 
received treatment, subjects who did not receive treatment, subjects who completed at 
least one treatment period, subjects who discontinued any treatment period, subjects 
who completed the study, and subjects who withdrew from the study early will be 
summarized overall.  The number and percent of subjects in the safety population, PD 
population, and PK population will be summarized by treatment sequence and overall.   
6.4 
Protocol Deviations 
All reported protocol deviations will be listed. Protocol deviations that are used to 
identify the Per Protocol population will be determined and finalized prior to DB lock. 
6.5 
Subject and Data Exclusions 
Listings will be provided showing any subjects or data excluded from the safety 
population, the PD population, and the PK population. 
6.6 
Demographic Data  
Demographic information will be listed.  Descriptive statistics will be obtained for the 
continuous variables: height, age, BMI, and baseline body weight.  Frequencies and 
percentage of subjects will be tabulated by treatment sequence and overall for the 
categorical variables ethnicity, race, and gender.  
6.7 
Informed Consent Response 
 
Each subject’s informed consent response will be listed including date and time of 
informed consent, whether a subject complies with all inclusion/exclusion criteria, 
and the actual date/time of eligibility. 
6.8 
Medical History 
Medical history data will be listed for each subject including a description of the 
condition or abnormality, system organ class, and preferred term.  Medical history 
will be coded using Medical Dictionary Regulatory Activities (MedDRA Version 
20.1). Only those body systems where a condition or abnormality has been reported 
will be listed. Included will be the date and time recoded. 


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6.9 
Pregnancy Test Results 
Pregnancy test results from serum and urine pregnancy tests will be listed for all 
female subjects. 
6.10 Medication on Entry and During the Study 
Medication on entry and during the study will be listed for each subject. 
Included will be the medication name, WHO Drug name, and ATC classification. 
 
Datasets 
Coding Dictionary 
Version 
Previous and Concomitant 
Medications 
WHODDE +HD  
WHODDE+HD 201709 
6.11 Dose Administration 
The in-clinic dose administration of each subject will be listed including the date and 
time of dose administration, drug name, and the nominal dose planned per protocol.  
 
A separate listing will be provided showing the home dosing of each subject. 
 
All drug accountability data collected will be listed for each subject. 
6.12 Meal Administration  
Controlled meals and fluid intake will be listed for each subject. 
  
7. 
Pharmacokinetic Concentrations and Parameters 
Table presentations of the PK concentrations and PK parameter data will be 
conducted using the PK analysis set. 
All tables, listings and figures for RDEA3170, febuxostat, dapagliflozin, M1, and 
M8 will be presented in the units as provided in the source file received from the 
bioanalytical laboratory.  
The following descriptive statistics will be presented in PK parameter summary 
tables: n (number of non-missing observations), arithmetic mean, SD, median, 
minimum, maximum, geometric mean, geometric CV% (CV%), geometric +GSD, 
geometric –GSD.  
The geometric mean is calculated as the exponential of the arithmetic mean calculated 
using log-transformed data. 
 


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CV%=SQRT[exp(s²)-1] x 100 and ‘s’ is the standard deviation of the log-transformed 
values.  
 
The standard deviation of the geometric mean (GSD) will be displayed as: 
exp(lgmean +/- s), where 'lgmean' is the mean of the data on the log scale. 
For tmax and tlast, only n, median, minimum and maximum will be presented. 
 
All PK tables, listings, and figures will be presented by analyte and treatment defined 
by the following two categories of drug administration:  
 
x Treatment A: 9 mg RDEA3170 + 80 mg febuxostat + 10 mg dapagliflozin 
x Treatment B: 9 mg RDEA3170 + 80 mg febuxostat 
 
For presentations in data listings, concentration data will be presented using the same 
number of significant figures as the data received from the bioanalytical laboratory.  
 
For PK parameters, the listings will be presented according to the following rules: 
 
x Cmax – will be presented to the same number of significant figures as received 
from the bioanalytical laboratory. 
x tmax and tlast – will be presented as received in the data, usually to 2 decimal 
places. 
x AUCĲ and AUClast - will be presented to 3 significant figures. 
 
