Conditions: Hyperuricemia Albuminuria Type 2 Diabetes
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 60
Healthy volunteers: no

Brief summary:
The purpose of this clinical research study is to evaluate signals of potential clinical benefit of the combination of Verinurad and Febuxostat in lowering concentrations of circulating uric acid and thus improving kidney or cardiovascular status of patients with hyperuricemia, albuminuria, and Type 2 diabetes (T2DM).

Detailed description:
Evidence shows independent associations between elevated serum uric acid (sUA) and the risk of hypertension, myocardial infarction (MI), chronic kidney disease (CKD), T2DM, heart failure (HF), and metabolic syndrome, including obesity. Gout is associated with an increased risk of all-cause death, as well as cardiovascular death. The causal relationship between elevated sUA, gout, and these disease outcomes remains to be proven.

Verinurad (RDEA3170), is a novel Urate Transporter 1 (URAT1) inhibitor in Phase II development. Verinurad combined with the xanthine oxidase (XO) inhibitor febuxostat has been shown to lower sUA in patients with recurrent gout in Phase II studies by \>80%. The extensive lowering of sUA delivered by the combination presents a unique opportunity to explore whether intensive urate lowering therapy can improve kidney and/or cardiac health.

This study will assess if intensive serum urate lowering therapy, more potent than ever explored before in the chronic out-patient setting, can improve chronic kidney or cardiac function in the study population.

In order to maximize the scientific value of the study and minimize the risk for systemic biases a parallel group, double blind, randomized design will be utilized.

The study will recruit patients with hyperuricemia and presenting with albuminuria.

Hyperuricemic patients are expected to benefit more from urate lowering, and albuminuria at baseline is required, as the primary objective of the study will be to assess changes in albuminuria.

Patients are also required to be diagnosed with T2DM. Patients with T2DM frequently exhibit changes in cardiac function detectable using magnetic resonance imaging (MRI) that represents an early, pre-symptomatic state of HF. By limiting recruitment to patients with T2DM and by performing MRI at baseline and 6 months of therapy, the study will deliver insights into whether or not intensive urate lowering therapy can positively affect not only chronic kidney disease, but also cardiac disease.

Arms:
arm 1: Capsule administered orally, once daily for 24 weeks arm 2: Capsule administered orally, once daily for 24 weeks

Interventions: intervention 1: Verinurad 9 mg+Febuxostat 80 mg intervention 2: Placebo
Intervention descriptions: intervention 1: Capsule administered orally, once daily for 24 weeks intervention 2: Capsule administered orally, once daily for 24 weeks

Protocol document:
Prot_SAP_000.pdf: 
 
                                                                              
 
 
1 
 
 
Statistical Analysis Plan 
Study Code 
D5495C00007 
Version 
2.0 
Date 
13 September 2018 
 
 
 
 
 
 
 
 
 
 
 
Effects of Intensive Uric Acid Lowering Therapy with RDEA3170 
(Verinurad) and Febuxostat in Patients with Albuminuria 
 
 
 
 
 
PROTOCOL DATE: Version 3.0:  25 May 2017 
SPONSOR: 
AstraZeneca AB, 
S-151 85 Södertälje, Sweden 
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TABLE OF CONTENTS 
 TITLE PAGE 
 ..................................................................................................................1 
 SIGNATURE OF STUDY STATISTICIAN ..............................................................................2 
 SIGNATURE OF ASTRAZENECA INC. ................................................................................ 3   
   
TABLE OF CONTENTS 
 ............................................................................................. 4 
LIST OF TABLES AND FIGURES ........................................................................................... 5 
LIST OF ABBREVIATIONS 
 ............................................................................................. 6 
1. 
INTRODUCTION 
 ............................................................................................. 8 
2. 
STUDY DETAILS 
 ............................................................................................. 8 
2.1 
Study Objectives ............................................................................................................. 8 
2.1.1 Primary Objectives .......................................................................................................... 8 
2.1.2 Secondary Objectives ...................................................................................................... 8 
2.1.3 Safety Objective .............................................................................................................. 8 
2.1.4 Exploratory Objective ..................................................................................................... 9 
2.2 
Study Design ................................................................................................................... 9 
2.3 
Schedule of Events ........................................................................................................ 10 
2.4 
Sample Size Consideration............................................................................................ 13 
3. 
ANALYSIS SETS 
 ........................................................................................... 13 
3.1.1 Full Analysis Set ........................................................................................................... 13 
3.1.2 Per-protocol Analysis Set .............................................................................................. 13 
3.1.3 Pharmacokinetics Analysis Set ..................................................................................... 14 
3.1.4 Safety Analysis Set........................................................................................................ 14 
4. 
PRIMARY AND SECONDARY VARIABLES ........................................................... 14 
4.1 
General Consideration ................................................................................................... 14 
4.2 
Primary Variable ........................................................................................................... 14 
4.3 
Secondary Variables ...................................................................................................... 14 
4.4 
Exploratory Variables ................................................................................................... 16 
4.5 
Safety Variables ............................................................................................................ 16 
5. 
STUDY SUBJECTS 
 ........................................................................................... 17 
5.1.1 Subject Disposition, Demographic and Baseline Characteristics ................................. 17 
5.1.2 Medical History and Surgical History ........................................................................... 17 
5.1.3 Randomized Study Medication Compliance ................................................................. 17 
5.1.4 Concomitant Medications ............................................................................................. 18 
5.1.5 Protocol Deviations ....................................................................................................... 18 
6. 
STATISTICAL ANALYSIS METHODS ..................................................................... 18 
6.1 
General Principles ......................................................................................................... 18 
6.1.1 Statistical Notation and Presentation ............................................................................ 18 
6.1.2 Handling of Multiple Observations ............................................................................... 19 
6.1.3 Handling of Missing or Partial Dates ............................................................................ 19 
6.1.4 Handling of Missing Data ............................................................................................. 19 
6.1.5 Study Baseline ............................................................................................................... 20 
6.2 
Analysis Methods .......................................................................................................... 20 
6.2.1 Primary Efficacy Analysis ............................................................................................ 20 
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6.2.2 Secondary Efficacy Analysis ........................................................................................ 21 
6.2.3 Pharmacokinetics Analysis ........................................................................................... 22 
6.2.4 Exploratory Analysis ..................................................................................................... 22 
6.2.5 Subgroup Analysis ........................................................................................................ 22 
6.3 
Safety Analysis .............................................................................................................. 23 
6.3.1 Adverse Events .............................................................................................................. 23 
6.3.2 Extent of Exposure ........................................................................................................ 23 
6.3.3 Gout Flare ...................................................................................................................... 23 
6.3.4 Hy’s Law ....................................................................................................................... 23 
6.3.5 Laboratory Safety Variables.......................................................................................... 24 
6.3.6 Vital Signs ..................................................................................................................... 24 
6.3.7 ECG  ........................................................................................................................... 24 
6.3.8 Physical Examinations .................................................................................................. 24 
7. 
REFERENCES 
 ........................................................................................... 24 
 
