Conditions: Diabetic Kidney Disease
Keywords: Diabetic Kidney Disease XO inhibitor UACR
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 130
Healthy volunteers: no

Brief summary:
The primary objective of this study is to assess the effect of 2 dose levels of TMX-049 on urinary albumin excretion in subjects with Type 2 diabetes and albuminuria (a urinary albumin-to-creatinine ratio (UACR) 200 to 3000 mg/g and an estimated glomerular filtration rate (eGFR) ≥30 ml/min/1.73m2). Effects of each TMX-049 dose on UACR will be assessed in terms of ratios using log-transformed UACR at Baseline and after a 12-week period of treatment.

Detailed description:

Arms:
arm 1: TMX-049: 40 mg of TMX-049 to be taken orally, once daily arm 2: TMX-049: 200 mg of TMX-049 to be taken orally, once daily arm 3: None

Interventions: intervention 1: TMX-049 intervention 2: Placebo
Intervention descriptions: intervention 1: A certain dose of TMX-049 to be taken orally, once daily intervention 2: Matching placebo to be taken orally, once daily

Protocol document:
Prot_002.pdf: 






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Protocol No.: TMX-049DN-201 
TMX-049 
 
 
Final Version 2.0 (07 February 2018) 
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(breakfast or a snack) rather than on an empty stomach beginning on the day 
after Visit 2. 
 
Subjects who meet all eligibility criteria, including UACR 200 to 3000 mg/g 
and eGFR ≥30 ml/min/1.73m2 at both Visit 1 and Visit 2 and who also have 
≥80% study medication compliance during the 2-week placebo run-in phase 
will be randomized at Visit 3 in a 1:1:1 ratio to 1 of 3 treatment groups: 
placebo, 40 mg TMX-049, or 200 mg TMX-049. Randomization will be 
stratified by sUA (< 6.0 vs ≥6.0 mg/dL) and UACR (200 to < 300 mg/g vs 300 
to ≤3000 mg/g) levels obtained at Visit 2. Study medication will be self-
administered by the subject qd in the morning at about the same time each day 
and taken with food (breakfast or a snack), rather than on an empty stomach 
during the randomized treatment phase beginning on the day after Visit 3 and 
continued until the morning prior to Visit 6. The time of dosing and time of any 
food intake will remain consistent during the period of randomized treatment. 
 
Randomized study participants will return to the site after 2 (Visit 4), 
6 (Visit 5), and 12 weeks (Visit 6) of double-blind treatment. Study medication 
compliance will be assessed by pill count at each visit. First-morning void urine 
samples will be collected on 2 consecutive days prior to each visit. Urine and 
blood samples for determination of eGFR, sUA levels, and other laboratory 
tests will also be obtained prior to and after initiation of randomized treatment. 
Results of sUA and UACR will not be reported to Investigators, subjects, and 
the Sponsor staff during the randomized treatment phase of the study. The time 
of PK sample acquisition, the time of dosing prior to the PK sample acquisition, 
and whether the subject took study medication with or without food will be 
recorded in the appropriate sections of the case report form (CRF) based on 
verbal communications with the subjects. 
At Visit 4, a sample will be obtained prior to TMX-049 dosing (trough sample). 
At Visit 5, a sample will be obtained 3 ± 1 hours after study medication dosing 
(time of maximum observed plasma concentration [tmax] sample). The timing of 
dosing can be adjusted to the time of visiting. At Visit 6, a sample will be 
obtained ≥6 hours (the ideal target is ≥8 hours) after study medication dosing 
(elimination phase sample). If a subject cannot visit within the time window, a 
sample will be obtained when the subject visits, even out of the time window. If 
the trough sample is not obtained at Visit 4, the trough sample should be 
obtained at Visit 6, instead of the elimination phase sample. If the trough 
sample is obtained at Visit 4 and the tmax sample is not obtained at Visit 5, the 
tmax sample should be obtained at Visit 6, instead of the elimination phase 
sample. Sites have the option to have a study participant return to the site on a 
separate day to obtain a properly-timed Visit 4, 5, or 6 sample for PK analysis. 
 
Safety assessment will be based on clinical laboratory evaluations, vital signs, 
physical examinations, and 12-lead ECG will be obtained prior to and during 
the period of randomized treatment. 
 
All study participants will attend a follow-up visit (Visit 7) 4 weeks after the 
last dose of study medication (Visit 6 or the Early Termination Visit). Two 
consecutive day urine samples for UACR determination will be submitted by all 
subjects at this final visit. Urine and blood samples for determination of eGFR, 
sUA levels, and other laboratory safety tests will be obtained at Visit 7 or at 
Visit 6 (or the Early Termination Visit). 
Number of Subjects 
(Planned and 
Analyzed): 
It is anticipated that approximately 132 subjects will be randomized into the 
study resulting in approximately 40 subjects per treatment group for inclusion in 
the primary endpoint assessment. 


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Protocol No.: TMX-049DN-201 
TMX-049 
 
 
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Diagnosis and Main 
Criteria for 
Inclusion: 
The randomized population will include males or females (using a highly 
effective birth control method or not of childbearing potential) who are at least 
18 years of age, have Type 2 diabetes treated with ≥1 glucose-lowering 
medication for at least 12 months, UACR 200 to 3000 mg/g at Visit 1 and 
Visit 2, eGFR ≥30 ml/min/1.73m2 at Visit 1 and Visit 2, and have been treated 
with at least the minimal recommended dose of an angiotensin converting 
enzyme inhibitor (ACEI) or an angiotensin II receptor blocker (ARB), but not 
both, for at least 3 months prior to Visit 1, without any adjustments to this 
therapy for at least 4 weeks prior to the Visit 1. Compliance (based on pill 
count) of ≥80% during the 2-week single-blind, placebo run-in phase of the 
study is also required for inclusion. 
Main Exclusion 
Criteria: 
History of Type 1 diabetes; women who are breast feeding; treatment with any 
uric acid-lowering therapy (eg xanthine oxidase [XO] inhibitors or uricosuric 
agents) within 2 weeks of Visit 1; history of intolerance to any XO inhibitor; 
history of a gout flare requiring pharmacologic treatment; history or presence of 
tophaceous gout; history of immunosuppressant treatment for any known or 
suspected renal disorder at any time prior to Visit 1; history of a non-diabetic 
form 
of 
renal 
disease; 
glycosylated 
hemoglobin 
(HbA1c) 
>11%; 
sUA  <4.0 mg/dL or >10.0 mg/dL; positive urinary pregnancy test; dialysis for 
acute renal failure within the previous 6 months prior to Visit 1; renal allograft 
in place or a scheduled kidney transplant within the next 22 weeks; congenital 
or acquired solitary kidney. 
Test Product, Dose, 
and Route of 
Administration: 
TMX-049 tablets (40 mg), TMX-049 capsules (80-mg capsule containing 2 x 
40-mg tablets), and matching placebo tablets/capsules will be administered 
orally. 
All eligible subjects will receive qd doses of placebo during a 2-week placebo 
run-in phase. 
During the treatment phase, subjects will be randomized at a 1:1:1 ratio to 
receive 1 of the following treatments: 
• 
40 mg TMX-049 (1 x 40-mg TMX-049 tablet and 2 x placebo 
capsules) 
• 
200 mg TMX-049 (1 x 40-mg TMX-049 tablet and 2 x 80-mg 
TMX-049 capsules) 
• 
Placebo (1 placebo tablet and 2 placebo capsules) 
Study medication will be self-administered qd in the morning at about the same 
time each day, and taken with food (breakfast or a snack) rather than on an 
empty stomach. 
Dose Modification 
Guidelines 
Interruption of dosing can be implemented at any time to manage adverse 
events (AEs) considered potentially treatment related. If study medication is 
interrupted, no study medication must be taken (as opposed to reducing the 
number of study medication tablets/capsules taken). 
Duration of 
Treatment: 
There will be a single-blind 2-week placebo run-in phase followed by a 
double-blind 12-week treatment phase. 
Duration of Subject 
Participation in 
Study: 
All pre-randomization study visits will be completed in ≤6 weeks. The 
randomized treatment phase of the study will be 12 weeks in duration. A 
post-treatment follow-up visit will be carried out 4 weeks after the last 
administered dose of study medication. The maximum duration of study 
participation will be 22 weeks. 


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Study Populations:  
The All Subjects Population will consist of any subjects who enrolled in the 
study (signed informed consent) and had study assessments recorded on the 
database as per the protocol. 
The Safety Population will consist of all randomized subjects who received at 
least one study medication tablet or capsule. 
The Modified Intention-to-Treat (mITT) Population will be used for the efficacy 
analysis and will consist of all subjects according to their randomization scheme 
regardless of whether they experienced protocol deviations. The last 
post-randomization UACR will be carried forward (LOCF) for subjects who did 
not have a Week 12 UACR determination. Randomized subjects with no 
post-randomization UACR will be excluded from the mITT analysis. 
The PK Population will consist of all subjects who received at least one dose of 
TMX-049 and have evaluable PK data. 
The Per Protocol Population will be used as a sensitivity analysis for the 
primary efficacy endpoint and will consist of all subjects according to their 
randomization scheme who experienced no major protocol deviations. 
Study Assessments 
Efficacy: UACR, eGFR, exploratory renal biomarkers, and sUA. 
Safety: Physical examination, vital signs, body weight and height, concomitant 
medications, 12-lead ECG, AE reports, measurement of HbA1c, clinical 
laboratory evaluations (hematology, serum chemistry, thyroid testing, lipid 
panel, and urinalysis parameters). 
PK: Plasma concentrations of TMX-049.  
Efficacy Endpoints 
Primary Endpoint: 
• Change from Baseline to Week 12 in log-transformed UACR 
Secondary Endpoints: 
• Proportion of subjects with >30% reduction from Baseline to Week 12 in 
UACR 
• Change in eGFR (Baseline compared to each post-treatment assessment) 
• Change in UACR (Baseline compared to each post-treatment assessment) 
• Change in renal biomarkers (Baseline compared to each post-treatment 
assessment) 
• Change in sUA (Baseline compared to each post-treatment assessment) 
Safety Endpoints 
• Proportion of subjects with reported AEs, discontinuation due to AEs or 
serious adverse events (SAEs) 
• Proportion of subjects with AEs considered by the Investigator to be related 
to study medication 
• Proportion of subjects with mild, moderate, or severe AEs as assessed by 
the Investigator 
• Changes in vital signs, ECGs, and laboratory parameters 


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Statistical Methods: 
General Statistical Considerations: 
Data will be summarized using descriptive statistics and include mean, standard 
deviation (SD), median, minimum, maximum, and corresponding number of 
subjects (n). For log-transformed data, the geometric mean and geometric 
coefficient of variation will be provided. For categorical variables, the number 
and percent in each category will be presented. Tables will include the placebo 
group and each of the TMX-049 dose groups and a separate category that 
combines all TMX-049 dose groups. 
 
Efficacy Analysis: 
The UACR values from the 2 consecutive day mid-stream, first-morning void 
urine samples that are submitted at Visits 2 to 7 will be based on the mean 
result of measurements in each of the paired samples. If only one sample is 
available, the results from that sample will be used. 
The change from Baseline to Week 12 (or the LOCF) in log-transformed 
UACR will be analyzed in an analysis of covariance model with a fixed effect 
for treatment, baseline log-transformed UACR and baseline serum uric acid as 
covariates. The least squares mean, p-value, and the corresponding 95% 
confidence interval (CI) for the treatment difference will be provided. The last 
post randomization UACR will be carried forward (LOCF) for subjects who did 
not have a Week 12 UACR determination. 
To analyze the effect of LOCF on missing data, the above analysis will be 
repeated using a mixed model repeated measures approach. The statistical 
model will feature a repeated statement and include treatment, timepoint, and 
treatment-by-timepoint interaction as fixed effects, baseline as a covariate, and 
subject as a random effect. 
The above analysis of covariance model and repeated measures models will also 
be used to analyze the secondary endpoints, change in eGFR, change in UACR, 
change in sUA, and change in renal biomarkers at each post-treatment 
assessment. The proportion of subjects with >30% reduction from Baseline to 
Week 12 in UACR will be analyzed using a Fisher’s exact test and logistic 
regression. 
Renal Biomarker Analysis: 
Descriptive statistics will be used for renal biomarker assessment. No inferential 
statistical analysis will be performed for the exploratory renal biomarkers. 
PK Analysis: 
PK samples that are obtained at Visits 4, 5, and 6 will be used to assess 
TMX-049 plasma concentrations and be used in a population PK analysis. 
Results will be summarized in each of the TMX-049 treatment groups. 
Safety Analysis: 
Descriptive statistics will be used in assessment of all safety parameters. No 
inferential statistical tests will be performed using safety data. Safety analyses 
will be performed on the Safety Population, and safety variables, including 
treatment-emergent AEs, laboratory tests, vital signs, and ECGs, will be 
summarized. 
 