Descriptive statistics and statistical analyses will be calculated using un-rounded 
results. For tmax and tlast, only median, minimum, maximum, and n will be 
calculated. 
Below is a summary of the rounding rules to be applied to the PK tables.  
Concentration Tables 
Rounding 
Individual concentrations 
n s.f. as supplied in source 
Minimum and Maximum 
3 s.f. 
Mean/SD/Median/Geomean/GSD 
4 s.f. 
CV% 
4 s.f.  
PK Parameter Tables 
  
Derived Individual parameters 
3 s.f. 
Directly Derived Individual parameters (Cmax, 
C12, C24) 
n s.f. as supplied in source 
Minimum and Maximum 
3 s.f. 
Mean/SD/Median/Geomean/GSD 
4 s.f. 
CV% 
4 s.f. 
CI and other percentages 
2 d.p. 
p-values 
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Exceptions for PK Tables 
  
tmax, tlast individual values and  
all descriptive statistics (median, minimum, and 
maximum) 
Presented as received in the data, usually 2 d.p. 
s.f = signficant figures, d.p. = decimal place 
7.1 
Handling Of Values Below The Limit Of Quantification (BLQ) 
Individual plasma concentrations below the LLOQ of the bioanalytical assay will be 
listed as NQ (not quantifiable) with the LLOQ defined in the Tables, Figures and 
Listings (TFLs), as applicable.  For calculation of descriptive statistics, plasma 
concentrations that are NQ or if there are missing values (e.g., no result [NR]) will be 
handled as follows: 
 
Where results are reported as ‘NR’, these will be set to missing in calculations of 
descriptive statistics. 
 
x At a time point where less than or equal to 50% of the values are NQ, all NQ 
values will be set to the LLOQ, and all descriptive statistics will be calculated. 
x At a time point where more than half (but not all) of the values are NQ, the mean, 
SD, geometric mean, geometric +GeoSD, geometric –GeoSD and CV% will be 
set to Not Calculated (NC).  The maximum value will be reported from the 
individual data, and the minimum and median will be set to NQ. 
x If all values are NQ at a time point, no descriptive statistics will be calculated for 
that time point.  Not calculated “NC” will be written in the field for SD, geometric 
+GeoSD, geometric –GeoSD and CV% and NQ will be written in fields for mean, 
geometric mean, minimum, median and maximum. 
x The number of NQ values (n below LLOQ) will be reported for each time point. 
 
Three observations > LLOQ are required as a minimum for a plasma concentration or 
PK parameter to be summarized.  Two values are presented as a minimum and 
maximum with the other summary statistics as NC. 
7.2 
PK Plasma Concentrations 
Pharmacokinetic concentration data for RDEA3170, febuxostat, dapagliflozin, M1, 
and M8 concentrations will be listed for each subject by treatment and time point.  
Actual sampling times relative to dosing, nominal scheduled times, and the difference 
between the actual and nominal sample time will also be listed.  
Plasma concentrations for RDEA3170, febuxostat, dapagliflozin, M1, and M8 will be 
summarized by treatment and nominal time.  


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7.3 
PK Parameters 
All derived plasma PK parameters for RDEA3170, febuxostat, dapagliflozin, M1, and 
M8 will be listed by subject and treatment, and summarized by treatment.  
7.4 
Graphical Presentation of PK Data 
PK plasma concentrations will be presented graphically by analyte, treatment and 
time point. Graphical presentations of the plasma concentrations will include 
geometric mean profiles of the plasma concentration vs. time data for each of 
RDEA3170, febuxostat, dapagliflozin, RDEA3170 M1metabolite, and M8. For each 
of the above analytes individual subject profiles on linear and semi-logarithmic scale 
will be provided as well as combined subject profiles on linear and semi-logarithmic 
scale. 
 
For each of the mean plasma concentrations profiles, error bars will be displayed as 
exp(lgmean +/- sd_lg), where 'lgmean' is the mean of the data on the log scale, and 
'sd_lg' is the SD of the data on the log scale. Error bars will be excluded from mean 
figures on the log scale. 
 