LIST OF TABLES AND FIGURES 
 
Table 1. Study Plan ................................................................................................................... 11 
Table 1. Study Plan (Continued) ............................................................................................... 12 
Table 2. MRI variables .............................................................................................................. 15 
Table 3. Exploratory Variables ................................................................................................. 16 
Table 4. Laboratory Safety Variables ....................................................................................... 16 
 
Figure 1. Study Flow Diagram ................................................................................................. 9 
 
 
 
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LIST OF ABBREVIATIONS 
Abbreviation or 
special term 
Explanation 
 
 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
AST 
Aspartate Aminotransferase 
ATC 
Anatomic Therapeutic Chemistry 
BMI 
Body Mass Index 
CK 
Creatinine Kinase 
CI 
Confidence Interval 
CSP 
Clinical Study Protocol 
CSR 
Clinical Study Report 
CV 
Coefficient of Variation 
CysC 
Cystatin C 
DBP 
Diastolic Blood Pressure 
ED 
Endothelial Dysfunction 
eDISH 
Evaluation of drug induced serious hepatotoxicity 
eGFR 
Estimated Glomerular Filtration Rate 
FAS 
Full Analysis Set 
Hb 
Hemoglobin 
HL 
Hy’s Law 
hs-CRP 
High-Sensitivity C-Reactive Protein 
hs-TropI 
High-Sensitivity Troponin I 
IMP 
Investigational Medicinal Product 
ITT 
Intent-To-Treat 
LS 
Least Squares 
LOCF 
Last Observation Carried Forward 
MAR 
Missing at Random 
 
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Abbreviation or 
special term 
Explanation 
 
 
Max 
Maximum 
MCMC 
Markov chain Monte Carlo  
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
MMRM 
Mixed-Model Repeated Measures 
Min 
Minimum 
MRI 
Magnetic Resonance Imaging 
PP 
Per-protocol 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
sCr 
Serum creatinine 
SD 
Standard Deviation 
SOC 
System organ class 
sUA 
Serum Uric Acid 
T2DM 
Type 2 Diabetes Mellitus 
TBL 
Total Bilirubin 
TEAE 
Treatment-emergent adverse event 
UACR 
Urinary Albumin to Creatinine Ratio 
ULN 
Upper Limit of Normal 
UALT 
Uric Acid Lowering Therapy 
WHO DDE 
WHO Drug Dictionary Enhanced 
 
 
 
 
 
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1. INTRODUCTION 
This document describes the statistical methods and data presentations to be used in the 
summary and analysis of efficacy and safety of the combination of RDEA3170 and febuxostat 
over 24 weeks in adult patients with hyperuricemia, albuminuria and Type 2 Diabetes (T2DM) 
without prior medical history of gout.  The version 1 SAP was developed based on Clinical 
Protocol Version 3.0 amended on May 25th, 2017.  This version 2 SAP is developed to include 
additional exploratory endpoints that will be analyzed based on the outcome of the primary 
study objective, and to include additional clarifications related to definitions and statistical 
analysis methods. 
2. STUDY DETAILS 
2.1 
Study Objectives 
2.1.1 Primary Objectives 
The primary objective of this study is to assess the effects of intensive uric acid lowering 
therapy (UALT) with RDEA3170 and febuxostat on albuminuria.  
2.1.2 Secondary Objectives 
The secondary objectives of this study are: 
 To assess the effects of intensive UALT with RDEA3170 and febuxostat on kidney 
function  
 To assess the metabolic effects of intensive UALT with RDEA3170 and febuxostat  
 To assess the structural and functional effects of intensive UALT with RDEA3170 and 
febuxostat on the heart and kidney using magnetic resonance imaging 
 To assess the effects of intensive UALT with RDEA3170 and febuxostat on biomarkers 
and parameters related to inflammation, and cardiac health 
 To assess the effects of intensive UALT with RDEA3170 and febuxostat on 
cardiovascular parameters  
 To assess plasma exposure of RDEA3170  
2.1.3 Safety Objective 
The safety objective of this study is to assess the safety and tolerability of intensive UALT with 
RDEA3170 and febuxostat. 
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2.1.4 Exploratory Objective 
 