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TABLE OF CONTENTS 
STUDY IDENTIFICATION ........................................................................................................................... 2 
SYNOPSIS ...................................................................................................................................................... 3 
TABLE OF CONTENTS ................................................................................................................................ 8 
LIST OF TABLES ........................................................................................................................................ 11 
LIST OF FIGURES ....................................................................................................................................... 11 
1. 
CONTACTS ......................................................................................................................................... 12 
1.1 
Emergency Contacts ................................................................................................................ 12 
2. 
INVESTIGATOR/SPONSOR AGREEMENT ..................................................................................... 13 
3. 
LIST OF ABBREVIATIONS ............................................................................................................... 14 
4. 
ETHICAL CONSIDERATIONS .......................................................................................................... 16 
4.1 
Institutional Review Board or Independent Ethics Committee ................................................ 16 
4.2 
Ethical Conduct of the Study ................................................................................................... 16 
4.3 
Subject Information and Consent ............................................................................................. 16 
5. 
INTRODUCTION ................................................................................................................................ 17 
5.1 
Study Rationale ........................................................................................................................ 17 
5.2 
Background Information .......................................................................................................... 17 
5.3 
Non-Clinical Studies ................................................................................................................ 18 
5.3.1 
Summary of Non-Clinical Pharmacology ................................................................... 18 
5.3.1.1 In Vitro Study ......................................................................................................... 18 
5.3.1.2 In Vivo Studies ....................................................................................................... 18 
5.3.2 
Summary of Safety Pharmacology .............................................................................. 19 
5.3.3 
Summary of Toxicology ............................................................................................. 19 
5.3.4 
Summary of Non-Clinical Pharmacokinetics .............................................................. 20 
5.4 
Summary of Clinical Experience ............................................................................................. 21 
5.4.1 
Study TMX-049-101 ................................................................................................... 21 
5.4.2 
Study TMX-049-102 ................................................................................................... 22 
5.4.3 
Study TMX-049DN-101 ............................................................................................. 23 
6. 
STUDY OBJECTIVES......................................................................................................................... 25 
7. 
INVESTIGATION PLAN .................................................................................................................... 26 
7.1 
Overall Study Design and Plan Description ............................................................................. 26 
7.2 
Discussion of Study Design, Including the Choice of Control Groups .................................... 27 
7.3 
Selection of Study Population .................................................................................................. 27 
7.3.1 
Inclusion Criteria ......................................................................................................... 28 
7.3.2 
Exclusion Criteria ....................................................................................................... 28 
7.3.3 
Withdrawal of Subjects ............................................................................................... 30 
7.3.3.1 Replacement Procedures ......................................................................................... 30 
7.3.3.2 Guidance to Investigators on When to End Study Treatment Regimen ................. 30 
7.3.3.3 Follow-Up of Subjects Prematurely Discontinued from the Study Treatment 
Regimen or Withdrawn from Study ........................................................................ 31 
7.4 
Treatment of Subjects .............................................................................................................. 31 
7.4.1 
Treatments Administered ............................................................................................ 31 
7.4.2 
Identity of Investigational Product .............................................................................. 32 


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7.4.2.1 Packaging and Labeling .......................................................................................... 32 
7.4.2.2 Storage and Stability ............................................................................................... 32 
7.4.2.3 Study Drug Accountability, Reconciliation, and Return ........................................ 33 
7.4.2.4 Study Drug Handling and Disposal ........................................................................ 33 
7.4.3 
Method of Assigning Subjects to Treatment Groups and Measures to Minimize/Avoid 
Bias ............................................................................................................................. 33 
7.4.3.1 Subject Identification .............................................................................................. 33 
7.4.3.2 Randomization ........................................................................................................ 33 
7.4.3.3 Blinding .................................................................................................................. 34 
7.4.3.3.1 
Unblinding in the Event of an Emergency .............................................................. 34 
7.4.4 
Selection of Doses in the Study................................................................................... 34 
7.4.5 
Dose Modification ....................................................................................................... 35 
7.4.6 
Prior and Concomitant Medications ............................................................................ 35 
7.4.6.1 Permitted ................................................................................................................. 35 
7.4.6.2 Caution ................................................................................................................... 35 
7.4.6.3 Prohibited ............................................................................................................... 36 
7.4.7 
Contraception .............................................................................................................. 37 
7.4.8 
Treatment Compliance ................................................................................................ 38 
7.5 
Study Procedures ..................................................................................................................... 38 
7.5.1 
Schedule of Study Procedures ..................................................................................... 38 
7.5.2 
Screening Procedures .................................................................................................. 42 
7.5.2.1 Screening Visit (Visit 1) Day -42 to Day -15 ......................................................... 42 
7.5.3 
Single-Blind, Placebo Run-in Phase (Visit 2): Day -14 ± 4 Days ............................... 42 
7.5.4 
Treatment Phase Procedures ....................................................................................... 43 
7.5.4.1 Pre- Visit Telephone Call ....................................................................................... 43 
7.5.4.2 Randomization Visit (Visit 3): Study Day 0 ........................................................... 44 
7.5.4.3 Visit 4: Study Day 14 ± 4 Days .............................................................................. 45 
7.5.4.4 Visit 5: Study Day 42 ± 7 Days .............................................................................. 45 
7.5.4.5 End of Treatment Visit 6: Study Day 84 ± 7 Days or Early Termination Visit ...... 46 
7.5.4.6 End of Study Follow-up (Visit 7): Visit 6/ET+28 ± 7 days .................................... 47 
7.5.5 
Procedures for Premature Discontinuation from the Study Treatment Regimen ........ 48 
7.5.6 
Temporary Discontinuation ........................................................................................ 48 
7.5.7 
Lost to Follow-up ........................................................................................................ 48 
7.6 
Efficacy and Safety Variables .................................................................................................. 49 
7.6.1 
Efficacy Assessments .................................................................................................. 49 
7.6.1.1 Urine Samples for the Calculation of Urinary Albumin-to-Creatinine Ratio ......... 49 
7.6.1.2 Blood Samples for the Calculation of Estimated Glomerular Filtration Rate ......... 49 
7.6.1.3 Urine Samples for the Analysis of Exploratory Biomarkers .................................. 49 
7.6.1.4 Blood Samples for the Analysis of Serum Uric Acid ............................................. 49 
7.6.1.5 Blood Samples for the Analysis of Exploratory Biomarkers .................................. 49 
7.6.2 
Safety Assessments ..................................................................................................... 50 
7.6.2.1 Adverse Events ....................................................................................................... 50 
7.6.2.1.1 
Definitions .............................................................................................................. 50 
7.6.2.1.2 
Reporting of Adverse Events .................................................................................. 50 
7.6.2.1.3 
Assessment of Severity ........................................................................................... 51 
7.6.2.1.4 
Relationship to Study Treatment ............................................................................ 51 
7.6.2.1.5 
Follow-up of Adverse Events ................................................................................. 51 
7.6.2.2 Serious Adverse Events .......................................................................................... 51 
7.6.2.2.1 
Reporting Serious Adverse Events ......................................................................... 52 
7.6.2.3 Pregnancy ............................................................................................................... 52 
7.6.2.4 Vital Signs .............................................................................................................. 53 
7.6.2.5 12-Lead Electrocardiogram .................................................................................... 53 
7.6.2.6 Clinical Laboratory Evaluations ............................................................................. 53 
7.6.2.7 Blood Sample for HbA1c ....................................................................................... 54 


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7.6.2.8 Physical Examinations ............................................................................................ 54 
7.6.2.9 Body Weight ........................................................................................................... 54 
7.7 
Pharmacokinetic Analysis ........................................................................................................ 54 
7.7.1 
Blood Sampling for the Analysis of Plasma TMX-049 .............................................. 54 
7.7.2 
Population Pharmacokinetic Analysis ......................................................................... 54 
7.8 
Pharmacogenetic/Pharmacogenomics Testing ......................................................................... 55 
7.9 
Data Quality Assurance ........................................................................................................... 55 
7.10 
Statistical Methods ................................................................................................................... 55 
7.10.1 Determination of Sample Size ..................................................................................... 55 
7.10.2 Subject Populations Analyzed ..................................................................................... 55 
7.10.3 General Statistical Considerations .............................................................................. 56 
7.10.4 Efficacy Analysis ........................................................................................................ 56 
7.10.4.1 Efficacy Endpoints ............................................................................................... 56 
7.10.4.2 Statistical Analysis of Efficacy ............................................................................ 56 
7.10.4.3 Safety Endpoints .................................................................................................. 57 
7.10.4.4 Statistical Analysis of Safety ................................................................................ 57 
7.10.5 Pharmacokinetic Analysis ........................................................................................... 58 
7.10.6 Interim Analysis .......................................................................................................... 58 
8. 
RISKS AND BENEFITS ...................................................................................................................... 59 
9. 
INVESTIGATOR’S REGULATORY OBLIGATIONS ...................................................................... 60 
9.1 
Prestudy Documentation .......................................................................................................... 60 
9.2 
Electronic Data Capture ........................................................................................................... 60 
9.3 
Adverse Event Reporting ......................................................................................................... 60 
9.4 
Review of Source Records ....................................................................................................... 60 
9.5 
Monitoring of the Study ........................................................................................................... 60 
9.6 
Protocol Amendments .............................................................................................................. 61 
9.7 
Investigator Meeting ................................................................................................................ 61 
9.8 
Change in Investigator ............................................................................................................. 61 
9.9 
Termination of the Study ......................................................................................................... 61 
9.10 
Final Study Report ................................................................................................................... 61 
9.11 
Reports to the Ethics Committee and Regulatory Authorities ................................................. 62 
9.12 
Confidentiality ......................................................................................................................... 62 
9.13 
Records Retention .................................................................................................................... 62 
9.14 
Publications .............................................................................................................................. 62 
9.15 
Subject Injury ........................................................................................................................... 62 
10. REFERENCES ..................................................................................................................................... 64 
11. APPENDICES ...................................................................................................................................... 65 
APPENDIX A - CLINICAL LABORATORY EVALUATIONS ................................................................ 65 
APPENDIX B – PERMITTED AND PROHIBITED CONCOMITANT MEDICATION ........................... 66 
 
 
 


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Protocol No.: TMX-049DN-201 
TMX-049 
 
 
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LIST OF TABLES 
 
Table 1:             List of Abbreviations .................................................................................................. 14 
Table 2:  
Schedule of Study Procedures ..................................................................................... 39 
 
LIST OF FIGURES 
 
Figure 1: Study Design ......................................................................................................................... 27 
 








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Protocol No.: TMX-049DN-201 
TMX-049 
 
 
Final Version 2.0 (07 February 2018) 
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Table 1: List of Abbreviations 
Abbreviation 
Definition 
qd 
once-daily  
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
SAE 
serious adverse event 
SD 
standard deviation 
SOC 
system organ class (MedDRA classification) 
sTNFR1 
soluble tumor necrosis factor receptor 1  
sUA 
serum uric acid 
t1/2 
terminal half-life 
TEAE 
treatment-emergent adverse event 
tmax 
time of maximum observed plasma concentration 
TMF 
Trial Master File 
tmin 
time of minimum concentration 
UACR 
urinary albumin-to-creatinine ratio  
UGT 
uridine 5'-diphospho-glucuronosyltransferase  
ULN 
upper limit of normal 
XO 
xanthine oxidase 
XOR 
xanthine oxidoreductase 
ZDF 
Zucker diabetic fatty 
ZL 
normoglycemic ZDF lean 
 




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5. 
INTRODUCTION 
TMX-049 (compound code TEI-R04969) is a novel, potent inhibitor of xanthine oxidase (XO), which 
catalyzes synthesis of uric acid. TMX-049 is currently under development as a therapeutic drug for the 
treatment of hyperuricemia associated with gout in Japan by Teijin Pharma Limited and is also proposed 
for development as a therapeutic drug for diabetic kidney disease (DKD) by Teijin America Inc. 
5.1 
Study Rationale 
In vivo non-clinical studies revealed that in addition to XO inhibition, TMX-049 showed reduction of urine 
albumin excretion in the rat model. The aim of this study is to obtain safety and tolerability data and also 
assess the renal effects in subjects with Type 2 diabetes and albuminuria treated with TMX-049 following 
12 weeks of exposure. The early proof-of-concept therapeutic effect of TMX-049 on reducing urinary 
albumin-to-creatinine ratio (UACR) in subjects with albuminuria (Baseline UACR 200 to 3000 mg/g) 
compared with placebo will be assessed in this study. 
5.2 
Background Information 
Uric acid is a final product of the metabolic breakdown of purine nucleotides in humans. Purine nucleotides 
are metabolized into hypoxanthine, then oxidized to xanthine, and finally further oxidized to uric acid; both 
oxidation reactions are catalyzed by XO. Uric acid is then excreted mainly through the kidney into the 
urine. Increased uric acid production or decreased renal clearance of uric acid may cause hyperuricemia, 
which is defined by serum uric acid (sUA) concentrations >6.8 mg/dL.1 
Gout is arthritis induced by the accumulation of urate crystals, usually on peripheral joints, due to 
hyperuricemia. For the treatment of gout, uric acid-lowering therapy using XO inhibitors such as febuxostat 
and allopurinol is mainly applied. 
In non-clinical studies, in vitro XO inhibition efficacy of TMX-049 was shown to be comparable to that of 
febuxostat. It was highly distributed in the liver, which is the main organ expressing XO, and persistently 
inhibited XO activity in this organ. TMX-049 showed a persistent plasma uric acid-lowering effect in in 
vivo pharmacology testing in dogs. Thus, it is expected that TMX-049 would show a longer uric acid-
lowering effect than febuxostat. 
The prevalence of chronic kidney disease (CKD) and end-stage kidney disease (ESKD), which is a 
consequence of long term CKD, is growing worldwide.2, 3, 4 This is becoming an important issue from a 
health care perspective, as ESKD patients need to be treated by costly renal replacement therapy such as 
hemodialysis and kidney transplant. Type 2 diabetes is the one of the main causes of CKD.3, 5, 6 Chronic 
kidney disease caused by Type 2 diabetes is generally recognized as DKD and defined as a persistent 
elevated urinary albumin excretion and/or reduction in estimated glomerular filtration rate (eGFR). At 
present, medication for the treatment of DKD is limited. TMX-049 decreased urine albumin excretion in 
Type 2 diabetes model Zucker diabetic fatty (ZDF) rats, indicating a potential renal protective effect. In 
addition, it is suggested that hyperuricemia could be associated with CKD onset and/or progression,7 and it 
has been reported that XO inhibitors, such as allopurinol, febuxostat, and topiroxostat, improve renal 
function or slow the kidney disease progression of hyperuricemia patients.8 ,9, 10 
The safety, tolerability, pharmacokinetics (PK) and metabolism, and pharmacodynamics (PD) of TMX-049 
have been evaluated in three Phase 1 studies. Single doses and multiple doses of up to 120 mg TMX-049 
showed no significant adverse drug reactions and were well tolerated in healthy adult males in Japan. 
Single doses and multiple doses of up to 380 mg TMX-049 showed no significant adverse drug reactions 
and were well tolerated in healthy male subjects of any ethnic origin. 
Based on these findings, TMX-049 is proposed as a novel XO inhibitor for the treatment of DKD and 
hyperuricemia with gout. 