For the mean figures and individual subject profiles, all treatments will be overlaid on 
the same plot, and seprate plot for each analyte. 
Nominal sampling times will be used in the PK concentrations summary tables and 
mean plasma concentration figures. Actual times from dosing will be used in the 
individual subject concentration -time profiles.   
 
For mean plots, NQ values will be handled as described for the summary tabulations; 
for individual plots, plasma concentrations which are NQ before the first quantifiable 
concentration will be set to a value of zero (linear plots only).  After the first 
quantifiable concentration, any NQ plasma concentrations will be regarded as 
missing.  All plots will be based on the PK analysis set, with the exception of 
individual plots by patient which will be based on the safety analysis set. 
7.5 
Statistical Analysis of Pharmacokinetic Drug-Drug Interaction 
To assess the potential drug-drug interaction of RDEA3170 and febuxostat given with 
and without dapagliflozin, the natural log-transformed PK parameters AUCĲ, 
AUClast and Cmax of RDEA3170, febuxostat, M1, and M8 will be separately 
analyzed using a linear mixed effects ANOVA model, with fixed effects terms for 
sequence, period, and treatment. In this analysis, subjects nested within sequence will 
be assumed to be a random effect.  Kenward and Roger's method will be used to 
calculate the denominator degrees of freedom for the fixed effects (DDFM=KR).  The 
point estimate and 90% CI for the difference between treatments (RDEA3170 + 
febuxostat + dapagliflozin versus RDEA3170 + febuxostat) will be constructed.  The 
point estimate and adjusted 90% CIs will be exponentially back transformed to 


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provide point and CI estimates for the treatment ratio (RDEA3170 + febuxostat + 
dapagliflozin versus RDEA3170 + febuxostat).  Additionally, for each treatment, back 
transformed geometric means together with 95% CIs for AUCĲ, AUClast and Cmax, 
for RDEA3170, M1, M8, and febuxostat will be estimated and presented. 
 
To make the treatment comparison the following SAS code maybe used as reference:  
 
PROC MIXED data = data ; 
CLASS subject treatment period sequence; 
MODEL log(var) = treatment period sequence ; 
RANDOM  subject(sequence) ; 
LSMEAN treatment /  CL ALPHA=0.05 ; 
ESTIMATE 'A vs. B' treatment 1 -1  / ALPHA=0.1 CL; 
RUN; 
 
For all ANOVA PK models described above the geometric mean ratios, their 90% CI, 
along with the ratios of individual patient values will be plotted to visualize the 
treatment comparisons. 
7.6 
Multiplicity 
Since there is only one primary hypothesis on pharmacokinetics there is no need for a 
multiplicity adjustment. 
8. 
Pharmacodynamic Results 
8.1 
Primary PD Variables 
PD urine collection times will be provided including the derived sampling time 
deviations.  From the uric acid concentrations the urinary excretion of uric acid will 
be derived as follows: 
   
x Amount Excreted = urine acid concentration * weight of produced urine * 
1.000 
 
The primary outcome variable,  the ‘Peak uric acid excretion during the first 8 
hours’, will be identified as the maximum amount excreted in an interval out of the 
first 8 hours of collection on Day 7 of treatment. Subject listings will be provided of 
the raw uric acid concentrations and the derived values for the urinary excretion of 
uric acid. Among the Day -1 and Day 7 timepoints tabulated below, the peak 
(maximum) uric acid excretion will be flagged in the data listing.  
 
The maximum change from baseline in the amount excreted in urine for each period 
will be derived as the difference between the peak amount excreted during Day 7 


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versus peak amount excreted during Day -1. For each day, only the first 8 hours of 
sampling will be considered when selecting the peak excretion.  
  