 
 
 
 
 
 
2.2 
Study Design 
This is a randomized, double-blind, double-dummy, multi-site, placebo-controlled, parallel, 
independent groups, repeated measures study designed to evaluate signals indicative of clinical 
outcomes by the combination of RDEA3170 and febuxostat in lowering concentrations of 
circulating uric acid and thus improving kidney or cardiovascular status of patients with 
hyperuricemia, albuminuria and T2DM.  Patients meeting clinical entry criteria will be 
randomly assigned to active or placebo treatment for a 24-week period and evaluated at multiple 
time points for changes in physiological parameters indicative of functional renal and 
cardiovascular status.  Study design is illustrated in Figure 1. 
Figure 1. Study Flow Diagram 
 
 
 
 
 
 
Abbreviations: eGFR - Estimated glomerular filtration rate; sUA - Serum uric acid; UACR - Urinary             
albumin to creatinine ratio 
Patients will be screened for entry into the study at Visit 1.  Those patients consenting to 
participate, who meet all the inclusion and none of the exclusion criteria (except laboratory test 
based criteria) will enter the screening phase of the study.  Within one week of Visit 1 patients 
will collect three morning void urinary samples on three separate consecutive days.  The 
samples will be delivered to the study site for proteinuria measurements.  Those patients with 
acceptable urinalysis results will be scheduled to participate in Visit 2.  Patients eligible to 
participate in the study will undergo magnetic resonance imaging prior to randomization and 
before or on the day of Visit 2. Visit 2 will occur no later than six weeks after Visit 1.  Patients 
will be randomized 1:1 at Visit 2 to receive either a combination of RDEA3170 (9 mg once 
Patient population: 
sUA >6.0 mg/dL 
eGFR ≥30 mL/min/1.73m2  
UACR 30 to 3500 mg/g 
RDEA3170 9 mg and  
Febuxostat 80 mg 
Placebo 
1
o Endpoint: 
UACR 
2
o Endpoint: 
sUA 
eGFR 
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daily) and febuxostat (80 mg once daily) or matching placebo.  The length of treatment period 
for patients will be 24 weeks. 
Markers of renal function (urinary albumin to creatinine ratio, estimated glomerular filtration 
rate, serum uric acid, and other markers) will be measured at 2, 4, 12, 24 weeks after 
randomization, and 4 weeks after the end of treatment.  Other endpoints may be assessed less 
frequently. 
Magnetic resonance imaging to examine functional changes in the heart and kidney will be 
performed at baseline and 24 weeks after randomization. Magnetic resonance imaging of the 
heart will allow assessment of left ventricular strain and end diastolic volume as sensitive 
markers of efficacy in pre-symptomatic heart failure frequently present in Type 2 diabetes 
patients. Blood oxygenation-dependent level magnetic resonance imaging will be utilized to 
measure kidney oxygenation in addition to the cardiac magnetic resonance imaging parameters 
described above, in patients undergoing cardiac magnetic resonance imaging. 
The 
, via a reactive hyperemic procedure, provides a direct measurement of 
endothelial dysfunction via a calibrated measurement of arterial compliance over the entire 
transmural pressure range of the artery at baseline, 12, and 24 weeks.  Reactive hyperemia (also 
referred to as Flow Mediated Dilatation) is defined as the transient change in vasomotor tone 
which occurs following a brief period of ischemia (e.g., arterial occlusion).  Urine and blood 
samples will be obtained and stored in a biobank and will be analyzed if there is evidence of 
efficacy in this study. 
2.3 
Schedule of Events 
The following table provides an overview of the clinical schedule of assessments and events for 
the screening, treatment and follow-up period in Table 1. Study Plan and elaborated in the 
Clinical Protocol Sections 4.1 through 4.3. 
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Table 1. Study Plan 
Study Period 
Screening 
period 
Treatment period 
Follow up 
period 
 
Visit 
Enrollment 
Randomization 
Treatment 
End of 
treatment 
Follow up 
 
Visit Number 
1a 
2 
3 
4 
5 
6 
7b 
8 
CSP Section 
Week 
-6 to-1 
0 
1 
2 
4 
12 
24 
EoT + 4w 
 
Day 
-42 to -7 
1 
8 
15 
29 
85 
169 
190 
 
Window 
 
 
 
±3d 
±3d 
±5d 
-14 to 0 d 
±7d 
 
Written informed consent 
 
X 
 
 
 
 
 
 
 
3.3, 10.4 
Demographics 
 
X 
 
 
 
 
 
 
 
4.1 
Physical examination, height, and weight 
X 
 
 
 
 
X 
X 
 
4.1 
Pregnancy test 
Xc 
 
 
 