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5.3 
Non-Clinical Studies 
Detailed data on non-clinical studies can be found in the latest version of the Investigator’s Brochure  
(IB).11 
5.3.1 
Summary of Non-Clinical Pharmacology 
5.3.1.1 
In Vitro Study 
The in vitro inhibition of xanthine oxidoreductase (XOR) activity by TMX-049 and febuxostat was 
evaluated using bovine milk XO. TMX-049 showed mixed types of inhibition (mixture of competitive and 
non-competitive inhibition). The inhibition constant of oxidized XO (Ki) was 0.4 ± 0.2 nmol/L and the 
inhibition constant of reduced XO (Ki’) was 1.2 ± 0.1 nmol/L for TMX-049, while the Ki and Ki’ were 
0.3 ± 0.1 nmol/L and 2.0 ± 0.1 (mean ± standard error, n=3) for febuxostat, respectively. 
To examine the selectivity of TMX-049 for XO, the inhibition of other purine-pyrimidine enzymes 
(guanine deaminase, hypoxanthine guanine phosphoribosyltransferase, purine nucleoside phosphorylase, 
and uridine monophosphate [UMP] synthase) and related enzymes (aldehyde oxidase) were evaluated. The 
concentrations at which 50% inhibition is observed (IC50) values of TMX-049 for all enzymes tested were 
>100 μmol/L. Results indicated that TMX-049 was a potent and specific inhibitor of XOR. 
5.3.1.2 
In Vivo Studies 
TMX-049 was assessed as a drug candidate for DKD by evaluating the effect on uric acid level and urine 
albumin excretion. 
The effects of TMX-049 and febuxostat on liver XOR activity were evaluated using Sprague Dawley rats. 
TMX-049 (0.1, 1, or 10 mg/kg), febuxostat (0.1, 1, or 10 mg/kg), or vehicle (0.5 w/v% methylcellulose 
solution [0.5% MC]) were administered by single oral gavage to male rats. Liver was harvested at either 2 
or 24 hours after administration and XOR activity was measured by pterin-based assay. Both TMX-049 and 
febuxostat inhibited liver XOR activity in a dose-dependent manner at 2 hours after administration, and 
percentages of inhibition at the respective dose levels against the vehicle-treated group were 55.5%, 97.2%, 
and 100.0% for TMX-049 and 62.8%, 93.1%, and 100.0% for febuxostat. Liver XOR activity was also 
inhibited at 24 hours after administration, and percentages of inhibition at the respective dose levels against 
the vehicle-treated group were 70.0%, 83.0%, and 88.9% for TMX-049, and 32.8%, 52.1%, and 64.4% for 
febuxostat. At 24 hours after administration, 0.1 mg/kg of TMX-049 showed comparable inhibition to 
10 mg/kg of febuxostat, indicating that TMX-049 demonstrated increased liver XOR inhibition activity 
over febuxostat. 
Hypouricemic efficacy of TMX-049 and febuxostat was evaluated in dogs by measuring allantoin in 
addition to plasma uric acid. TMX-049 (1, 3, or 10 mg/kg), febuxostat (1, 3, or 10 mg/kg), or vehicle (0.5% 
MC) were administered by single oral gavage to male beagle dogs. Plasma uric acid and allantoin 
concentration up to 24 hours after administration were measured and both TMX-049 and febuxostat 
significantly decreased area under the plasma concentration-time curve (AUC) from time zero to 24 hours 
postdose (AUC0-24h) at 1 mg/kg or higher. 
The effect on urine albumin excretion was evaluated in Type 2 diabetes mellitus model ZDF rats. Eight-
week-old rats were orally administered TMX-049 (1 or 3 mg/kg), febuxostat (3 mg/kg), losartan potassium 
(10 mg/kg), or vehicle once-daily (qd) for 13 weeks. Normoglycemic ZDF lean (ZL) rats were also 
administered vehicle orally qd for 13 weeks (non-diabetic nephropathy control animals). Urine albumin 
excretion was measured up to 12 weeks. Plasma uric acid levels and XO activity in the renal cortex were 
determined at 13 weeks. Urine albumin excretion in vehicle-treated ZDF rats was significantly higher than 
ZL rats. Oral administration of both TMX-049 and losartan potassium significantly decreased urine 
albumin excretion compared with the vehicle-treated group, while febuxostat had no significant effect. 
Plasma uric acid in both the TMX-049-treated group and febuxostat-treated group was decreased compared 


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with the vehicle-treated group. Xanthine oxidase activity in the renal cortex was significantly inhibited by 
TMX-049 at doses of 1 and 3 mg/kg, whereas febuxostat and losartan potassium showed no inhibition. 
5.3.2 
Summary of Safety Pharmacology 
The effects of TMX-049 on the central nervous system and respiratory system were investigated in male 
rats given a single oral dose of TMX-049 (at dose levels of 40, 120, and 500 mg/kg). No treatment-related 
findings were noted compared to vehicle control in general physical condition and behavior or respiratory 
rate, tidal volume, and minute volume (assessed up to 24 hours after administration) at any dose levels. In 
conclusion, under the conditions of this study, TMX-049 had no effects on the central nervous system or 
respiratory system in rats at doses of up to 500 mg/kg. 
The effects of TMX-049 on human ether-a-go-go related gene (hERG) tail peak currents in hERG 
transfected Chinese hamster ovary cells were evaluated using the whole-cell patch clamp method. 
TMX-049 at 10, 30, and 100 µmol/L had no statistically significant effect compared with the negative 
control. 
The effects of TMX-049 (single oral dose at dose levels of 100, 300, and 1000 mg/kg) on the 
cardiovascular system were investigated in 4 conscious male cynomolgus monkeys, using a telemetry 
system. There were no test article-related changes in blood pressure (systolic, diastolic, and mean), heart 
rate, electrocardiogram (ECG; PR interval, QRS duration, QT interval, and QT interval corrected for heart 
rate using Fridericia’s formula [QTcF]), intra-abdominal body temperature, and clinical signs compared to 
vehicle control. In conclusion, under the conditions of this study, TMX-049 had no effect on the 
cardiovascular system in monkeys up to 1000 mg/kg. 
5.3.3 
Summary of Toxicology 
Four pivotal repeat-dose toxicity studies were conducted in rats and monkeys, and TMX-049 was 
administered orally qd for 4 and 16 weeks for both species. The dose ranges were from 2.5 to 
120 mg/kg/day in rats for 4 weeks, from 2.5 to 40 mg/kg/day in rats for 16 weeks, and from 100 to 
1000 mg/kg/day in monkeys for 4 and 16 weeks. 
In the 4-week rat toxicity study, the no observed adverse effect level (NOAEL) was considered to be 
10 mg/kg/day (maximum plasma concentration [Cmax] of 843 and 785 ng/mL and AUC0-24h of 4310 and 
3030 ng·h/mL for males and females, respectively). No toxicologically significant changes related to 
TMX-049 were observed at 10 mg/kg/day or below. Major toxicologically significant changes at 
≥40 mg/kg/day included: urinary crystals; increased neutrophil count; and histopathological changes in the 
kidney, urinary bladder, and thyroid gland (eg basophilic crystals, inflammatory cell infiltration, and 
tubular regeneration in the kidney, urothelial hyperplasia in the urinary bladder, and follicular cell 
hypertrophy in the thyroid gland). At the highest dose of 120 mg/kg/day, toxicologically significant 
changes included clinical pathological changes (eg decreased levels of red blood cell count and hemoglobin 
concentration, and increased levels of urea nitrogen and creatinine), increased kidney weight, renal 
macroscopic changes (eg yellowish granular substances and discoloration), renal microscopic changes (eg 
fibrosis and hyperplasia of urothelium), and microscopic changes in the urinary bladder (eg basophilic 
crystals and urothelial hyperplasia). 
In the 16-week rat toxicity study, the NOAEL was considered to be 10 mg/kg/day (Cmax of 792 and 
830 ng/mL and AUC0-24h of 3720 and 3880 ng·h/mL for males and females, respectively). No 
toxicologically significant changes related to TMX-049 treatment were observed at 10 mg/kg/day or below. 
At the highest dose of 40 mg/kg/day, major toxicologically significant changes included urinary crystals, 
discoloration of the kidney, and renal microscopic changes (eg basophilic crystals, inflammatory cell 
infiltration, and tubular regeneration). 
In the 4-week monkey toxicity study, the NOAEL was considered to be 1000 mg/kg/day (Cmax of 27 900 
and 34 600 ng/mL and AUC0-24h of 179 000 and 133 000 ng·h/mL for males and females, respectively). 


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There were no toxicologically significant changes in any examination, and TMX-049 was well tolerated at 
oral doses up to 1000 mg/kg/day for 4 weeks. 
In the 16-week monkey toxicity study, the NOAEL was considered to be 300 mg/kg/day (Cmax of 3520 and 
3730 ng/mL and AUC0-24h of 34 100 and 39 000 ng·h/mL for males and females, respectively). There were 
no toxicologically meaningful changes up to 300 mg/kg/day. At the highest dose of 1000 mg/kg/day, the 
only toxicologically significant change observed was an increase in alanine aminotransferase (ALT). Other 
TMX-049-related changes observed at 1000 mg/kg/day included slight increases in aspartate 
aminotransferase (AST), total bilirubin, and glucose; however, these changes were not considered to be 
toxicologically meaningful because individual values of these parameters were slightly deviated from the 
range of those in the control background data at the test facility. All TMX-049-related changes showed a 
tendency to recover or had completely recovered by the end of the 4-week recovery period. 
In vitro and in vivo genotoxicity studies for TMX-049 were conducted (bacterial reverse mutation study 
and in vitro chromosomal aberration study in human lymphocytes, and in vivo micronucleus study in rat 
bone marrow). TMX-049 showed no genotoxic potential. 
Embryo fetal developmental toxicity studies were conducted in rats and rabbits. TMX-049 had no effect on 
reproductive function of dams and development of embryos and fetuses at up to 120 mg/kg/day in rats and 
100 mg/kg/day in rabbits. 
An in vivo phototoxicity study in pigmented female rats was conducted with oral administration of up to 
500 mg/kg/day TMX-049 for 3 days, followed by a single exposure to ultraviolet radiation. There was no 
evidence of cutaneous or ocular phototoxicity. 
5.3.4 
Summary of Non-Clinical Pharmacokinetics 
After single oral administration of TMX-049 to rats, monkeys, and dogs in the fasted condition, plasma 
concentration of TMX-049 reached Cmax at 1 to 4 hours after administration and decreased with a terminal 
half-life (t1/2) of 3 to 6 hours. The oral absorption of TMX-049 was high (67% to 94% in rats and 61% in 
monkeys). Bioavailability of TMX-049 in rats, monkeys, and dogs was 26.0% to 35.3%, 50.7%, and 
46.6%, respectively. The bioavailability of TMX-049 in dogs was 5.5% following single oral 
administration after a meal, indicating that drug absorption decreased with meal intake. In repeat dosing of 
TMX-049 in rats and monkeys, Cmax and AUC0-24h values generally increased dose-dependently in rats (2.5 
to 120 mg/kg) and monkeys (100 to 1000 mg/kg). No clear differences due to repeated dosing were 
observed in the Cmax and AUC0-24h values in either species. There were no apparent gender differences in 
Cmax and AUC0-24h values in either species. 
After single oral administration of [14C]-TMX-049 to rats, radioactivity absorbed from the gastrointestinal 
tract was widely distributed in various tissues with high levels in the liver and the gastrointestinal tract. 
Distribution of radioactivity in the brain was low. After single oral administration of [14C]-TMX-049 to 
pregnant rats, radioactivity was detected in fetal tissues; however, the concentration was lower than that in 
maternal plasma, showing limited distribution in the fetus. 
In vitro plasma protein binding of TMX-049 was high in human plasma (99.6% to 99.7%) and was 
consistently high across species (human, rat, rabbit, dog, and monkey). The major binding protein of 
TMX-049 in human plasma was albumin. Distribution of TMX-049 in human blood cells was low (1.1% to 
5.4%). 
In human hepatocytes, glucuronides of TMX-049 and 2 hydroxylated metabolites were the main 
metabolites. There were no human-specific metabolites among human, rat, and monkey hepatocytes. In 
reaction phenotyping, cytochrome P450 (CYP) 1A2, CYP2C8, and CYP2C9 were involved in the oxidative 
metabolism of TMX-049, and uridine diphosphate glucuronate transferase (UGT1)A1/9 inhibitors 
(UGT1A1 and UGT1A9) were involved in the glucuronidation of TMX-049, suggesting that TMX-049 is 
metabolized by multiple metabolic enzymes. 


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After single oral administration of [14C]-TMX-049 to rats, excretion was mainly into feces (83.0% to 90.8% 
of dose up to 168 hours). The urinary excretion of the parent compound TMX-049 was low (7.7% to 15.7% 
of dose up to 48 hours). After single oral administration of [14C]-TMX-049 to monkeys, excretion was 
mainly into feces (83.0% of dose up to 168 hours). The urinary excretion of the parent compound 
TMX-049 was low (3.7% of dose up to 48 hours). 
TMX-049 had an inhibitory effect on CYP2C8 (IC50: 18.6 µmol/L), CYP2C9 (IC50: 266 µmol/L), and 
CYP3A4 (substrates: testosterone [IC50: 94.8 µmol/L] and midazolam [IC50: 283 µmol/L]). There was no 
significant inhibition for CYP1A2, CYP2B6, CYP2C19, and CYP2D6. 
TMX-049 had no inductive effect on CYP1A2 and CYP2B6 up to 300 µmol/L. TMX-049 had no inductive 
effect on CYP3A4 up to 100 µmol/L, but had an inductive effect at 300 µmol/L. However, the inductive 
effect was 20% or less of the positive control (20 µmol/L rifampicin). 
TMX-049 was a substrate of breast cancer resistance protein (BCRP), organic anion-transporting 
polypeptide (OATP) 1B1, and OATP1B3. There was no significant inhibition for P-glycoprotein (IC50: 
>250 µmol/L), organic cation transporter (OCT) 2 (IC50: >10 µmol/L), and multidrug and toxin extrusion 
(MATE) 1 (IC50: >10 µmol/L), but TMX-049 had an inhibitory effect on BCRP (IC50: 18.6 µmol/L), 
OATP1B1 (IC50: 3.71 µmol/L) and OATP1B3 (IC50: 10.9 µmol/L), organic anion transporter (OAT) 1 
(IC50: 7.37 µmol/L), MATE2-K (IC50: 0.887 µmol/L), and bile salt export pump (IC50: 37.7 µmol/L). Also, 
TMX-049 inhibited the OAT3 and multidrug resistance-associated protein (MRP) 2-mediated active 
transport by 45% and 36% at the highest concentration, respectively (IC50: OAT3: >10 μmol/L, MRP2: 
>100 μmol/L). 
5.4 
Summary of Clinical Experience 
5.4.1 
Study TMX-049-101 
A Phase 1 first-in-human study has been completed to investigate the safety, tolerability, PK, and PD of 
TMX-049 in healthy male subjects in Japan (study TMX-049-101). TMX-049 was administered as single 
ascending oral doses from 1 to 120 mg in the fasted condition. Single oral doses of 5 and 40 mg TMX-049 
were also administered after a meal to investigate food effect. 
Over the dose range tested in the fasted condition, the time of maximum observed plasma concentration 
(tmax) ranged from 1.75 to 3.000 hours, with mean Cmax ranging from 16.672 to 1675.657 ng/mL. Mean t1/2 
ranged from 5.432 to 18.708 hours. Area under the plasma concentration-time curve from time zero to 
infinity (AUCinf) was 93.19 to 10 764.20 ng·h/mL. Plasma drug concentration parameters (Cmax and AUCinf) 
showed dose proportionality over the dose range tested. After administration of 5 mg TMX-049, the 
fed/fasted geometric mean ratio (90% confidence intervals [CIs]) was 0.758 (0.498 to 1.155) for Cmax and 
0.961 (0.599 to 1.542) for AUCinf, showing no significant food effect. However, at 40 mg TMX-049, the 
fed/fasted geometric mean ratio (90% CIs) was 0.495 (0.300 to 0.818) for Cmax and 0.610 (0.395 to 0.943) 
for AUCinf, showing that plasma exposure to TMX-049 was decreased when administered with food. After 
single oral administration of TMX-049 at doses of 1 to 120 mg in the fasted condition, or 5 and 40 mg in 
the fed condition, the mean cumulative urinary excretion rate up to 72 hours after administration was low, 
ranging from 3.17% to 6.03%. Renal clearance of TMX-049 ranged from 0.24 to 0.62 L/h. 
In the fasted condition over the dose range tested, sUA concentrations decreased compared with the 
placebo group. The time to reach minimum concentration (tmin) for serum uric acid tended to increase (from 
18.0 hours at 1 mg to 38.7 hours at 120 mg) with increasing dose. The ratio of minimum concentration 
(Cmin) of sUA relative to Baseline value decreased from -8.30% to -45.51% as the dose increased from 1 to 
120 mg. Mean tmax of plasma xanthine increased from 5.3 to 22.7 hours and mean Cmax of plasma xanthine 
increased from 0.0857 to 0.2405 mg/dL as the dose of TMX-049 increased from 1 to 120 mg. In the fed 
condition, sUA concentrations decreased which was consistent with the results following administration in 
the fasted state. Minimum plasma concentration and tmin values following a dose of 5 mg TMX-049 were 
5.30 mg/mL and 12.7 hours in the fasted condition, and 4.63 mg/dL and 12.7 hours in the fed condition, 
respectively; and following a dose of 40 mg TMX-049 were 4.30 mg/dL and 27.0 hours in the fasted 