 
PD Urine Samples  
Day -1 
Day 7 
 
-24 to -23 hours  
0 to 1 hour  
 
 
 
 
First 8 hours of 
assessment 
-23 to -22 hours 
1 to 2 hours 
-22 to -21 hours 
2 to 3 hours 
-21 to -20 hours 
3 to 4 hours 
-20 to -19 hours 
4 to 5 hours 
-19 to -18 hours 
5 to 6 hours 
-18 to -17 hours 
6 to 7 hours 
-17 to -16 hours 
7 to 8 hours 
-16 to -15 hours 
8 to 9 hours  
 
-15 to -14 hours 
9 to 10 hours 
 
-14 to -13 hours 
10 to 11 hours  
 
-13 to -12 hours 
11 to 12 hours 
 
-12 to 0 hours* 
12 to 24 hours** 
 
*single 12-hour collection, **Single Pooled Collection 
 
For each subject the derived values for the maximum change from baseline in the 
amount excreted in urine for each period will be listed. 
 
Descriptive summary tables will be provided for the raw uric acid concentrations, the 
derived values for the urinary excretion of uric acid, the peak uric acid excretions, as 
well as the change from baseline of the peak uric acid excretions. 
 
Subject profiles will be used to visualize the derived values for the urinary excretion 
of uric acid for each treatment over time. Side-by-side box plots will be used to 
visualize the distribution of the peak uric acid excretions at Day -1 and Day 7 for each 
treatment.  
 
For the data analysis, only subjects with urine data collected every hour as per the 
schedule of events will be included.  
8.2 
Secondary Pharmacodynamic Variables 
Subject listings will be provided for the raw serum uric acid concentrations. The 
serum uric acid results will be analyzed for each period as the Day 7 predose 
assessment compared to the Day -1 assessment using change from baseline (Day 7 
predose versus Day -1). Change from baseline values will be listed for each subject. 
 


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Descriptive summary tables will be provided for the raw serum uric acid 
concentrations as well as the derived change from baseline serum uric acid values 
looking at Day 7 predose versus Day -1. 
 
Subject profiles will be used to visualize the raw serum uric acid concentrations for 
each treatment over time. 
 
Other secondary PD outcome variables of interest include change from baseline (Day 
7 versus Day -1) for the following clinical laboratory parameters:  
 
x Estimated glomerular filtration rate  
x serum levels of creatinine 
x urinary levels of creatinine 
x cystatin-C 
x Blood urea nitrogen 
x Serum electrolytes 
x Urinary electrolytes 
x Urinary pH 
 
All secondary PD variables will be listed for each subject as observed values and 
changes from baseline. Descriptive summary tables by treatment and day for the 
observed and change from baseline values will be provided for each secondary PD 
variable. 
8.3 
Statistical Analysis of Pharmacodynamic Variables 
Due to the explorative nature of this study, no adjustment for multiple testing of 
primary variable and secondary variables will be done. 
8.3.1 Analysis of Primary PD Variable 
The primary PD variable of interest is the peak uric acid excretion in subject urine per 
hour observed over the first 8 hours. Analysis of the primary variable will be done on 
log-transformed values. Using the peak uric acid excretion the analysis will consider 
the maximum change from baseline difference from placebo at day 7 of treatment. 
The maximum change from baseline is the change from baseline (Day 7 versus Day -
1) in the peak uric acid excretion where the  baseline is the peak urine excretion 
observed over the first 8 hours of Day -1. A linear mixed effects analysis of variance 
(ANOVA) model will be used, with fixed effects terms for sequence, period, and 
treatment. In this analysis, subjects nested within sequence will be assumed to be a 
random effect.  Kenward and Roger's method will be used to calculate the 
denominator degrees of freedom for the fixed effects (DDFM=KR). A geometric 
mean ratio for the change from baseline response will be calculated by taking the 
anti-logarithm of the difference between treatment means.  A 95% CI for each 
treatment ratio will be obtained by taking the anti-logarithm of the 95% CI endpoints 