 
 
 
 
4.1 
Medical/surgical history 
X 
 
 
 
 
 
 
 
4.1 
Inclusion / exclusion criteria 
X 
X 
 
 
 
 
 
 
3.1, 3.2 
12-lead ECG 
 
X 
 
 
 
X 
X 
 
5.2.3 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
5.2.4 
Randomization to study treatment 
 
X 
 
 
 
 
 
 
3.5 
Treatment dispensed 
 
X 
 
 
X 
X 
 
 
7.1 
Treatment returned and compliance checked 
 
 
 
 
X 
X 
X 
 
7.5, 7.6 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
7.7 
Adverse event collection (AEs and SAEs) 
X 
X 
X 
X 
X 
X 
X 
X 
6 
UACR, eGFR, sUA and Serum cystatin-C 
X 
X 
X 
X 
X 
X 
X 
X 
4.2.2, 5.1.1 
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Table 1. Study Plan (Continued) 
Study Period 
Screening 
period 
Treatment period 
Follow up 
period 
 
Visit 
Enrollment 
Randomization 
Treatment 
End of 
treatment 
Follow up 
 
Visit Number 
1a 
2 
3 
4 
5 
6 
7b 
8 
CSP Section 
Week 
-6 to-1 
0 
1 
2 
4 
12 
24 
EoT + 4w 
 
Day 
-42 to -7 
1 
8 
15 
29 
85 
169 
190 
 
Window 
 
 
±3d 
±3d 
±3d 
±5d 
-14 to 0 d 
±7d 
 
Samples for 
 
 
 
 
 
 
 
 
 
 
 
 
Blood samples for hematology and additional 
clinical chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
4.2.2, 5.2.1 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
5.2.1 
MRI 
 
Xe 
 
 
 
 
Xf 
 
5.1.2 
Reactive hyperemia 
 
Xe 
 
 
 
X 
Xf 
 
5.1.4.1 
Blood sampling for limited PK 
 
 
Xg 
Xg 
Xg 
Xg 
Xg 
 
4.2.2, 5.4.1 
a. Patient to deliver 3 morning urine samples to site within 1 week 
b. Visit 6 has to be before or on last day of treatment 
c. Women of Childbearing Potential only 
d. NT-pro-BNP will be assessed at Visit 2, Visit 5 and Visit 6 
e. MRI and Reactive hyperemia must be performed before randomization, but not before Visit 1. 
f. Post-treatment MRI and Reactive hyperemia to be performed earlier than at 24 weeks if patient is withdrawing and has been treated with study drug for 
at least 2 months. The MRI and Reactive hyperemia may be performed up to 2 weeks before the End of Treatment Visit (Visit 6), but not later than the 
last day of treatment. 
g. Trough levels; i.e., prior to dosing on the day of the Visit 
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2.4 
Sample Size Consideration 
Based on the results of a prior study, the standard deviation (SD) for change in natural 
logarithmic log-transformed Urinary Albumin to Creatinine Ratio (UACR), ln(UACR), is 
assumed to be 0.8, based on the AVOID study with aliskiren in 599 patients with albuminuria 
and T2DM (Parving et al 2008), as well as a study with tenapanor in a patient population similar 
to that planned for this study (Ardelyx 2015). 
A placebo-corrected reduction in UACR of 30%, corresponding to a ratio of 0.7 (-0.357 on 
natural logarithmic log-scale) was considered a clinically meaningful target for further 
investigation of RDEA3170 and febuxostat in this patient population. 
Twenty-seven (27) patients per arm with available UACR data at baseline and 12 weeks should 
ensure with 90% probability that the observed placebo-controlled reduction does not differ from 
the true, unknown reduction with more than this clinically meaningful effect under the assumed 
SD above.  To ensure the availability of 27 evaluable patients per arm, 30 patients per arm will 
be randomly assigned in a 1:1 fashion. 
3. ANALYSIS SETS 
The following analysis sets will be used in study summaries and analyses.     
3.1.1 Full Analysis Set 
All efficacy analyses will be performed on the Full Analysis Set (FAS) following the Intent-To-
Treat (ITT) principle.  The FAS will consist of all randomized subjects.  Summary tables of 
baseline and demographic data will be calculated based on FAS. 
3.1.2 Per-protocol Analysis Set 
The per-protocol (PP) analysis set is defined as all subjects in the FAS that are compliant with 
treatment and have appropriate exposure to study medication for the 12-week treatment period 
and without any major protocol deviations that may impact primary efficacy analysis.  The set of 
major protocol deviations and the range of treatment compliance percentage required will be 
finalized prior to database lock.  If a subject withdrew from the study prematurely without Week 
12 data to assess the primary and/or key secondary endpoints, he or she may be excluded from 
the PP analysis set.  A memo-to-file will be prepared to document the selection of PP analysis 
set prior to study database lock.  The PP analysis set will be used for supportive analyses of the 
efficacy endpoints.  Summary tables of baseline and demographic data will also be calculated 
based on the PP analysis set. 
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3.1.3 Pharmacokinetics Analysis Set 
The PK analysis set will include all subjects who received febuxostat and RDEA3170 treatment 
and have at least 1 post-dose plasma concentration measurement of RDEA3170 at a scheduled 
time point, without major protocol deviations or violations that would have an impact on the 
absorption, distribution, metabolism or excretion of RDEA3170.  The PK analysis set will be 
used to summarize the PK data.  Subjects’ inclusion/exclusion to the PK analysis set will be 
documented in the memo-to-file.  
3.1.4 Safety Analysis Set 
The Safety analysis set will consist of all randomized subjects exposed to study drug and with 
available post dose safety data.  Summary tables of baseline and demographic data will also be 
presented based on the Safety analysis set if it is different from full analysis set.  As the safety 
evaluation will be based on the as-treated principle, errors in study medication dispense and 
administration will be evaluated to determine if any adjustments to safety data analysis are 
needed upon treatment unblinding.  The rationale and method will be discussed in the clinical 
study report (CSR), if any.   
If the Safety analysis set contains same subjects as the FAS and there is no dosing error that 
distinguishes the two populations, statistical analyses and summary tables will be provided for 
either the FAS or Safety analysis set. 
4. PRIMARY AND SECONDARY VARIABLES 
4.1 
General Consideration 
Detailed descriptions of most of the study variables are provided in the clinical study protocol 
(CSP) and will not be repeated for those variables in the SAP. 
4.2 
Primary Variable  
 