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condition, and 4.12 mg/dL and 23.3 hours in the fed condition, respectively, showing no significant food 
effect. 
Single oral doses of TMX-049 from 1 to 120 mg had no safety issues and were well tolerated. Six adverse 
events (AEs) were reported by 4 out of 48 subjects administered TMX-049 in the fasted condition, 
including C-reactive protein increased, testicular neoplasm, foot deformity, ALT increased, and blood 
lactate dehydrogenase increased. One AE (urine ketone body present) was reported by 1 out of 20 subjects 
in the placebo group. There was no tendency to onset of AEs associated with dose increase and causal 
relationship with TMX-049 was ruled out for all of the AEs. 
One serious adverse event (SAE) was observed (testicular neoplasm). The Principal Investigator judged 
that the event did not have a causal relationship with TMX-049 and the Sponsor considered that the 
judgment by the Principal Investigator was appropriate. 
No subjects died or discontinued the study treatment during the study period. 
Based on non-clinical study findings, urinary sediment and endocrine parameters were monitored in the 
clinical study; however, no abnormal changes in urinary sediment or abnormal changes related with thyroid 
hormone in the endocrine test were detected. Also, no AEs related to deposition of xanthine crystals in the 
kidney or bladder or AEs related with the thyroid gland were observed. No other clinically significant 
abnormal findings were observed. 
5.4.2 
Study TMX-049-102 
A Phase 1 multiple dose study has been conducted in healthy male subjects in Japan to investigate the 
safety, tolerability, PK, and PD of TMX-049 administered qd for 10 days at dose levels ranging from 3 to 
120 mg in the fed state. 
Following the initial administration of TMX-049 at 3 to 120 mg, median tmax ranged from 2.50 to 
4.00 hours, with mean Cmax ranging from 37.487 to 2088.050 ng/mL. Mean t1/2 ranged from 4.148 to 
7.029 hours. The plasma drug concentration parameters Cmax, AUC0-24h, AUC from time zero to the final 
quantitative point (AUCt), and AUCinf showed dose proportionality over the dose range studied. Following 
the final administration in the repeated qd administration of TMX-049 for 10 days at 3 to 120 mg, median 
tmax ranged from 2.00 to 4.00 hours, with mean Cmax ranging from 46.165 to 1873.007 ng/mL. Mean t1/2 
ranged from 7.883 to 15.166 hours. The Cmax, AUC0-24h, and AUCt of the plasma unchanged drug showed 
dose proportionality over the dose range studied. The AUCinf increased dose-dependently, but dose 
proportionality could not be confirmed. The mean accumulation ratio ranged from 0.9092 to 1.2548 for 
Cmax and 0.9152 to 1.1608 for AUC0-24 across the dose range studied, showing no increase in the blood 
exposure. Based on the changes in trough plasma concentrations of unchanged drug, steady-state was 
reached by Day 7 at the latest in all the groups treated with TMX-049. 
After the initial administration of TMX-049, sUA levels remained low depending on the dose of TMX-049. 
The mean Cmin of sUA was 5.35 mg/dL in the placebo group compared with 5.55, 4.67, 4.40, and 
4.08 mg/dL in the groups treated with 3, 10, 40, and 120 mg of TMX-049, respectively. Compared with 
Baseline sUA levels, the mean percent change in Cmin was -7.96% in the placebo group 
and -15.64%, -22.07%, -30.55%, and -35.79% in the groups treated with at 3, 10, 40, and 120 mg of 
TMX-049, respectively, showing that the Cmin decreased with an increase in TMX-049 dose. 
When TMX-049 was administered qd for 10 days at 3 to 120 mg, the sUA levels reached steady-state by 
Day 9 at the latest in any group, based on the changes in the trough sUA concentrations. The sUA levels 
after the last administration remained low depending on the dose of TMX-049. The mean Cmin of sUA was 
5.54 mg/dL in the placebo group compared with 4.95, 3.50, 2.45, and 1.13 mg/dL in the groups treated with 
3, 10, 40, and 120 mg of TMX-049, respectively. The mean Cmin of sUA was lower after the last 
administration compared with after the initial administration. Compared with Baseline sUA levels, the 
mean percent change in Cmin was -4.61% in the placebo group and -24.04%, -41.32%, -61.30%, 


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and -82.33% in the groups treated with 3, 10, 40, and 120 mg of TMX-049, respectively, showing that the 
Cmin decreased with an increase in TMX-049 dose. The mean percent change in Cmin of sUA decreased after 
the repeated administration compared with that after the initial administration. After the completion of 
administration on Day 10, the mean sUA levels returned to the same levels as Baseline (0 h on Day 1) by 
Day 17, the final observation day, in all the groups. 
After oral administration of TMX-049 at 3 to 120 mg, the urinary uric acid excretion decreased in 
association with a decrease in the sUA levels. The plasma xanthine increased after oral administration of 
TMX-049 at 3 to 120 mg and the urinary xanthine excretion also increased in association with the increased 
plasma xanthine. Likewise, the plasma hypoxanthine increased after administration of TMX-049 and the 
urinary hypoxanthine excretion also increased in association with the increased plasma hypoxanthine. 
Adverse events were noted in 3 of 24 subjects treated with TMX-049 at 3, 10, 40, and 120 mg, and in 1 of 
8 subjects treated with placebo. The incidence of AEs was 50.0% (3/6 subjects) in the group treated with 
120 mg of TMX-049 and 12.5% (1/8 subjects) in the placebo group. No AEs were noted in the groups 
treated with 3, 10, and 40 mg of TMX-049. One occurrence each of dizziness postural, white blood cell 
count increased, and transaminases increased were noted in the group treated with 120 mg of TMX-049. 
The event of transaminases increased was considered to be an adverse drug reaction (ADR), but this 
occurred on Day 11, its severity was mild, and this reaction disappeared without any treatment. No deaths, 
other SAEs, or AEs leading to discontinued administration of the investigational drug were noted. Apart 
from abnormal laboratory values counted as AEs, no safety concerns were noted in the laboratory values, 
vital signs, and physical findings. No AEs related to standard 12-lead ECG were noted. In summary, the 
repeated qd oral administration of TMX-049 for 10 days at 3 to 120 mg was well tolerated by healthy male 
subjects, and no safety concerns were noted. 
5.4.3 
Study TMX-049DN-101 
A further Phase I study has been completed to investigate the safety, tolerability, PK, and PD of single and 
multiple oral doses of TMX-049 in healthy male subjects of any ethnic origin. TMX-049 was administered 
as single ascending doses from 10 to 380 mg in the fasted condition and as multiple oral doses from 40 to 
380 mg, administered qd for 10 days in the fed condition. 
Following single and multiple qd oral dose administration in the fasted and fed states, TMX-049 was 
characterised by rapid to steady absorption with median tmax between 1.5 and 3.5 hours. Plasma 
concentrations declined in a biphasic manner with t1/2 ranging from 10 to 19 hours. Systemic exposure to 
TMX-049 increased in a dose-proportional manner across the fasted 10 to 380 mg single oral dose range. 
Following 40 to 380 mg qd multiple dosing of TMX-049 in the fed state, dose-proportional increases in 
AUC values and slightly greater than dose-proportional increases in Cmax were indicated; however, these 
assessments of dose proportionality were not entirely conclusive due to high between-subject variability 
and wide confidence intervals. Following multiple qd oral dosing, minimal accumulation of TMX-049 in 
plasma was observed. Steady-state was generally achieved within 5 days of dosing and no time-dependent 
change in exposure was detected with multiple dosing. Urinary excretion was low with arithmetic means 
ranging from approximately 3% to 5% of the dose excreted as unchanged drug following single fasted 
doses of TMX-049. 
Regarding PD parameters, the sUA level reached Cmin (mean: 3.62 to 5.12 mg/dL) at a median tmin of 12, 
16, 24, 24, and 24 hours, following single oral administration of 10, 40, 120, 220, and 380 mg TMX-049, 
respectively, and then increased. There was a delay in time to Cmin with an increase in dose between 10 and 
120 mg TMX-049 and then tmin reached 24 hours for the 120 to 380 mg dose levels. The percent change 
from baseline of Cmin (mean) of sUA decreased from −17.0% to −41.5% as the dose of TMX-049 increased 
from 10 to 380 mg. 
Following single doses of 10 to 380 mg TMX-049 under fasted conditions, and multiple qd oral dosing for 
10 days under fed conditions, plasma xanthine increased after administration, and the urinary xanthine 
excretion also increased in association with the increased plasma xanthine. Likewise, the plasma 
hypoxanthine, and oxypurine increased after administration of TMX-049, and the urinary hypoxanthine and 


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oxypurine excretion also increased in association with the increased plasma hypoxanthine.  
When TMX-049 was orally administered repeatedly qd for 10 days at 40 to 380 mg after breakfast, the 
sUA concentrations reached a steady state by Day 9 in all dosing groups. On Day 10 in the qd oral dosing 
regimen of TMX-049, the sUA levels in the groups treated with 40, 120, 240, and 380 mg TMX-049 
decreased with an increase in the doses of TMX-049 compared with baseline (sUA level at predose, Day 1). 
The mean percent change from baseline in Cmin for sUA was -61.8%, -75.9%, -83.4% and -85.4% for the 
40, 120, 240, and 380 mg TMX-049 dose levels, respectively. After the completion of administration on 
Day 10, the mean sUA levels returned to the same levels as baseline (predose, Day 1) by Day 17/18, the 
final observation day, in all the groups. 
There was no formal food effect analysis performed on the PD parameters. Different groups of subjects in 
Part A and Part B received 40, 120, and 380 mg TMX-049 on Day 1 under fasted (Part A) or fed (Part B) 
conditions. Changes from baseline in mean sUA levels in the 40, 120 and 380 mg TMX-049 dose groups 
were similar following administration under fed and fasted conditions. The Cmin occurred at a similar time 
for the fed and fasted TMX-049 doses. 
After administration of single doses of 10 to 380 mg TMX-049 under fasted conditions, and multiple qd 
oral doses of 40 to380 mg TMX-049 under fed conditions, there was a decrease in urinary uric acid.. 
Overall, in Part A (single ascending-dose), 9 treatment emergent adverse event (TEAE)s were noted in 7 
(17.5%) subjects administered single oral doses of between 10 and 380 mg TMX-049 as tablets under 
fasting conditions. Headache was the most frequently reported TEAE being reported by 3 subjects 
(1 subject following placebo and 2 subjects following 220 mg TMX-049). All 4 instances of headache were 
mild and only one instance was considered possibly related to the study drug (220 mg TMX-049). Two 
subjects received concomitant medication for the treatment of headache. There were no other TEAEs in 
Part A reported by more than 1 subject. Overall, in Part B (multiple ascending dose), 40 TEAEs were noted 
in 15 (46.9%) subjects administered qd oral doses of between 40 and 380 mg TMX-049 qd as tablets under 
fed conditions. Headache and pollakiuria were the most frequently reported TEAEs, each being reported by 
3 subjects. A total of 4 events of headache were reported. Three headache events were reported by 
2 subjects receiving placebo; 2 of which were mild in severity and 1 which was moderate and considered to 
be possibly related to treatment, requiring concomitant medication. One event of headache was reported by 
1 subject receiving 40 mg TMX-049 (considered to possibly related and mild in severity). All events of 
headache had an onset day between Day 1 and Day 8, and the duration varied from approximately 1 to 
4 days. A total of 3 events of pollakiuria were reported (2 events for 2 subjects receiving 380 mg and 1 
event by 1 subject receiving placebo). These events of pollakiuria were mild in severity and considered to 
be possibly related to the study drug. No concomitant medication was required for any event. All events of 
pollakiuria had an onset day of Day 3, however the duration varied from approximately 1 to 5 days. Rash, 
nausea, dizziness, and nasopharyngitis were the only other TEAEs reported by more than 1 subject in Part 
B, each being reported by 2 subjects. With the exception of rash (120 mg TMX-049 qd), these TEAEs were 
generally considered to be not related or unlikely related to the study drug and were mild in severity, with 
the exception of 1 moderate TEAE of nasopharyngitis. One subject reported mild nasopharyngitis on Day 6 
that developed to moderate severity on Day 7, requiring concomitant medication. There were no deaths or 
SAEs reported during the study and none of the subjects discontinued from the study due to a TEAE. There 
were no treatment-or dose-related trends and no clinically significant findings in the clinical laboratory 
evaluations, endocrine data, vital signs data, 12-lead ECG measurements, or physical examination findings 
during the study. In summary, single oral administration of TMX-049 from 10 to 380 mg under fasted 
conditions, and the repeated qd oral administration of TMX-049 for 10 days from 40 to 380 mg under fed 
conditions, were well tolerated by healthy male subjects, and no safety concerns were noted. 


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6. 
STUDY OBJECTIVES 
The primary objective of this study is: 
• 
To assess the effect of 2 dose levels of TMX-049 on urinary albumin excretion in subjects with 
Type 2 diabetes and albuminuria (a UACR 200 to 3000 mg/g and an eGFR ≥30 ml/min/1.73m2). 
Effects of each TMX-049 dose on UACR will be assessed in terms of ratios using log-transformed 
UACR at Baseline and after a 12-week period of treatment 
The secondary objectives of this study are: 
• 
To assess the effect of each dose of TMX-049 on eGFR during the 12-week period of treatment 
• 
To determine the percentage of subjects with >30% decrease in UACR with placebo and each 
dose of TMX-049 after 12 weeks of treatment 
• 
To assess the effect of each dose of TMX-049 on exploratory renal biomarkers during the 12-week 
period of treatment 
• 
To assess the effect of each dose of TMX-049 on sUA during the 12-week period of treatment 
• 
To assess the PK of TMX-049 in subjects with Type 2 diabetes and albuminuria 
• 
To assess safety and tolerability of TMX-049 




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Safety assessment will be based on clinical laboratory evaluations, vital signs, physical examinations, and 
12-lead ECG, which will be obtained prior to and during the period of randomized treatment. 
 
All study participants will attend a Follow-up Visit (Visit 7) 4 weeks after the last dose of study 
medication. Two consecutive day urine samples for UACR determination will be submitted by all subjects 
at this final visit. Urine and blood samples for determination of eGFR, sUA levels, and other laboratory 
safety tests will be obtained at Visit 7 or at Visit 6 (or the Early Termination Visit). 
 