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for each mean difference. Results will be presented as geometric mean ratios for the 
change from baseline difference from placebo including 95% Cis for the mean ratios, 
based on Student’s t-distribution.   
8.3.2 Analysis of Secondary PD Variables 
The PD variable of secondary interest is the serum uric acid (sUA) levels on Day 7. 
Analysis of serum UA will be conducted in an equivalent way as urine UA, using 
log-transformed values and change from baseline (Day -1) to observed serum UA at 
Day 7.  A linear mixed effect model of the change from baseline will be used with 
fixed effects terms for sequence, period, and treatment. In this analysis, subjects 
nested within sequence will be assumed to be a random effect.  Kenward and Roger's 
method will be used to calculate the denominator degrees of freedom for the fixed 
effects (DDFM=KR). Results will be presented in the same way as the results for 
urine UA: using the geometric mean ratios for the change from baseline difference 
from placebo including 95% Cis for the mean ratios.  
  
Statistical analysis of the other secondary PD variables will be conducted in an 
equivalent way as described for serum and urine UA.  
 
8.3.3 Analysis of Exploratory PD Variables 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
8.3.4 Visualizing the Pharmacodynamic Results 
For all ANOVA PD models described above the geometric mean ratios, their 95% CI, 
and data permitting the ratio of individual patient values will be plotted to visualize 
the treatment comparisons. 
 
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8.3.5 Analysis of Urinary PD Variables Over a 24 hour Interval 
Using the amount excreted in urinary uric acid, derived as: 
x Amount Excreted = urine uric acid concentration * weight of produced urine 
* 1.000 
 
For each 24 hour profile (Day -1 and Day 7 ), the amount excreted for each individual 
time point will be summed over each 24 hour period. For each subject this will 
provide a total value for each period for each day defined as: the ‘Total Amount of 
Uric Acid Excreted in Urine over a 24 hour period (mg/day)’.   
 
Similar calculations will be applied to the other quantitative urinalysis PD parameters: 
Sodium, Creatinine, Cystatin-C, and pH. 
 
For each of these secondary urine PD parameters, the amount excreted will be listed 
and the total amount excreted in urine over a 24 hour period will be listed. These total 
values derived over a 24 hour period will be summarize by treatment and day. 
  
9. 
Safety Analysis 
The analysis of the safety variables will be conducted using the safety analysis set. 
9.1 
Adverse Events 
 
All verbatim AE terms reported will be coded according to MedDRA, version 20.1. 
A treatment-emergent adverse event (TEAE) is defined as an AE with onset (start 
date/time) after the first dose of IMP in Treatment period 1. 
 
Adverse events will be assigned to a treatment based on the start date/time of the AE 
in relation to dosing in that period; for tabulation purposes the AE will then be 
assigned to the treatment received in the respective treatment period as follows: 
 
x Screening: all AEs with start date/time before dosing in Treatment period 1. 
x Treatment period 1: AEs with start date/time at the time of or after dosing in 
Treatment period 1 until the time of dosing in Treatment period 2 will be assigned 
to the treatment received in period 1. 
x Treatment period 2: AEs with start date/time at the time of or after dosing in 
Treatment period 2 until the Follow-up Visit, will be assigned to the treatment 
received in period 2. 
 
Adverse events with missing start dates/times will be handled as follows: 
x If the start date is completely missing but the end date is known and shows that 
the AE ended on or after the first dose date, then the start date will be imputed as 
the first day of dosing; if the end date is known and shows that the AE ended 


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before the first dose date, then the screening date will be used for the start date.  If 
the end date is non-informative (i.e., is missing or does not contain enough 
information), the start date will be imputed as the first date of dosing; 
x If only the start day is missing the day will be imputed as the first day on which a 
dose was given in that month unless the end date is known and shows that the AE 
ended before a dose was given in that month; in which case the date will be 
imputed as 01.  If the end date is non-informative (i.e., is missing or does not 
contain enough information), the start date will be imputed as the first date of 
dosing in the known month.  If the month is not a dosing month the date will be 
imputed as 01; 
x If the start day and month are missing the date will be imputed as the first day of 
dosing in the known year unless the end date is known and shows that the AE 
ended before a dose was given in that year; in which case the start day and month 
will be imputed as 01Jan or with the date of screening if this is later.  If the end 
date is non-informative (i.e., is missing or does not contain enough information), 
the start date will be imputed as the first date of dosing in the known year.  If the 
year is not a year of dosing, then the date will be imputed as 01Jan or with the 
date of screening if this is later. 
 