Change from baseline in UACR and ln(UACR) 
4.3 
Secondary Variables 
 
Change from baseline in sUA levels and ln(sUA) 
 
Change from baseline in eGFR (calculated using CKD-EPI equation) and ln(eGFR) 
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CKD-EPI equation is defined as: 
eGFR = 141 × min (sCr/k, 1)
 α × max (sCr/k, 1)
-1.209 × 0.993Age × 1.018 [if female] x 1.159 [if black]  
 sCr is serum creatinine (mg/dL) 
 k is 0.7 for females and 0.9 for males 
 α is -0.329 for females and -0.411 for males 
 min indicates the minimum of sCr/k or 1, and 
 max indicates the maximum of sCr/k or 1. 
 
Change from baseline in serum cystatin C (CysC), ln(CysC), serum creatinine (sCr), 
and ln(sCr)  
 
Change from baseline in serum high-sensitivity C-reactive protein (hs-CRP), ln(hs-
CRP), serum high-sensitivity Troponin I (hs-TropI), and ln(hs-TropI) 
 
Systolic blood pressure (SBP), diastolic blood pressure (DBP)  
 
RDEA3170 at trough plasma concentrations  
 
MRI variables listed in Table 2 
Table 2. MRI variables 
 
 
Variables 
Unit 
 
 
LV global longitudinal strain 
% 
LV global radial strain 
% 
LV global circumferential strain 
% 
LV global diastolic longitudinal strain rate 
s-1 
LV global systolic longitudinal strain rate 
s-1 
LV global diastolic radial strain rate 
s-1 
LV global systolic radial strain rate 
s-1 
LV global diastolic circumferential strain rate 
s-1 
LV global systolic circumferential strain rate 
s-1 
LV end-diastolic volume 
mL 
LV end-systolic volume 
mL 
LV stroke volume 
mL 
LV mass 
g 
LV mass/end-diastolic volume 
g/mL 
LVEF 
% 
Kidney cortex T2* 
ms 
Kidney medulla T2* 
ms 
 
 
Abbreviations: LV Left ventricle; LVEF Left ventricular ejection fraction 
Kidney cortex T2* and Kidney medulla T2* will be analyzed as % change from baseline. 
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4.4 
Exploratory Variables 
 
.  
 
Reactive hyperemia parameters: pulse, systolic and diastolic blood pressure and the 
score for endothelial dysfunction. 
Table 3. Exploratory Variables 
 
 
Urinalysis 
Clinical chemistry 
 
 
Protein 
aldosterone 
Albumin 
Hemoglobin A1c 
Creatinine 
N-terminal pro b-type natriuretic peptide 
 
 
Uric Acid 
 
Urinary protein to creatinine ratio 
 
 
 
 
 
  
 
  
 
      
 
 
 
 
 
 
 
 
 
 
* indicates the biomarkers that will be analyzed and reported in an addendum to the CSR.  
4.5 
Safety Variables 
The incidence of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), 
changes in vital signs, physical exams, ECG, and the changes in clinical laboratory variables 
listed in Table 4.  
Table 4. Laboratory Safety Variables 
 
 
Hematology/hemostasis 
 
Clinical chemistry (serum or plasma) 
 
 
B-Hemoglobin (Hb)  
 
S/P-Creatinine 
B-Leukocyte count  
 
S/P-Bilirubin, total 
B-Leukocyte differential count (absolute count)  
S/P-Alkaline phosphatise (ALP) 
B-Platelet count  
 
S/P-Aspartate transaminase (AST) 
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S/P-Alanine transaminase (ALT) 
Urinalysis (dipstick)  
 
S/P-Albumin 
U-Hb/Erythrocytes/Blood  
 
S/P-Potassium 
U-Glucose 
 
S/P-Calcium, total 
 
 
S/P-Sodium 
 
 
S/P-Creatine kinase (CK) 
 