Figure 1: Study Design 
 
 
 
7.2 
Discussion of Study Design, Including the Choice of Control Groups 
A single-blind, 2-week placebo run-in phase will be conducted prior to randomization to study treatment in 
order to enter only those subjects who can be expected to have an acceptable level of treatment compliance 
in the randomized treatment phase of the study. 
This treatment phase of the study will be double-blind and placebo-controlled in order to avoid bias in the 
collection and evaluation of data during its conduct. Placebo has been chosen as the control treatment to 
assess whether any observed effects are treatment related or simply reflect the study conditions. 
The aim of the study is to obtain safety, tolerability, and PK data and to assess effects of TMX-049 on 
UACR in subjects with Type 2 diabetes and albuminuria. The selected doses are anticipated to be 
reasonably well tolerated by subjects with Type 2 diabetes and albuminuria for the duration of the 
investigational treatment period. 
A 12-week treatment represents an adequate time to permit the assessment of safety and tolerability of 
TMX-049 as well as a determination of early proof-of-concept therapeutic effect on reducing UACR 
compared with placebo, while limiting the potential risk associated with a novel investigational drug. 
7.3 
Selection of Study Population 
The study protocol can only fulfil its objectives if appropriate subjects are enrolled. The following 
eligibility criteria are designed to select subjects for whom protocol treatment is considered appropriate. All 
relevant medical and non-medical conditions should be taken into consideration when deciding if 
participation in this study is suitable for a particular subject. 
Note: Subjects with exclusionary laboratory tests or other assessments at Visit 1 and/or Visit 2 may have a 
 
2 weeks 
(single -blind)  
12 weeks (double-blind) 
High Dose (200 mg TMX-049) 
Low Dose (40 mg TMX-049) 
Visit 1   
Visit  2   
Visit 3 
Randomization   
Visit 4 
Visit 5 
Placebo 
Placebo 
4 weeks 
Visit 7 
Follow -Up Visit 
≤ 6 weeks  
Visit 6/ 
Early Termination  






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symptoms (New York Heart Association [NYHA] class III-IV) at Visit 1 
33. History or presence of any clinical condition which, in the opinion of the Investigator, impedes 
ability for the subject to complete all study protocol requirements, increases risk of participation, 
or is not in the best interest of the study participant 
7.3.3 
Withdrawal of Subjects 
7.3.3.1 
Replacement Procedures 
Subjects who are withdrawn or who choose to withdraw from this study will not be replaced. 
7.3.3.2 
Guidance to Investigators on When to End Study Treatment Regimen 
Subjects will be withdrawn if any of the following criteria are met: 
• 
subject decision (withdrawal of consent) 
• 
any clinically relevant signs or symptoms that in the opinion of the Investigator warrant subject 
withdrawal 
• 
ALT or AST >8 x ULN 
• 
ALT or AST >5 x ULN for more than 2 weeks 
• 
ALT or AST >3 x ULN and with either a total bilirubin >2 x ULN or and International 
Normalized Ratio (INR) >1.5 
• 
ALT or AST >3 x ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
• 
eGFR ≤15 ml/min/1.73m2, confirmed with repeat measurement 
• 
development of an inter-current illness, condition, or procedural complication that in the opinion 
of the Investigator would interfere with the subject’s continued participation 
• 
development of an intolerable AE as determined by the Investigator and/or subject 
• 
positive pregnancy test result 
• 
significant protocol non-compliance in the study, as considered applicable by the Investigator 
• 
if it becomes necessary to break the blinding code for a subject 
A subject is free to withdraw from the study at any time for any reason without prejudice to their medical 
care. In addition, the Investigator may decide, for reasons of medical prudence, to withdraw a subject. In 
either event, the Sponsor will be notified and the date and reason(s) for the withdrawal will be documented 
in the subject's source data. Should the randomization code be broken for a subject, the date, time, and 
reason will be recorded in the subject’s source data. 
The Investigator will also withdraw the subject from the study upon the request of the Sponsor or if the 
Sponsor terminates the study. Upon occurrence of a serious or intolerable AE, the Investigator should 
confer with the Sponsor before discontinuing the subject. 


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If a subject has started the investigational medicinal product (IMP) and subsequently develops an 
inter-current medical problem, the Investigator may decide to withdraw IMP administration temporarily on 
clinical grounds. If the subject recovers and there are no clinical contraindications to resuming IMP 
administration this should be allowable within the protocol if the treating clinician feels it is appropriate to 
do so. 
7.3.3.3 
Follow-Up of Subjects Prematurely Discontinued from the Study Treatment Regimen or 
Withdrawn from Study 
If a subject is withdrawn or chooses to withdraw, an early termination visit and end of study visit will be 
performed if possible (see Table 2). The Investigator may also request that the subject returns for an 
additional follow-up visit. 
Where possible all subjects who discontinue due to AE will be followed up at suitable intervals to evaluate 
the course of the AE and to ensure reversibility or stabilization. The subsequent outcomes of these events 
will be recorded on the paper CRF. 
If a subject is withdrawn or chooses to withdraw prior to randomization, no additional tests are required. 
7.4 
Treatment of Subjects 
Study medication is defined as any investigational treatment(s) or placebo intended to be administered to a 
study participant according to the study randomization or treatment allocation. 
7.4.1 
Treatments Administered 
All eligible subjects will receive qd doses of placebo during a 2-week placebo run-in phase. Subjects with 
≥80% study medication compliance during the 2-week placebo run-in phase will be randomized to receive 
qd doses of 40 mg TMX-049, 200 mg TMX-049, or placebo during the double-blind 12-week treatment 
phase. 
On each dosing occasion, subjects assigned to the placebo group will swallow 1 tablet (placebo) and 
2 capsules (placebo), subjects assigned to the low-dose group (40 mg TMX-049) will swallow 1 tablet 
(40 mg TMX-049) and 2 capsules (placebo), and subjects assigned to the high-dose group (200 mg 
TMX-049) will swallow 1 tablet (40 mg TMX-049) and 2 capsules (80 mg TMX-049) with water. All 
tablets/capsules making up a dose must be taken at the same time (ie dividing a dose is not permitted). 
Treatment group 
Capsule 
Tablet 
TMX-049 200-mg group 
2 x 80-mg TMX-049 capsules 
1 x 40-mg TMX-049 tablet 
TMX-049 40-mg group 
2 x placebo capsules 
1 x 40-mg TMX-049 tablet 
Placebo group 
2 x placebo capsules 
1 x placebo tablet  
 
Subjects will be instructed to take study medication qd in the morning at approximately the same time each 
day. Subjects should take study medication with food, rather than on an empty stomach whenever possible, 
although occasional administration on an empty stomach is permissible. Subjects who don’t usually eat 
breakfast should eat something (a snack would be acceptable), prior to dosing. Study medication will begin 
the morning after Visit 2 in the placebo run-in phase and the morning after Visit 3 at the beginning of the 
randomized treatment phase. The last dose of study medication will be taken in the morning before Visit 6. 
If a subject does not take a dose of study drug within +12 hours of their regular dosing time, then the dose 
of study drug should be skipped and the subject should be instructed to take the study drug at the next 
regularly scheduled time. If a dose is missed, the site notified and recorded in the appropriate sections of 
the CRF based on verbal communications with the subjects. If a subject takes more than the intended dose, 


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they should report this to the site and an AE will be recorded if there were symptoms that accompanied the 
additional dose taken. 
At Visit 4, subjects should not take study medication in the morning before their visit. Subjects can take 
study medication after the PK sample is obtained provided it is taken within +12 hours of their regular 
dosing time. 
At Visit 5, subjects should take study medication approximately 3 hours before the visit. Therefore, the 
time of dosing may not necessarily be in the morning and can be adjusted according to the time of the visit. 
At Visit 6, subjects should take study medication in the morning. 
The time of PK sample acquisition, the time of dosing prior to the PK sample acquisition and whether the 
subject took study medication with or without food will be recorded in the appropriate sections of the CRF 
based on verbal communications with the subjects. 
7.4.2 
 Identity of Investigational Product 
The IMP, TMX-049 tablets at 40-mg strength, TMX-049 capsules at 80-mg strength (the capsule will 
contain 2 x 40-mg tablets), and matching placebo tablets and capsules, will be supplied by the Sponsor, 
along with batch numbers, Transmissible Spongiform Encephalopathy statements, safety data sheets, and 
Certificates of Analysis. 
7.4.2.1 
Packaging and Labeling 
The study drugs will be supplied by the Sponsor as treatment kits consisting of 1 tablet and 2 capsules for 
each dosing day (placebo: 1 x placebo tablet and 2 x placebo capsules; 40-mg dose group: 1 x 40-mg 
TMX-049 tablet and 2 x placebo capsules; 200-mg dose group: 1 x 40-mg TMX-049 tablet and 2 x 80-mg 
TMX-049 capsules). The treatment kits will consist of aluminum pouches containing 2 wallets, each wallet 
will contain sufficient tablets/capsules for 9 days qd dosing (18 days dosing per treatment kit). The 
treatment kits will be identical in appearance in order to maintain the double-blind status of the treatment 
phase. 
All packaging and labeling will be in compliance with Good Manufacturing Practice (GMP) specifications, 
as well as applicable local regulations. 
The subject will be provided with a treatment kit for the placebo run-in phase at Visit 2 and will return the 
empty wallet/wallet containing unused medication at Visit 3 when an assessment of compliance during the 
run-in phase will be made. 
The subject will be provided with the relevant number of treatment kits at Visits 3, 4, and 5 for qd dosing at 
home during the double-blind treatment phase and the subject will return the empty wallet/wallets 
containing unused medication at the subsequent visit (Visit 4, 5, and 6). 
7.4.2.2 
Storage and Stability 
The IMP may be dispensed only by the Investigator, by a staff member specifically authorized by the 
Investigator, or by a pharmacist, as appropriate. 
The treatment kits will be stored at between 20°C and 25°C (68°F and 77°F) in each study site pharmacy, 
which will be locked with restricted access. No special procedures are required for the safe handling of the 
tablets/capsules. 
Prior to dispensing of the treatment kits for home dosing, subjects will be instructed to keep the 
tablets/capsules in the original packaging and store the treatment kits at room temperature, and out of reach 


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of children. The study drug must not be given to other persons. The subject must return the empty 
wallet/wallets containing unused medication to the study site for a compliance check at Visit 3 (following 
the placebo run-in) and Visits 4, 5, and 6 (during the treatment phase). The subjects will receive 
instructions for medication intake from the Investigator. 
7.4.2.3 
Study Drug Accountability, Reconciliation, and Return 
The Investigator will maintain accurate records showing the receipt and disposition of the study supplies. 
Records will be maintained showing the receipt and disposition of the study supplies both at site and at 
subject level. 
The IMP accountability records and inventory will be available for verification by the Sponsor, or designee, 
at intervals and upon request during the study to check the supplies' storage (provided that this does not 
unblind the study). At the completion of the study, there will be a final reconciliation of all IMP. 
The IMP must not be used for any purpose other than the present study. Study drug that has been dispensed 
to a subject must not be re-dispensed to a different subject. 
The empty aluminum pouches and wallets will be discarded upon satisfactory completion of accountability 
procedures. Any unused treatment packs will be retained until completion of the study. 
The Study Monitor will periodically collect the study drug accountability forms and check all study drug 
dispensation and returns during the entire study period. 
Details of retention and reference samples will be documented in the pharmacy records. The interactive 
voice/web response system (IXRS) vendor can manage damaged study drug in the IXRS. Once drug is 
received at site, they will acknowledge receipt of the study drug. During this acknowledgement transaction, 
they will be asked to indicate if any of the study drug was received in damaged condition. 
7.4.2.4 
Study Drug Handling and Disposal 
No special procedures are required for the safe handling of the tablets/capsules. 
Following completion of the clinical phase of the study and Sponsor review of accountability, all unused 
supplies will either be returned to the Sponsor (together with the accountability records) or will be 
destroyed locally in agreement with the Sponsor and Certificates of Destruction provided to the Sponsor. 
Only participants enrolled in the study may receive study treatment and only authorized site staff may 
dispense or administer study treatment. 
7.4.3 
Method of Assigning Subjects to Treatment Groups and Measures to Minimize/Avoid Bias 
7.4.3.1 
Subject Identification 
Subjects will be identified by a subject number and site number. 
A list identifying the subjects by subject number and site number will be kept in the Trial Master File 
(TMF). 
7.4.3.2 
Randomization 
Subjects who meet all eligibility criteria and who also have ≥80% study medication compliance during the 
2-week placebo run-in phase will be centrally randomized at Visit 3 to receive placebo, 40 mg TMX-049, 
or 200 mg TMX-049 in a 1:1:1 ratio. Randomization will be stratified by sUA (<6.0 vs ≥6.0 mg/dL) and 
UACR (200 to <300 mg/g vs 300 to ≤3000 mg/g) levels obtained at Visit 2. Randomization will be 








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study. 
7.4.7 
Contraception 
Female subjects participating in the study who are of non-childbearing potential will not be required to use 
contraception. Women of non-childbearing potential are defined as permanently sterile (ie due to 
hysterectomy, bilateral salpingectomy, bilateral oophorectomy, or confirmed tubal occlusion) or 
postmenopausal (defined as at least 12 months postcessation of menses without an alternative medical 
cause). Postmenopausal status will be confirmed with a screening serum follicle-stimulating hormone 
(FSH) test. 
Female subjects of childbearing potential will be required to follow contraception requirements from the 
time of signing the ICF until 3 months after the last dose of TMX-049 or placebo. Male subjects and their 
partners of childbearing potential will be required to follow contraception requirements from Visit 2 until 
3 months after the last dose of TMX-049 or placebo. 
Female subjects of childbearing potential must be willing to use a highly effective method of birth control 
(ie contraceptive measure with a failure rate of <1% per year) in conjunction with male contraception 
(ie male condom with spermicide). Highly effective methods of contraception include: 
• 
intrauterine device (IUD; eg Mirena Coil). Steel or copper IUDs are not acceptable. 
• 
established use of oral, injected, or implanted hormonal method of contraception associated with 
inhibition of ovulation. 
• 
male sterilization, with verbal confirmation of surgical success (for female subjects on the study, 
the vasectomized male subjects should be the sole partner for that subject). 
• 
bilateral tubal ligation. 
Male subjects with partners of childbearing potential must use a barrier method of contraception (ie male 
condom with spermicide) in addition to a second method of acceptable contraception used by their female 
partners. In addition to the list of effective contraception methods above, other acceptable methods of 
contraception include: 
• 
established use of progesterone only oral contraception, where inhibition of ovulation is not the 
primary mode of action. 
• 
diaphragm, cap, or sponge in conjunction with spermicide. 
Subjects who practice true abstinence, which must be due to the subject’s lifestyle choice; ie the subjects 
should not become abstinent just for the purpose of study participation, are exempt from contraceptive 
requirements. Periodic abstinence (eg calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception. 
For male subjects, sexual intercourse with female partners who are pregnant or breastfeeding should be 
avoided unless condoms are used from the time of the first dose of TMX-049 or placebo until 3 months 
after the last dose. Male subjects are required to refrain from donation of sperm from Visit 2 until 3 months 
after the last dose of study drug. 
For subjects who are exclusively in same-sex relationships and do not have heterosexual intercourse, 
contraceptive requirements do not apply. However, subjects must not be intending to become pregnant 
during the study. 