Missing times will be imputed as 00:00 h or with the time of dosing for events starting 
on a dosing day. 
 
All AE data as captured in 
 will be listed for each subject (Listing 16.2.7.1). 
All serious AEs (SAEs) will be listed (Listing 16.2.7.2). A listing of all AEs leading 
to treatment discontinuation will be presented, if applicable (Listing 16.2.7.3).   
The following information will be included in the listings: verbatim term, SOC, 
Preferred Term and lowest level term, start date/time, end date/time, time from most 
recent dose, causality, action taken, whether the AE was classified as serious and the 
outcome. 
 
Unless specified otherwise, all adverse event summaries will include the TEAEs only 
and adverse event summary counts of AEs will be the number of subjects reporting 
adverse events and not the number of events reported. The number and percentage of 
subjects with adverse events will be tabulated by body system and preferred term by 
treatment. A subject with multiple adverse events within a body system is only 
counted once towards the total of that body system.  If the same AE (preferred term) 
is reported several times for the same subject within a treatment period, it will only 
appear once for that specified treatment in the summary tables. 
 
For purposes of the summary tables, AEs will be classified as either being related to 
study drug or not related.  
As defined in the protocol, within the source data all AEs will be assigned a severity 
grade of: Mild, Moderate, Severe. For subjects with multiple adverse events of the 
same preferred term and of different severities, the AE with the highest assessment of 
severity will be used in the summaries presented by severity.   
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A general summary of all treatment-emergent adverse events will show the number 
and percentage of subjects, as well as the number of events, according to the 
following categories: 
x All treatment emergent adverse events  
x Treatment emergent adverse events ‘Related to IMP’ 
x Mild treatment emergent adverse events 
x Moderate treatment emergent adverse events 
x Severe treatment emergent adverse events 
x Treatment emergent adverse events leading to death 
x Serious treatment emergent adverse events 
x Treatment emergent adverse events leading to early termination 
 
Other summary tables for adverse events will include: 
x Number and Percentage of Subjects with Treatment Emergent Adverse Events by 
System Organ Class, Preferred Term, and Treatment 
x Number and Percentage of Subjects with Treatment Emergent Adverse Events 
‘Related to IMP’ by System Organ Class, Preferred Term, Severity, and 
Treatment. 
x Number and Percentage of Subjects with Treatment Emergent Adverse Events 
‘Not Related to the IMP’ by System Organ Class, Preferred Term, Severity, and 
Treatment. 
x Number and Percentage of Subjects with Treatment Emergent Adverse Events by 
Preferred Term and Treatment  
For tabulations of AEs by treatment; for those subjects assigned to the ‘AB’ treatment 
sequence, any AE occurring during the first period and before the Period 2 dose, will 
be assigned to the ‘A’ treatment (9 mg RDEA3170 + 80 mg febuxostat + 10 mg 
dapagliflozin). Any AE occurring after the period 2 dose, will be assigned to the ‘B’ 
treatment (9 mg RDEA3170 + 80 mg febuxostat + placebo).  
 
For those subjects assigned to the ‘BA’ sequence, any AE occurring during the first 
period and before the period 2 dose, will be assigned to the ‘B’ treatment (9 mg 
RDEA3170 + 80 mg febuxostat + placebo). Any AE occurring after the period 2 dose, 
will be assigned to the ‘A’ treatment (9 mg RDEA3170 + 80 mg febuxostat + 10 mg 
dapagliflozin).  
 
If a subject has multiple AEs with the same preferred term but occurring after each 
dose administration, then one AE will be counted for each treatment.  Adverse events 
that emerge in one treatment period and carry over into the next period will be 
attributed to only the period in which the AE emerged. 