 
S/P-Blood Urea Nitrogen 
 
5. STUDY SUBJECTS 
5.1.1 Subject Disposition, Demographic and Baseline Characteristics 
The number and percentage of enrolled subjects that are randomized, randomized and treated 
with study medication, randomized but not treated with study medication will be summarized by 
treatment group and overall.  Number and percentage of subjects who completed or 
discontinued from the study (including the reason for discontinuation) will be summarized by 
treatment group.   
Demographic and baseline characteristics will be summarized using descriptive statistics for 
FAS, PP, and Safety analysis sets.  The summary include age, gender, race, ethnicity, height, 
weight, body mass index (BMI), HbA1C. 
5.1.2 Medical History and Surgical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
and summarized by System Organ Class (SOC) and Preferred Term (PT) by treatment.  Medical 
history will also be listed. 
5.1.3 Randomized Study Medication Compliance 
Randomized study medication compliance within the whole 24-week study period will be 
calculated and summarized using descriptive statistics and by categories (<80%, 80%-
120%, >120%) for each treatment group using Safety analysis set.  Treatment compliance data 
will also be listed.   
Randomized study medication compliance will be calculated as (total number of tablets taken/ 
(2*total days on randomized study medication)) * 100%, where total days on randomized study 
medication will be calculated as (last randomized study medication dose date – first randomized 
study medication dose date + 1). 
Additional treatment compliance for the 12-week treatment period will be computed for the 
selection of PP analysis set. 
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5.1.4 Concomitant Medications 
The WHO DRUG Dictionary Enhanced (WHO DDE) will be used to categorize the verbatim 
descriptions of medications into the Anatomic Therapeutic Chemistry (ATC) classification 
system.  Each verbatim name will be classified by anatomical main group (ATC level 1), 
therapeutic subgroup (ATC level 2), pharmacological subgroup (ATC level 3), chemical 
subgroup (ATC level 4), and trade name. 
A prior concomitant medication is defined as any medications that start before the first 
randomized study dose date and continue beyond that date; while a new concomitant medication 
is defined as any medications the start after the first randomized study dose date, including those 
started in the follow-up period (Visit 8). 
The number and percentage of subjects receiving concomitant medications will be summarized 
by treatment group and by ATC classification level 4 and trade name for the Safety analysis set.  
Any non-study medications that stop before the first randomized study dose date are deemed the 
pre-treatment medications which will be provided in listing and may be summarized if needed.  
5.1.5  Protocol Deviations 
Major protocol deviations will be identified prior to study database lock, and will be 
summarized by treatment group and listed by subjects for FAS.  Subjects with major protocol 
deviations that may impact the primary efficacy endpoint will be excluded from the PP analysis 
set.  Refer to Section 3.1.2 for PP analysis set definition and memo-to-file. 
6. STATISTICAL ANALYSIS METHODS 
6.1 
General Principles 
6.1.1 Statistical Notation and Presentation 
The continuous variables will be summarized by number of observations (n), mean, standard 
deviation (SD), median, minimum (min), and maximum (max).  For categorical variables, 
frequency and percentage in each category will be provided.   
Min and max values will be rounded to the precision of the original value.  Means, least squares 
(LS) means, and medians will be rounded to one decimal place greater than the precision of the 
original value.  SDs, standard errors (SEs), and 95% and 90% confidence intervals (CIs) will be 
rounded to two decimal places greater than the precision of the original value.  Percentages for 
summarizing categorical data will be rounded to one decimal place.  P-values will be presented 
with four decimal places and values less than 0.0001 will be presented as <0.0001. 
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All inferential statistical testing will be two-sided and conducted at the 0.10 significance level 
for between treatment comparisons and 0.05 significant level for the change from baseline 
assessment.  No multiplicity adjustment is planned for this study.  
6.1.2 Handling of Multiple Observations 
A subject may have multiple scheduled or unscheduled visits that are associated with a protocol 
defined visit (nominal visit).  Each unscheduled visit is assigned a nominal scheduled visit 
number (e.g., unscheduled visit number 5.1 is associated with protocol scheduled visit 5) in the 
clinical database.  The assessment at the scheduled visit will be used for data summary and 
analysis.  If no scheduled visit assessment exists but at least one unscheduled visit assessment is 
available within that visit window (e.g., unscheduled visit number 5.1 and 5.2 exist but not the 
scheduled visit 5), then the latest unscheduled visit within the visit window will be used for data 
summary and analysis. 
All values, scheduled or unscheduled, will be presented in data listings.  
6.1.3 Handling of Missing or Partial Dates 
In cases of incomplete dates for adverse events (AEs) or non-study medications, the missing 
component(s) will be assumed as the most conservative value(s) possible.  For example, the 
imputation rule is to conservatively capture AEs with missing start dates as TEAEs: 
 If “day” is the only missing field, impute the “day” as the first randomized dose date if 
their “month” are the same; otherwise, the first day of the non-missing month. 
 If “day” and “month” are the only missing fields, impute the “day” and “month” as the 
first randomized dose date if their “year” are the same; otherwise, January 1 of the non-
missing year. 
 If “day”, “month”, and “year” are all missing, to be conservative, the event will be 
assumed to occur on the same day as the first randomized dose date.   
Non-study medications with missing or partial dates will be imputed similarly. 
Date imputation will only be used for computational purposes; e.g., treatment-emergent status 
or identifying concomitant medications.  Actual data values as they appear in the clinical 
database will be shown in the data listings. 
6.1.4 Handling of Missing Data 
Missing data will be handled by mixed-model repeated measures (MMRM) method based on 
observed-case data under the assumption of missing at random (MAR).  Additional sensitivity 