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7.4.8 
Treatment Compliance 
Study medication compliance will be assessed following a 2-week placebo run-in phase and only subjects 
with ≥80% study medication compliance will be randomized to receive study treatment in the double-blind 
treatment phase. 
The subject must return the empty packaging as well as the packaging containing unused medication to the 
study site for a compliance check at the visits specified in Table 2. Each site will reconcile the medication 
dispensed and returned by their subjects. 
7.5 
Study Procedures 
7.5.1 
Schedule of Study Procedures 
Study procedures and their timing are summarized in Table 2. The order of the procedures in the sections 
below does not reflect the order in which they will be conducted. 
 
 


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Table 2:  
Schedule of Study Procedures 
 
Screening
 
Single-Blind, 
Placebo, Run-in 
Phase 
 
Double-Blind Treatment Phase 
Follow-up 
 
Visit 1 
Visit 2 
 
Visit 3 
Start of 
study drug
Visit 4 
Visit 5 
Visit 6/ET
Visit 7
Study days and visit window 
guidelines 
Day -42 to 
Day -15 
Day -14 
± 4 days 
Day -14  ± 4 days to 
Day 0 
Day 0 
Day 1 
Day 14 
± 4 days
Day 42 
± 7 days
Day 84 
± 7 days 
Visit 
6/ET+28 ± 7 
days 
Administrative Procedures 
 
 
 
 
 
 
 
 
 
 Informed consent 
X 
 
 
 
 
 
 
 
 
 Assignment of Screening number 
X 
 
 
 
 
 
 
 
 
 Contact IXRS 
X 
X 
 
X 
 
X 
X 
X 
X 
 Check of eligibility based on inclusion/ 
exclusion criteria 
X 
X 
 
X 
 
 
 
 
 
 Assignment of randomization number 
 
 
 
X 
 
 
 
 
 
Pre-visit telephone reminder for urine 
and PK 1 
 
X 
 
X 
 
X 
X 
X 
X 
Trial Compliance 
 
 
 
 
 
 
  
 
 Prior/concomitant medication review 
X 
X 
 
X 
 
X 
X 
X 
X 
 Dispense urine collection supplies 
X 
X 
 
X 
 
X 
X 
X 
 
Investigational Product 
 
 
 
 
 
 
 
 
 
 Dispense study drug (placebo) for 
single-blind run-in 
 
X 
 
 
 
 
 
 
 
 Administration of placebo 
 
 
qd dosing for 2 
weeks 
 
 
 
 
 
 
 Assess single-blind compliance  
 
 
 
X 
 
 
 
 
 
 Dispense double-blind study drug 
(placebo or TMX-049) 
 
 
 
X 
 
X 
X 
 
 
 Administration of TMX-049 or placebo 
 
 
 
 
                 qd dosing for 12 weeks 
 
 Assess double-blind compliance 
 
 
 
 
 
X 
X 
X 
 
Clinical Procedures/Assessments 
 
 
 
 
 
X 
X 
X 
 
 Demographics and medical history 
X 
 
 
 
 
 
 
 
 
 Height 
X 
 
 
 
 
 
 
 
 
 Body weight 
X 
 
 
X 
 
 
X 
X 
X 
 Vital signs (blood pressure2, pulse rate, 
and body temperature) 
X 
X 
 
X 
 
X 
X 
X 
X 
 Physical examination 
 
X 
 
 
 
 
 
X 
 


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Screening
 
Single-Blind, 
Placebo, Run-in 
Phase 
 
Double-Blind Treatment Phase 
Follow-up 
 
Visit 1 
Visit 2 
 
Visit 3 
Start of 
study drug
Visit 4 
Visit 5 
Visit 6/ET
Visit 7
Study days and visit window 
guidelines 
Day -42 to 
Day -15 
Day -14 
± 4 days 
Day -14  ± 4 days to 
Day 0 
Day 0 
Day 1 
Day 14 
± 4 days
Day 42 
± 7 days
Day 84 
± 7 days 
Visit 
6/ET+28 ± 7 
days 
 12-lead ECG 
 
X 
 
 
 
 
 
X 
 
AE monitoring 
X 
X 
X 
X 
 
 
 
 
 
TEAE monitoring 
 
 
 
 
X 
X 
X 
X 
X 
Laboratory Assessment 
 
 
 
 
 
 
 
 
 
 
 UACR3 
X 
 
 
 
 
 
 
 
 
 First morning void UACR  
 
X4 
 
X4,5 
 
X4,5 
X4,5 
X4,5 
X4,5 
Complete blood count (CBC) 
X 
 
 
X 
 
X 
X 
X 
X 
Serum chemistry profile (including sUA 
and serum creatinine to calculate eGFR) 
X 
X 
 
X5 
 
X5 
X5 
X5 
X5 
Serology: HIV, hepatitis B, and 
hepatitis C 
 
X 
 
 
 
 
 
 
 
Thyroid hormones 
 
X 
 
X 
 
X 
X 
X 
X 
Lipid panel 
 
X 
 
X 
 
X 
X 
X 
X 
HbA1c 
X 
 
 
X 
 
 
 
X 
 
Urine pregnancy (females of 
childbearing potential) 
X 
 
 
X 
 
 
 
X6 
X 
FSH (females of non-childbearing 
potential) 
X 
 
 
 
 
 
 
 
 
 Urinalysis 
X 
 
 
X 
 
X 
X 
X 
X 
 Blood and urine samples for 
biomarkers7 
 
 
 
X 
 
X 
X 
X 
X 
 Pharmacokinetic sampling 
 
 
 
 
 
X8
X9
X10
 
Pharmacogenomics sampling 
 
 
 
X11 
 
 
 
 
 
AE = adverse event; CRF = Case Report Form; ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; ET = early termination; FSH = follicle-
stimulating hormone; HbA1c = glycosylated hemoglobin; HIV = human immunodeficiency virus; IXRS = interactive voice/web response system; KIM-1 = 
kidney injury molecule-1; L-FABP = liver fatty acid-binding protein; NAG = N-acetyl-β-D-glucosaminidase; PK = pharmacokinetic; 8-OHdG = 
8-hydroxy-2'-deoxyguanosine; qd = once-daily; sUA = serum uric acid; TEAE = treatment-emergent adverse event; tmax = time of maximum observed plasma 
concentration; UACR = urinary albumin-to-creatinine ratio. 
1Telephone contact around 3 days prior to scheduled visits. 
2Average of triplicate measurements. 
3Urine sample for assessment of UACR to be collected at the study site once subjects have signed the informed consent form. 


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4The average of the 2 consecutive day mid-stream, first-morning void UACR results will be used. The 2 consecutive day first-morning void urine samples will be 
collected at the subject’s home the morning before and the morning of each visit. 
5Results of sUA and UACR will not be reported to Investigators, subjects, and the Sponsor staff. 
6Only Early Termination Visit. 
 
7Urine sample for the analysis of KIM-1, L-FABP, 8-OHdG, and NAG; the mid-stream, first-morning void urine samples collected by the subjects at home will 
be used for the analysis of exploratory biomarkers. Aliquots of serum, plasma, and urine will be stored for potential use in other biomarker assays. 
8At Visit 4, a sample will be obtained prior to TMX-049 dosing (trough sample). The time of PK sample acquisition, the time of dosing prior to the PK sample 
acquisition, and whether the subject took study medication with or without food should be recorded in the CRF. 
9At Visit 5, a sample will be obtained 3 ± 1 hours after study medication dosing (tmax sample). The timing of dosing can be adjusted to the time of visiting. The 
time of PK sample acquisition, the time of dosing prior to the PK sample acquisition, and whether the subject took study medication with or without food should 
be recorded in the CRF. 
10At Visit 6, a sample will be obtained ≥6 hours (the ideal target is ≥8 hours) after study medication dosing (elimination phase sample). If a subject cannot visit 
within the time window, a sample will be obtained when the subject visits, even out of the time window. If the trough sample is not obtained at Visit 4, the trough 
sample should be obtained at Visit 6, instead of the elimination phase sample. If the trough sample is obtained at Visit 4 and tmax sample is not obtained at Visit 5, 
the tmax sample should be obtained at Visit 6, instead of the elimination phase sample. The time of PK sample acquisition, the time of dosing prior to the PK 
sample acquisition, and whether the subject took study medication with or without food should be recorded in the CRF. 
Sites have the option to have a study participant return to the site on a separate day to obtain a properly-timed Visit 4, 5, or 6 sample for PK analysis. 
11Sample will be obtained only from subjects that consent to pharmacogenomics sampling. 
 
See full set of evaluations in Appendix A. 
 
 
 


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7.5.2 
Screening Procedures 
Refer to Table 2 for the timing and frequency of all assessments. The order of the procedures in the 
sections below does not reflect the order in which they will be conducted. 
7.5.2.1 
Screening Visit (Visit 1) Day -42 to Day -15 
The information recorded for all subjects, regardless of their suitability for the study, will be retained and 
archived. The following information and procedures will be recorded and performed for all potential 
subjects as part of the screening assessments: 
• 
informed consent (signed prior to any screening procedures being performed) 
• 
assignment of screening number 
• 
contact IXRS 
• 
confirmation of subject eligibility based on inclusion/exclusion criteria 
• 
complete blood count 
• 
FSH (females of non-childbearing potential) 
• 
demography including sex, race/ethnic origin, age, body mass index, smoking status, and alcohol 
consumption 
• 
medical history (including information obtained from the subject’s general practitioner) 
• 
height, body weight 
• 
urine pregnancy test for female subjects of childbearing potential 
• 
urinalysis and urine sample for UACR (to be obtained at the study site) 
• 
serum chemistry profile (including sUA and serum creatinine to calculate eGFR); see Appendix A 
for the evaluations to be performed 
• 
HbA1c 
• 
adverse event recording 
• 
prior medication review 
• 
vital signs, consisting of supine blood pressure, supine pulse rate, and oral body temperature 
• 
dispense urine collection supplies (for collection of 2 consecutive day mid-stream, first-morning 
void urine samples on the morning before and the morning of Visit 2) 
Single re-testing of laboratory parameters or other assessments may be performed at the Investigator's 
discretion. 
7.5.3 
Single-Blind, Placebo Run-in Phase (Visit 2): Day -14 ± 4 Days 
The following information and procedures will be recorded and performed for all eligible subjects at 


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Visit 2: 
• 
pre-Visit 2 call for reminder of urine collection 
• 
confirmation of subject eligibility based on inclusion/exclusion criteria 
• 
contact IXRS 
• 
urine sample for UACR (2 consecutive day mid-stream, first-morning void urine samples to be 
collected at the subject’s home on the morning before and the morning of Visit 2) 
• 
serum chemistry profile (including sUA and serum creatinine to calculate eGFR); see Appendix A  
for the evaluations to be performed 
• 
viral serologies 
• 
thyroid hormones 
• 
lipid panel 
• 
adverse event recording 
• 
prior/concomitant medication review 
• 
vital signs, consisting of supine blood pressure, supine pulse rate, and oral body temperature 
• 
resting 12-lead ECG 
• 
physical examination 
• 
dispense treatment kit for 2-week placebo run-in 
• 
dispense urine collection supplies (for collection of 2 consecutive day first-morning void urine 
samples on the morning before and the morning of Visit 3) 
• 
before leaving the site, each subject will be given a card to carry at all times in case of an 
emergency outside the site. The card gives details of the study number, start and end date of the 
subject’s involvement in the study, subject details, name of the relevant study physician, and the 
address and telephone number of the site. Subjects may destroy this card 4 weeks after they have 
completed the study 
Single re-testing of laboratory parameters or other assessments may be performed at the Investigator's 
discretion. 
7.5.4 
Treatment Phase Procedures 
7.5.4.1 
Pre- Visit Telephone Call 
Subjects will receive a telephone call around 3 days prior to their scheduled visits to remind the subject to 
collect 2 consecutive mid-stream, first-morning urine samples at home, prior to the day and on the morning 
of the scheduled visits and bring these to the site. Subjects will also be reminded to return their treatment 
kits for a compliance check. During the call, the subject must ONLY be reminded about at-home urine 
collection, returning their treatment kits and dosing before visit. No other questions should be asked and no 
additional conversation should take place. 


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7.5.4.2 
Randomization Visit (Visit 3): Study Day 0 
Subjects who meet all eligibility criteria and who also have ≥80% study medication compliance during the 
2-week placebo run-in phase will be randomized to study treatment at Visit 3. The following information 
and procedures will be recorded and performed at Visit 3 as part of the Baseline assessments: 
• 
pre-Visit 3 call for reminder of urine collection 
• 
subjects who don’t meet eligibility criteria or the criteria of study medication compliance during 
the 2-week placebo run-in phase will be withdrawn from the study 
• 
confirmation of subject eligibility based on inclusion/exclusion criteria 
• 
contact IXRS 
• 
assignment of randomization number 
• 
assessment of treatment compliance during the 2-week run-in period 
• 
urine pregnancy test for female subjects of childbearing potential 
• 
urine sample for UACR (2 consecutive day mid-stream, first-morning void urine samples to be 
collected at the subject’s home on the morning before and the morning of Visit 3) 
• 
complete blood count 
• 
serum chemistry profile (including sUA and serum creatinine to calculate eGFR); see Appendix A 
for the evaluations to be performed 
• 
thyroid hormones 
• 
lipid panel 
• 
HbA1c 
• 
urinalysis 
• 
blood (plasma and serum) and urine sample for biomarkers (the mid-stream, first-morning void 
urine samples collected by the subjects at home will be used for the analysis of biomarkers) 
• 
blood sample for pharmacogenomics (only from subjects that consent to pharmacogenomics 
sampling) 
• 
adverse event recording 
• 
concomitant medication review 
• 
vital signs, consisting of supine blood pressure, supine pulse rate, and oral body temperature 
• 
body weight 
• 
1 study drug treatment kit will be dispensed to the subject 


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• 
dispense urine collection supplies (for collection of 2 consecutive day mid-stream, first-morning 
void urine samples on the morning before and the morning of Visit 4) 
7.5.4.3 
Visit 4: Study Day 14 ± 4 Days 
The following information and procedures will be recorded and performed at Visit 4: 
• 
contact IXRS 
• 
pre-Visit 4 call for reminder of urine collection and not dosing in the morning before the visit 
• 
study drug administration; see Section 7.4.1 
• 
urine sample for UACR (2 consecutive day mid-stream, first-morning void urine samples to be 
collected at the subject’s home on the morning before and the morning of Visit 4) 
• 
complete blood count 
• 
serum chemistry profile (including sUA and serum creatinine to calculate eGFR eGFR); see 
Appendix A for the evaluations to be performed 
• 
thyroid hormones 
• 
lipid panel 
• 
urinalysis 
• 
blood (plasma and serum) and urine sample for biomarkers (the mid-stream, first-morning void 
urine samples collected by the subjects at home will be used for the analysis of biomarkers) 
• 
treatment-emergent adverse event recording 
• 
concomitant medication review 
• 
vital signs, consisting of supine blood pressure, supine pulse rate, and oral body temperature 
• 
PK sampling; see Section 7.7.1 
• 
2 study drug treatment kits will be dispensed to the subject 
• 
dispense urine collection supplies (for collection of 2 consecutive day first-morning void urine 
samples on the morning before and the morning of the subsequent visit) 
• 
assess double-blind compliance 
 