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9.2 
Diabetic Ketoacidosis (DKA) 
 
All DKA events will be listed for each subject. 
9.3 
Clinical Safety Laboratory Tests (Hematology, Chemistry, Urinalysis) 
9.3.1 Hematology and Chemistry 
 
A by-subject listing of all observed chemistry and hematology laboratory data will be 
provided.  Laboratory results outside the normal range will be flagged.  The abnormal 
values will be flagged with ‘L’ (low) for values below the lower limit of the 
laboratory’s normal range or ‘H’ (high) for values above the upper limit of the 
laboratory’s normal range. Abnormal values will be graded as not clinically 
significant (NCS) or clinically significant (CS). Clinically significant laboratory 
results will be included in the AE listings.   
 
Change from baseline will be derived and listed for each subject. 
 
The observed values and change from baseline values of all safety laboratory 
assessments for clinical chemistry and hematology will be summarized using 
descriptive statistics showing the number of observations (n), mean, median, SD, 
minimum, and maximum value. Table summaries will be presented by and time point. 
 
Baseline values for all clinical chemistry and hematology parameters will be 
categorized as being below the normal range (Low), within the normal range 
(Normal), and above the normal range (High).  Shift from baseline tables will present 
the frequency and percentage of subjects who have observations that are Normal, 
Low, or High. Shift tables will be presented by time point.  
 
A moving baseline will be used for shift tables and calculation of change from 
baseline: baseline in each period will be the last laboratory assessment prior to the 
first dose day 1 of each period.  
 
Only laboratory parameters noted in Section 4.2.2 of this SAP will be tabulated.   
 
Clinical laboratory data will be reported in the units provided by the clinical 
laboratory and in Système International units in the CSR. 
 
9.3.2 Urinalysis 
 
Urinalysis test results noted in Section 4.2.2 of this SAP will be listed for each 
subject.  All positive findings in the microscopic examination will be listed.   
 
Observations outside the normal range will be flagged.  The abnormal quantitative 


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values will be flagged with ‘L’ for values below the lower limit of the laboratory’s 
normal range, ‘H’ for values above the upper limit of the laboratory’s normal range, or 
‘Ab’ for abnormal qualitative test results.  All original and unscheduled assessments 
will be listed.  Clinically significant laboratory results that are considered by the 
investigator to be AEs will be included in the AE listings. 
 
9.4 
Vital Signs 
 
The observed data for blood pressure (systolic and diastolic), heart rate (pulse), will 
be listed by subject, treatment, and time point (Listings 16.2.9.1).  Change from 
baseline for blood pressure (systolic and diastolic), heart rate (pulse), will be derived 
and listed by subject, treatment, and time point (Listing 16.2.9.2).  
 
The baseline for vital signs measurements will be the pre-dose assessment on Day 1 in 
each treatment period. 
 
For systolic, diastolic blood pressure, and heart rate, the observed and change from 
baseline data will be summarized by treatment and time point. Summaries will 
include tables of descriptive statistics showing the number of observations (n), mean, 
SD, median, minimum, and maximum value. 
 
 
 
9.5 
12-Lead Safety ECG 
 
Raw quantitative results for: PR interval, QRS interval, RR interval, QT interval,  
QTcB (corrected QT according to Bazett), QTcF (corrected QT according to 
Fridericia), and heart rate will be listed for each subject.   
 
The overall qualitative ECG assessment for each subject will be listed by subject, and 
time point. 
9.6 
Physical Examination 
 
All abnormal physical examination findings (pre and post-dose assessments) will be 
listed. Weight collected at pre and post dose time points will be listed. 
 
 
10. 
Reporting Output 
 


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The tables, listings, figures and any non-descriptive statistical analysis will be 
produced using 
 
).  The REPORT 
procedure will be used to produce all tables and listings; SAS/GRAPH will be used to 
produce all figures.   
 
Tables, listings, and figures will be produced in the order that they appear in the 
textual sections of the plan.  
 
All tables, listings, and graphs will be produced to landscape orientation using Courier 
New 8pt font and will be incorporated into a MS Word document as a (RTF) rich text 
file (margins: top, left, right, and bottom: 1 inch).  A separate RTF document will be 
created for each table, figure and listing individually. 
 
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