analysis to assess the impact of missing data on the estimated treatment effect, e.g. multiple 
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imputation (MI), last observation carried forward (LOCF) method, or applying the PP analysis 
set, will be performed.  Refer to Section 6.2.1.2 for methodology.  
6.1.5 Study Baseline 
Baseline is defined as the last non-missing observation obtained prior to administration of the 
first randomized study medication.  For parameters measured at multiple time-points prior to 
randomization, such as UACR and other urinalysis laboratory tests that were collected from 
three separate days in the week prior to receiving the first randomized dose, baseline is defined 
as the mean of the reported measurements from all days prior to randomization.  For secondary 
endpoints CysC and sCr where the data were collected at multiple visits at Screening, Visit 2 
(Day 1), or any Unscheduled visits prior to randomization, baseline is defined as the mean of the 
reported measurements from all visits prior to randomization.  
6.2 
Analysis Methods 
6.2.1 Primary Efficacy Analysis 
The primary efficacy endpoint, UACR will be collected per applicable visit.  The mean ratio 
will be reported for each time-point based on the three samples.  Patients will receive a urine 
sample collection kit allowing them to collect the first morning void urine on three days.  
Ideally the urine samples should be collected 2 days before, the day before and on the day of a 
study visit to minimize storage and transportation of collected samples.  If a patient has 
forgotten to collect one or more of the samples before a visit, then the samples should be 
collected on the up to three consecutive days following the visit instead (with exception for the 
Visit 2 urine samples, which must be collected before treatment is started).  In the absence of 
results from three analyzed samples the UACR for a time-point will be calculated based on the 
available results.  
The analysis of the primary efficacy endpoint UACR will be based on the FAS.  UACR and the 
ratio of UACR from baseline will be summarized using descriptive statistics by treatment and 
visit.  Change from baseline in ln(UACR) will be analyzed using MMRM model with treatment 
group, visit, interaction of treatment group and visit as fixed effects, ln(UACR) at baseline as a 
covariate, and subjects as random effects.  The least squared (LS) mean change from baseline in 
ln(UACR) and the 95% CI of the LS mean change will be derived from the model by treatment 
and by visit.  The LS mean difference between the two treatments and the 90% CI of the LS 
mean difference will be derived from the same MMRM model by visit.  
The above LS mean change from baseline and the 95% CI for each treatment at each visit will 
be exponentiated to yield the geometric LS estimated mean ratio versus baseline and the 
geometric 95% CI at the original scale of UACR.  The LS mean difference between the two 
treatments and its 90% CI at each visit will also be exponentiated to yield the geometric LS 
estimated mean ratio between the two treatments at each visit and its geometric 90% CI at the 
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original scale of UACR.  Percent change from baseline will be derived from the LS estimated 
mean ratio by (exp(LS mean ratio)-1)×100%. 
In addition, the primary endpoint will be presented graphically.  The first graph will present the 
LS estimated mean ratio from baseline in UACR with 95% CI over time (visits) by treatment. 
The second graph will present LS estimated mean ratio (active vs. placebo) with 90% CI over 
time (visits).  The third graph will present the descriptive mean change from baseline with SE in 
UACR over time (visits) by treatment, with data from the follow-up visit. 
6.2.1.1 
Supportive Analyses to the Primary Efficacy Analyses 
The same MMRM model for the primary endpoint will also be performed for the PP analysis set. 
6.2.1.2 
Sensitivity Analyses to the Primary Efficacy Analyses 
Additional sensitivity analyses will be explored to exam the impact of missing data on the 
conclusion of the primary endpoint analysis. 
The MI method will be based on regression model for monotonic missing pattern under the 
assumption of MAR, and will be performed for the FAS including data up to Week 24.  The 
intermittent missing data will be imputed for 100 sets using MI Markov chain Monte 
Carlo (MCMC) procedure.  ANCOVA model with treatment as a factor and baseline ln(UACR) 
as a covariate will be applied to the multiple-imputed change from baseline in ln(UACR) at 
Week 12 and Week 24.  The results of ANCOVA model on the multiple imputed datasets will 
be combined and summarized.     
In addition, the missing UACR at Week 12 and Week 24 will be imputed using LOCF on FAS.  
The same ANCOVA model will be applied to the imputed change from baseline in ln(UACR) at 
Week 12 and Week 24. 
6.2.2 Secondary Efficacy Analysis 
The analysis of the secondary efficacy endpoints will be based on the FAS.  The following 
secondary efficacy endpoints and the change from baseline values will be summarized using 
descriptive statistics by treatment and visit.  Change from baseline in these secondary efficacy 
endpoints will also be assessed in a similar MMRM model as the one applied to the primary 
efficacy analysis.  Natural log-transformation will be applied to these endpoints to ensure data 
normality for statistical modeling assumption.  eGFR will be analyzed with MMRM model at 
both logarithm and original scales.  All secondary efficacy endpoints will be plotted similarly as 
the primary efficacy endpoint. 
 sUA  
 eGFR  
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 Serum CysC 
 sCr  
 Serum hs-CRP 
 Serum hs-TropI 
MRI variables and change from baseline of these endpoints will be summarized by treatment 
and visit with descriptive statistics on FAS.  Additional sensitivity analyses excluding 
measurements collected after the last treatment date or measurements that could be impacted by 
a protocol deviation will be conducted.  Kidney Cortex T2* and Kidney Medulla T2* will be 
analyzed using percent change from baseline. 
6.2.3 Pharmacokinetics Analysis 
The analysis of PK data will be based on the PK analysis set.  Plasma concentrations of 
RDEA3170 will be summarized using descriptive statistics (e.g., n, arithmetic mean, SD, 
geometric mean, coefficient of variation (CV), minimum, median, maximum) by visit and by 
baseline renal function (eGFR >90, ≥60 to <90, and ≥30 to <60 ml/min/1.73 m2).  The plasma 
trough concentration will be plotted. 
6.2.4 Exploratory Analysis 
 