7.5.4.4 
Visit 5: Study Day 42 ± 7 Days 
The following information and procedures will be recorded and performed at Visit 5: 
• 
pre-Visit 5 call for reminder of urine collection and dosing approximately 3 hours before the visit 
before visit 
 
• 
contact IXRS 


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• 
study drug administration; see Section 7.4.1 
• 
urine sample for UACR (2 consecutive day mid-stream, first-morning void urine samples to be 
collected at the subject’s home on the morning before and the morning of Visit 5) 
• 
complete blood count 
• 
serum chemistry profile (including sUA and serum creatinine to calculate eGFR); see Appendix A 
for the evaluations to be performed 
• 
thyroid hormones 
• 
lipid panel 
• 
urinalysis 
• 
blood (plasma and serum) and urine sample for biomarkers (the mid-stream, first-morning void 
urine samples collected by the subjects at home will be used for the analysis of biomarkers) 
• 
treatment-emergent adverse event recording 
• 
concomitant medication review 
• 
vital signs, consisting of supine blood pressure, supine pulse rate, and oral body temperature 
• 
body weight 
• 
PK sampling, see Section 7.7.1 
• 
3 study drug treatment kits will be dispensed to the subject 
• 
dispense urine collection supplies (for collection of 2 consecutive day first-morning void urine 
samples on the morning before and the morning of the subsequent visit) 
• 
assess double-blind compliance 
 
7.5.4.5 
End of Treatment Visit 6: Study Day 84 ± 7 Days or Early Termination Visit  
The following information and procedures will be recorded and performed at Visit 6: 
• 
contact IXRS 
• 
pre-Visit 6 call for reminder of urine collection, dosing in the morning before the visit 
 
• 
dispense urine collection supplies (for collection of 2 consecutive day first morning void urine 
samples on the morning before and the morning of the subsequent visit) 
• 
urine sample for UACR (2 consecutive day mid-stream, first-morning void urine samples to be 
collected at the subject’s home on the morning before and the morning of Visit 6) 
• 
complete blood count 
• 
serum chemistry profile (including sUA and serum creatinine to calculate eGFR); see Appendix A 


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for the evaluations to be performed 
• 
thyroid hormones 
• 
lipid panel 
• 
HbA1c 
• 
urinalysis 
• 
urine pregnancy test for female subjects of childbearing potential (only Early Termination Visit) 
• 
blood (plasma and serum) and urine sample for biomarkers (the mid-stream, first-morning void 
urine samples collected by the subjects at home will be used for the analysis of biomarkers) 
• 
treatment-emergent adverse event recording 
 
• 
concomitant medication review 
• 
vital signs, consisting of supine blood pressure, supine pulse rate, and oral body temperature 
• 
body weight 
• 
resting 12-lead ECG 
• 
physical examination 
• 
PK sampling; see Section 7.7.1 
• 
assess double-blind compliance 
 
7.5.4.6 
End of Study Follow-up (Visit 7): Visit 6/ET+28 ± 7 days 
The following information and procedures will be recorded and performed for all subjects as part of the 
follow-up assessments: 
• 
contact IXRS 
• 
pre-Visit 7 call for reminder of urine collection 
 
• 
urine pregnancy test for female subjects of childbearing potential 
• 
urine sample for UACR (2 consecutive day mid-stream, first-morning void urine samples to be 
collected at the subject’s home on the morning before and the morning of Visit 7) 
• 
complete blood count 
• 
serum chemistry profile (including sUA and serum creatinine to calculate eGFR); see Appendix A 
for the evaluations to be performed 
• 
thyroid hormones 
• 
lipid panel 


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• 
urinalysis 
• 
blood (plasma and serum) and urine sample for biomarkers (the mid-stream, first-morning void 
urine samples collected by the subjects at home will be used for the analysis of biomarkers) 
• 
treatment-emergent adverse event recording 
 
• 
concomitant medication review 
• 
vital signs, consisting of supine blood pressure, supine pulse rate, and oral body temperature 
• 
body weight 
7.5.5 
Procedures for Premature Discontinuation from the Study Treatment Regimen 
At any time, subjects are free to discontinue the IMP without prejudice to further treatment. A subject who 
decides to discontinue the IMP will always be asked about the reason(s) for withdrawal and the presence of 
any AEs. Any such AEs will be followed up and the Medical Monitor should be notified of any ongoing 
AE that may delay treatment or necessitate permanent discontinuation of treatment. Subjects who are 
permanently discontinued from further receipt of IMP, regardless of the reason, will be identified as having 
permanently discontinued treatment. Subjects who are permanently discontinued will be asked to attend an 
early termination visit and an end of study visit for follow-up evaluations (see Table 2). Subjects who 
decline to return to the site for those visits should be contacted by telephone as an alternative. 
7.5.6 
Temporary Discontinuation 
If a subject does not take a dose of study drug within +12 hours of their regular dosing time, then the dose 
of study drug should be skipped and the subject should be instructed to take the study drug at the next 
regularly scheduled time. 
7.5.7 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled visits and 
is unable to be contacted by the study site. The following actions must be taken in relation to a subject who 
fails to attend the site for a required study visit: 
• 
The site must attempt to contact the subject and reschedule the missed visit as soon as possible. 
• 
The site must counsel the subject on the importance of maintaining the assigned visit schedule and 
ascertain whether or not the subject wishes to and/or should continue in the study. 
• 
In cases in which the subject is deemed lost to follow-up, the Investigator must make every effort 
to regain contact with the subject (where possible, 3 telephone calls and, if necessary, a certified 
letter to the subject’s last known mailing address or local equivalent methods). These contact 
attempts should be documented in the subject’s medical record. 
Should the subject continue to be unreachable, only then will he/she be considered to have withdrawn from 
the study with a primary reason of lost to follow-up. 




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7.6.2 
Safety Assessments 
Safety will be monitored throughout the study for all subjects. The analysis of the safety data will be 
performed using the Safety Population. The timings of all measurements to be performed during the study 
may be subject to change based on the ongoing review of the safety, tolerability, efficacy, and PK results. 
All changes will be agreed with the Sponsor and documented in the TMF. The IRB will be notified of the 
changes, if appropriate. 
7.6.2.1 
Adverse Events 
7.6.2.1.1 
Definitions 
The term "adverse event," as used by the Sponsor, is synonymous with the term "adverse experience," 
which is used by the Food and Drug Administration. 
An AE is any untoward, undesired, unplanned clinical event in the form of signs, symptoms, disease, or 
laboratory or physiological observations occurring in a human being participating in a clinical study with a 
Sponsor test article, regardless of causal relationship. This includes the following: 
• 
Any clinically significant worsening of a pre-existing condition. 
Note: Emergence of a new pathogen associated with a clinical event during therapy at a site other than the 
initial site of infection will be considered to be an AE. 
• 
Any recurrence of a historical condition. 
• 
An AE occurring from overdose of a Sponsor study drug whether accidental or intentional (ie a 
dose higher than that prescribed by a health care professional for clinical reasons). 
• 
An AE occurring from abuse of a Sponsor study drug (ie use for non-clinical reasons). 
• 
An AE that has been associated with the discontinuation of the use of a Sponsor study drug. 
Note: A procedure is not an AE, but the underlying cause/reason for a procedure may be an AE. 
A pre-existing condition is a clinical condition (including a condition being treated) that is diagnosed 
before the subject signs the ICF and that is documented as part of the subject’s medical history. 
The questions concerning whether the condition existed before the start of the active phase of the study and 
whether it has increased in severity and/or frequency will be used to determine whether an event is a 
TEAE. An AE is considered to be treatment-emergent if (1) it is not present when the active phase of the 
study begins and is not a chronic condition that is part of the subject’s medical history, or (2) it is present at 
the start of the active phase of the study or as part of the subject’s medical history, but the severity or 
frequency increases during the active phase. The active phase of the study begins at the time of the first 
dose of the study drug. The active phase of the study ends at the follow-up visit. 
7.6.2.1.2 
Reporting of Adverse Events 
At each visit the Investigator, or delegate, will determine whether or not any AEs have occurred. The 
subject will be questioned in a general way and no specific symptoms will be suggested. If any AEs have 
occurred, they will be recorded in the AE section of the CRF and in the subject’s medical records. If 
known, the diagnosis should be recorded, in preference to listing the individual signs and symptoms. 
Adverse event reporting begins from the time of informed consent and ends at the Follow-up Visit 
(Visit 7). For subjects without the Follow-up Visit, the reporting ends 28 days after the last dose of IMP. 


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7.6.2.1.3 
Assessment of Severity 
The Investigator will be asked to provide an assessment of the severity of the AE using the following 
categories: mild, moderate, and severe: 
• 
Mild: Easily tolerated by the subject, causes minimal discomfort, and does not interfere with 
everyday activities. 
• 
Moderate: Sufficiently discomforting to interfere with normal everyday activities; intervention 
may be needed. 
• 
Severe: Prevents normal everyday activities; treatment or other intervention usually needed. 
7.6.2.1.4 
Relationship to Study Treatment 
The Investigator will make a determination of the relationship of the AE to the study drug using a 
2-category system according to the following guidelines: 
• 
Not related: There is not a reasonable possibility the adverse event is related to study drug 
• 
Related: There is a reasonable possibility the adverse event is related to study drug 
7.6.2.1.5 
Follow-up of Adverse Events 
Every reasonable effort will be made to follow-up subjects who have an AE at the follow-up visit, if 
possible, until resolution. 
7.6.2.2 
Serious Adverse Events 
A serious adverse event (SAE) is any AE occurring at any dose that meets 1 or more of the following 
criteria: 
• 
Results in death 
• 
Is life threatening (see below) 
• 
Requires inpatient hospitalization or prolongation of an existing hospitalization (see below) 
• 
Results in a persistent or significant disability or incapacity (see below) 
• 
Results in a congenital anomaly or birth defect 
• 
Results in another important medical event (see below). 
Additionally, important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they may 
jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed above. Examples of such events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias, or convulsions that do not require hospitalization, or 
development of drug dependency or drug abuse. 
A life-threatening adverse event is any AE that places the subject at immediate risk of death from the 
event as it occurred. A life-threatening event does not include an event that might have caused death had it 
occurred in a more severe form but that did not create an immediate risk of death as it actually occurred. 
For example, drug-induced hepatitis that resolved without evidence of hepatic failure would not be 
considered life threatening, even though drug-induced hepatitis of a more severe nature can be fatal. 
Hospitalization is to be considered only as an overnight admission. 




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within 24 hours of being notified of the pregnancy. Details of the pregnancy will be reported on a 
pregnancy report form. The subject or partner of a subject shall receive any necessary counselling 
regarding the risks of continuing the pregnancy and the possible effects on the fetus. Monitoring of the 
subject or the partner of a subject will continue until the conclusion of the pregnancy, and the outcome of 
the pregnancy will be reported to the Sponsor. 
7.6.2.4 
Vital Signs 
Supine blood pressure, supine pulse rate, and oral body temperature will be measured at the times indicated 
in the Schedule of Assessments (Table 2). Subjects must be supine for at least 5 minutes before blood 
pressure and pulse rate measurements. 
Vital signs will also be performed at other times if judged to be clinically appropriate or if the ongoing 
review of the data suggests a more detailed assessment of vital signs is required. 
Blood pressure measurements will be performed in triplicate at approximately 2-minute intervals. Pulse 
rate measurements will be performed singly and repeated once if outside the relevant clinical reference 
ranges. If repeated, the repeat value will be used in the data analysis. Site reference ranges will be applied 
to all vital sign determinations. 
Oral body temperature will be measured singly using a digital thermometer. 
7.6.2.5 
12-Lead Electrocardiogram 
A single 12-lead resting ECG with a 10-second rhythm strip will be recorded after the subject has been 
supine for at least 5 minutes at the times indicated in the Schedule of Assessments (Table 2). The 12-lead 
ECG will be repeated once if either of the following criteria apply: 
• 
The QTcF is >500 msec 
• 
The QTcF change from the Baseline is >60 msec. 
If repeated, the repeat values will be used for data analysis. 
Additional 12-lead ECGs will be performed at other times if judged to be clinically appropriate or if the 
ongoing review of the data suggests a more detailed assessment of ECGs is required. 
An Investigator will perform a clinical assessment of each 12-lead ECG. Site reference ranges will be 
applied to all ECG parameters determined throughout the study. 
The ECG machine will compute the PR and QT intervals, QTc, QRS duration, and heart rate. The QTcF 
will also be calculated. 
7.6.2.6 
Clinical Laboratory Evaluations 
Blood and urine samples will be collected for clinical laboratory evaluations at the times indicated in the 
Schedule of Assessments (Table 2). 
Additional clinical laboratory evaluations will be performed at other times if judged to be clinically 
appropriate or if the ongoing review of the data suggests a more detailed assessment of clinical laboratory 
safety evaluations is required. 
An Investigator will perform a clinical assessment of all clinical laboratory data. 
The evaluations to be performed are listed in Appendix A. 




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7.8 
Pharmacogenetic/Pharmacogenomics Testing 
From subjects that consent to pharmacogenetic/pharmacogenomics sampling, a whole blood sample will be 
collected at Visit 3 and shipped to the Sponsor for possible future pharmacogenetic/pharmacogenomics 
testing. These samples may be used to explore the relationship between response to TMX-049 and 
pharmacogenomics differences. Pharmacogenetic testing will be limited to the genome biomarkers related 
to the response to TMX-049. 
If the subject withdraws consent to long term storage and pharmacogenetic/pharmacogenomics testing, the 
Investigator will inform the Sponsor in writing and the Sponsor will destroy the sample. Samples will be 
de-identified by assigning a number other than the subject’s study number. 
The laboratory performing the testing will not be able to identify the study or the subject in any way. 
Samples will be stored for an indefinite period until the study drug is approved or drug development is 
ceased, whichever comes sooner. At this time, the Sponsor will be contacted and samples will be destroyed. 
The individual subject results of the analysis will not be reported to the subject, relatives, or attending 
physician and will not be included in the subject’s medical record. There will be no follow-up contact with 
subjects regarding this data. 
7.9 
Data Quality Assurance 
The Sponsor performs quality control and assurance checks on all clinical studies that it sponsors. Before 
enrolling any subjects in this study, the Sponsor or Sponsor’s designee personnel and the Investigator will 
review the protocol, the brochure for clinical Investigators, the CRFs and instructions for their completion 
and return, the procedure for obtaining informed consent, and the procedure for reporting AEs and SAEs. A 
qualified representative of the Sponsor will monitor the conduct of the study, and CRFs will be verified 
against source documents. The Medical Monitor will review the data for safety information. Clinical data 
associates from the Sponsor’s representative will review the data for completeness and logical consistency. 
Additionally, the clinical data associates will use automated validation programs to help identify missing 
data, selected protocol violations, out-of-range data, and other data inconsistencies. Requests for data 
clarification or correction will be electronically provided to the investigative site for resolution. Clinical 
data associates will assure that corrections have been applied properly. 
7.10 
Statistical Methods 
The statistical analysis plan will be developed and finalized before database lock and will describe the 
selection of subjects to be included in the analyses, and procedures for accounting for missing, unused, and 
spurious data. Below is a summary of planned statistical analyses of the outcome measures for this study. 
7.10.1 
Determination of Sample Size 
Approximately 132 subjects will be randomized at a 1:1:1 ratio to each of the 3 treatment groups (40 mg 
TMX-049, 200 mg TMX-049, and placebo). Assuming that 10% of all randomized subjects will not be 
included in the primary endpoint analysis, this would result in approximately 40 subjects per treatment 
group for inclusion in the primary endpoint assessment. 
A sample size of 40 per group will have more than 80% power on the primary endpoint assessment to 
detect a difference in means of 35% reduction (-0.431 for log-transformed value) of UACR assuming that 
the common standard deviation (SD) is 0.670 (log-scale) using a 2-group t-test with a 0.050 two-sided 
significance level. 
7.10.2 
Subject Populations Analyzed 
The All Subjects Population will consist of any subjects who enrolled in the study (signed informed 
consent) and had study assessments recorded on the database as per the protocol. 