 
  
 
 
 
 
6.2.5 Subgroup Analysis 
The primary efficacy endpoint will be analyzed with descriptive and inferential statistical 
models by subgroups of race, sex, age-group category (<65 vs. ≥65 yr), BMI category (<30, ≥30 
kg/m2), and baseline renal function (eGFR >90, ≥60 to <90, and ≥30 to <60 ml/min/1.73 m2).  
The treatment-by-subgroup interaction will be evaluated using ANCOVA model with observed 
data at Week 12 and Week 24 on FAS.   
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6.3 
Safety Analysis 
The analysis of the safety variables will be based on the Safety analysis set.  Safety parameters 
in the study include TEAEs, clinical laboratory evaluations (hematology, serum chemistry, and 
urinalysis), vital signs, ECGs, and physical examinations.  Safety variables will be summarized 
descriptively if continuous variables or by frequency and percentage if categorical variables.   
6.3.1 Adverse Events 
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA, 
version 20.0).  AEs with onset date/time on or after receiving the first dose of randomized study 
medication, or pre-existing AEs that increase severity on or after receiving the first dose of 
randomized study medication will be considered as TEAE.  AEs with onset during the follow-
up period (Visit 8) will also be considered as TEAE.  AEs with onset on or after the date of 
informed consent but before the date of first dose of blinded study medication will be 
considered pre-treatment AEs.  Pre-treatment AE will be listed separately, but not be 
summarized. 
TEAE will be summarized by treatment group and by: 
 SOC and PT 
 PT in descending order 
 SOC, PT and maximum severity 
TEAE leading to study discontinuation, TEAE related to study medication, and SAE will be 
summarized by treatment group, SOC, and PT. 
6.3.2 Extent of Exposure 
The duration of study medication administration will be calculated as the date of the last 
randomized dose in the double-blind treatment period minus the date of first randomized dose, 
plus 1 day.  Extent of exposure will be summarized with descriptive statistics by treatment 
group.   
6.3.3 Gout Flare 
The incidence of gout flares be summarized by treatment group. 
6.3.4 Hy’s Law 
Hy’s Law (HL): cases where a patient shows elevations in aspartate aminotransferase (AST) or 
alanine aminotransferase (ALT) evaluation ≥ 3x upper limit of normal (ULN) together with 
total bilirubin (TBL) ≥ 2xULN, where no other reason, other than investigational medicinal 
product (IMP), can be found to explain the combination of increase. 
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eDISH (evaluation of drug induced serious hepatotoxicity) plot will be generated with the peak 
TBL values vs peak ALT values to visualize the Hy’s Law cases.   
6.3.5 Laboratory Safety Variables 
Laboratory safety values (serum chemistry, hematology, and urinalysis) and change from 
baseline will be summarized with descriptive statistics by visit and by treatment group.  
Laboratory data will also be summarized using shift tables by treatment group.  These tables 
compare the baseline value (low, normal, high) vs post-baseline value (low, normal, high).  
Additionally, percentages of abnormal laboratory tests will be summarized and listed by visit 
and by treatment group.    
Number of subjects with sCr elevation will be summarized as ≥1.5 to < 2.0 × baseline, ≥2.0 to 
<3.0×baseline or absolute value ≥3.0 mg/dL, ≥3.0 × baseline or absolute value ≥ 4.0 mg/dL by 
treatment group. 
6.3.6 Vital Signs 
Vital signs (systolic and diastolic blood pressure, pulse rate,) values and changes from baseline 
will be summarized by visit and treatment group using descriptive statistics. 
6.3.7 ECG 
The overall assessment of the ECG (i.e., normal, abnormal but not clinically significant, 
abnormal and clinically significant) will be summarized using shift table by treatment group.  
All data will be provided in listing as well. 
6.3.8 Physical Examinations 
Clinically significant post-baseline physical exam findings will be reported as AEs. Physical 
examination data will be listed by subject.   
7. REFERENCES 
Ardelyx 2015 
Ardelyx. A study in CKD patients with type 2 diabetes mellitus and albuminuria. Last 
verified September 2015. http:\\www.ClinicalTrials.gov, NCT01847092. Accessed 24 
February 2017. 
Parving et al 2008 
Parving HH, Persson F, Lewis JB, Lewis EJ, Hollenberg NK.  Aliskiren combined with 
losartan in type 2 diabetes and nephropathy. N Engl J Med 2008;358(23):2433-2446. 
 
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