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The Safety Population will consist of all randomized subjects who received at least one study medication 
tablet or capsule. 
The Modified Intention-to-Treat (mITT) Population will be used for the efficacy analysis and will 
consist of all subjects according to their randomization scheme regardless of whether they experienced 
protocol deviations. The last post randomization UACR will be carried forward (LOCF) for subjects who 
did not have a Week 12 UACR determination. Randomized subjects with no post randomization UACR 
will be excluded from the mITT analysis. 
The Per Protocol Population will be used as a sensitivity analysis for the primary efficacy endpoint and 
will consist of all subjects according to their randomization scheme who experienced no major protocol 
deviations. 
The PK Population will consist of all subjects who received at least one dose of TMX-049 and have 
evaluable PK data. 
All protocol deviations that occur during the study will be considered prior to database lock for their 
severity/impact and will be taken into consideration when subjects are assigned to analysis populations. 
Details of subject assignment to the analysis populations will be listed. 
Efficacy will be analyzed using the mITT Population (primary analysis) and the Per Protocol Population 
(supportive analysis), and safety will be analyzed using the Safety Population. Changes from Baseline will 
utilize values obtained at Visit 3 (the randomization visit) except for the change from baseline in UACR. 
7.10.3 
General Statistical Considerations 
Data will be summarized using descriptive statistics and include mean, SD, median, minimum, maximum, 
and corresponding number of subjects (n). For log-transformed data, the geometric mean and geometric 
coefficient of variation will be provided. For categorical variables, the number and percent in each category 
will be presented. Tables will include the placebo group and each of the TMX-049 dose groups and a 
separate category that combines all TMX-049 dose groups. 
7.10.4 
Efficacy Analysis 
7.10.4.1 
Efficacy Endpoints 
The primary efficacy endpoint for this study is: 
• 
Change from Baseline to Week 12 in log-transformed UACR 
The secondary efficacy endpoints for this study are: 
• 
Proportion of subjects with >30% reduction from Baseline to Week 12 in UACR 
• 
Change in eGFR (Baseline compared to each post-treatment assessment) 
• 
Change in UACR (Baseline compared to each post-treatment assessment) 
• 
Change in renal biomarkers (Baseline compared to each post-treatment assessment) 
• 
Change in sUA (Baseline compared to each post-treatment assessment) 
7.10.4.2 
Statistical Analysis of Efficacy 
The UACR values from the 2 consecutive day mid-stream, first morning void urine samples that are 


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submitted at Visits 2 to 7 will be based on the mean result of measurements in each of the paired samples. 
If only one sample is available, the results from that sample will be used. 
The change from Baseline to Week 12 (or the LOCF) in log-transformed UACR will be analyzed in an 
analysis of covariance model with a fixed effect for treatment, baseline log-transformed UACR and 
baseline serum uric acid as covariates. The least squares mean, p-value, and the corresponding 95% CI for 
the treatment difference will be provided. The last post randomization UACR will be carried forward 
(LOCF) for subjects who did not have a Week 12 UACR determination. 
To analyze the effect of LOCF on missing data, the above analysis will be repeated using a mixed model 
repeated measures approach and an observed case analysis. The statistical model will feature a repeated 
statement and include treatment, timepoint, and treatment-by-timepoint interaction as fixed effects, baseline 
as a covariate, and subject as a random effect. 
The above analysis of covariance model and repeated measures models will also be used to analyze the 
secondary endpoints, change in eGFR, change in UACR, change in sUA, and change in renal biomarkers at 
each post-treatment assessment. The proportion of subjects with >30% reduction from Baseline to Week 12 
in UACR will be analyzed using a Fisher’s exact test and logistic regression. 
7.10.4.3 
Safety Endpoints 
The safety endpoints for this study are: 
• Proportion of subjects with reported AEs, discontinuation due to AEs or SAEs 
• Proportion of subjects with AEs considered by the Investigator to be related to study medication 
• Proportion of subjects with mild, moderate, or severe AEs as assessed by the Investigator 
• Changes in vital signs, ECGs, and laboratory parameters 
7.10.4.4 
Statistical Analysis of Safety 
Safety evaluation will include incidence of AEs (or TEAEs), laboratory test results, vital signs, ECG 
results, and physical examination findings. All summaries of safety data will be based on the Safety 
Population. No formal statistical analysis of the safety data will be performed. There will be safety 
summary tables produced and no modeling of data. 
Summary tables will be provided for all AEs by treatment group. The incidence of AEs, AEs related to 
study medication, SAEs, and AEs leading to discontinuation of the study treatment will be presented by 
MedDRA (Medical Dictionary for Regulatory Activities) system organ class (SOC) and preferred term. In 
addition, the incidence of AEs by severity will be presented by SOC and preferred term. 
The AE summary tables will include counts of subjects. Therefore, if a subject experiences more than 
1 episode of a particular AE, the subject will be counted only once for that event. If a subject has more than 
1 AE that is coded to the same preferred term, the subject will be counted only once for that preferred term. 
Similarly, if a subject has more than 1 AE within a SOC, the subject will be counted only once in that SOC. 
Laboratory test variables will be summarized by treatment group and visit using descriptive statistics 
(number of subjects, mean, SD, minimum, median, maximum, as well as mean change from Baseline, and 
number and percent of subjects within specified categories). Shift tables (ie cross-tabulations of below the 
lower limit of the normal range, within the limits of the normal range and above the upper limit of the 
normal range at Baseline versus scheduled visits) will be presented by laboratory test. Laboratory tests with 
categorical results that cannot be analyzed by change from Baseline or shift table analysis will not be 
included in these summaries, but will be listed. Data obtained from laboratory tests not required by the 


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protocol will not be summarized, but will be listed. 
Descriptive statistics of vital signs and ECG results at each visit will be presented by treatment group. 
Physical examination findings will be listed for each subject. 
No inferential safety statistical analysis will be performed. 
7.10.5 
Pharmacokinetic Analysis 
Pharmacokinetic samples that are obtained at Visits 4, 5, and 6 will be used to assess TMX-049 plasma 
concentrations and be used in a population PK analysis. Results will be summarized in each of the 
TMX-049 treatment groups. 
TMX-049 plasma concentrations will be listed and summarized. 
7.10.6 
Interim Analysis 
No formal interim analysis is planned for this study. 








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involve extra time and cost. 
9.11 
Reports to the Ethics Committee and Regulatory Authorities 
Upon completion of the study, the Investigator will provide the IRB with a summary of its outcome. 
The relevant regulatory authorities will be provided with a Declaration of the End of a Clinical Trial form 
and safety report (or local equivalent) within 90 days of completion or within 15 days of a premature 
termination. These will also be provided to the IRB. 
9.12 
Confidentiality 
All unpublished information that the Sponsor gives to the Investigator shall be kept confidential and shall 
not be published or disclosed to a third party without the prior written consent of the Sponsor. 
When the Sponsor generates reports for presentations to regulatory agencies, one or more of the 
Investigators who has/have contributed significantly to the study will be asked to endorse the final report. 
The endorsement is required by some regulatory agencies. 
The Investigator shall not make a patent application based on the results of this study and shall not assist 
any third party in making such an application without the written authorization of the Sponsor unless 
otherwise specified in the Clinical Study Agreement. 
The subject must be informed that his/her personal study related data will be used by the Sponsor in 
accordance with the local data protection law. The level of disclosure must also be explained to the subject. 
9.13 
Records Retention 
The Investigator must maintain all study documentation as confidential, and take measures to prevent 
accidental or premature destruction of these documents. 
 
The Investigator must retain the study documents until at least 2 years after the last approval of a marketing 
application/new drug application for the indication investigated or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product (eg the Investigational New 
Drug application is withdrawn). These documents should be retained for a longer period, however, if 
required by the applicable regulatory requirements or by an agreement with the Sponsor. 
 
The Investigator must notify the Sponsor prior to destroying any study essential documents. 
 
If the Investigator can no longer ensure archiving, he/she shall inform the Sponsor. The relevant records 
shall be transferred to a mutually agreed upon designee. 
9.14 
Publications 
The Sponsor holds all publication rights to the data obtained from this study. Before any data from this 
study are published on the initiative of the Investigator, the Investigator should obtain written approval 
from the Sponsor. A manuscript will be sent to the Sponsor for review and written approval at least 60 days 
prior to submission to the publisher, and according to any additional publication details in the Investigator 
Agreement. 
9.15 
Subject Injury 
In general, if a subject is injured as a direct result of the study drug, the Sponsor will pay for reasonable and 
necessary medical treatment for the injury, to the extent the expenses are not covered by the subject’s 
medical insurance, a government program, or other responsible third party. If laws or regulations of the 


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TMX-049 
 
 
Final Version 2.0 (07 February 2018) 
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locality in which the trial is taking place require additional payment of expenses, the Sponsor shall comply 
with such law or regulation. Where applicable, the Sponsor has taken specific national insurance. 


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TMX-049 
 
 
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10. 
REFERENCES 
1. Neogi T. Clinical practice: gout. N Engl J Med. 2011; 364 (5):443-452. 
2. Thomas M C, Cooper ME, Zimmet P. Changing epidemiology of type 2 diabetes mellitus and 
associated chronic kidney disease. Nat Rev Nephrol. 2016; 12 (2): 73-81. 
3. Jha V, Garcia-Garcia G, Iseki K, Li Z, Naicker S, Plattner B, Saran R, Wang AY, Yang CW. Chronic 
kidney disease: global dimension and perspectives. Lancet. 2013;  382(9888): 260-272. 
4. National Institute of Diabetes and Digestive and Kidney Diseases, Kidney Disease Statistics for the 
United States.Prevalence. Available at https://www.niddk.nih.gov/health-information/health 
statistics/kidney-disease. Accessed October 23, 2017. 
5. Tanaka K, Hara S, Hattori M, Sakai K, Onishi Y, Yoshida Y, Kawazu S, Kushiyama A. Role of 
elevated serum uric acid levels at the onset of overt nephropathy in the risk for renal function decline 
in patients with type 2 diabetes. J Diabetes Investig. 2015; 6(1): 98-104. 
6. Wakai K, Nakai S, Kikuchi K, Iseki K, Miwa N, Masakane I, Wada A, Shinzato T, Nagura Y, Akiba 
T.. Trends in incidence of end-stage renal disease in Japan, 1983-2000: age-adjusted and age-specific 
rates by gender and cause. Nephrol Dial Transplant. 2004; 19(8): 2044-2052. 
7. Zhu P, Liu Y, Han L, Xu G, Ran JM. Serum uric acid is associated with incident chronic kidney 
disease in middle-aged populations: a meta-analysis of 15 cohort studies. PLoS One. 2014; 9(6): 
e100801. 
8. Goicoechea M, de Vinuesa SG, Verdalles U, Ruiz-Caro C, Ampuero J, Rincón A, Arroyo D, Luño J. 
Effect of allopurinol in chronic kidney disease progression and cardiovascular risk. Clin J Am Soc 
Nephrol. 2010; 5(8): 1388-1393. 
9. Sircar D, Chatterjee S, Waikhom R, Golay V, Raychaudhury A, Chatterjee S, Pandey R. Efficacy of 
Febuxostat for Slowing the GFR Decline in Patients With CKD and Asymptomatic Hyperuricemia: A 
6-Month, Double-Blind, Randomized, Placebo-Controlled Trial. Am J Kidney Dis. 2015; 66(6): 
945-950. 
10. Hosoya T, Ohno I, Nomura S, Hisatome I, Uchida S, Fujimori S, Yamamoto T, Hara S. Effects of 
topiroxostat on the serum uric acid levels and urinary albumin excretion in hyperuricemic stage 3 
chronic kidney disease patients with or without gout. Clin Exp Nephrol. 2014; 18(6): 876-884. 
11. TMX-049 [Investigator’s Brochure]. Teijin America, Inc. Version 4.0, 31 Oct 2017. 
 
 
 


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11. 
APPENDICES 
Appendix A - Clinical Laboratory Evaluations 
aAt Visits 1, 3, and 6 only 
b At Visits 2, 3, 4, 5, 6, and 7 only 
c At Visits 1, 3, 4, 5, 6, and 7 only 
d Females of childbearing potential only, at Visits 1, 3, 6 (Early Termination Visit only), and 7. Positive 
pregnancy result will result in hormone panel analyzed in serum 
e Postmenopausal females at Visit 1 only 
f Only analyzed at Visit 2 
g HIV1/2 antibody test 
h Results at Visits 3, 4, 5, 6, and 7 will not be reported to Investigators, subjects, and the Sponsor staff. 
Investigators must not measure UACR or sUA at local sites 
i At Visits 3, 4, 5, 6, and 7 only. These values are corrected with urinary creatinine. 
Serum Chemistry: 
Complete Blood Countc 
Aspartate aminotransferase (AST) 
White blood cell count (WBC) 
Alanine aminotransferase (ALT) 
Red blood cell count (RBC) 
Alkaline phosphatase 
Hemoglobin 
Gamma glutamyl transferase (GGT) 
Hematocrit (PCV) 
Lactate dehydrogenase (LDH) 
Mean cell volume (MCV) 
Sodium 
Mean cell hemoglobin (MCH) 
Potassium 
MCH concentration (MCHC) 
Chloride 
Platelet count 
Calcium 
Differential WBC 
Bicarbonate 
Urinalysisc: 
Inorganic phosphate 
Microscopic examination 
Glucose 
Specific gravity 
Urea 
pH 
Uric acid (sUA)h 
Protein 
Total bilirubin 
Glucose 
Direct bilirubin 
Ketones 
Creatinine 
Blood 
Blood urea nitrogen (BUN) 
Urobilinogen 
Total protein 
 
Albumin 
For Females Only: 
Creatinine phosphokinase (CPK) 
Urine pregnancy testd 
Glycosylated hemoglobin (HbA1c)a 
 
 
For Postmenopausal Females Only: 
Lipid Panelb: 
Follicle-stimulating hormone (FSH) e 
Total cholesterol 
Serologyf: 
High-density lipoprotein cholesterol (HDL-C) 
Hepatitis B surface antigen (HBsAg) 
Hepatitis C antibody 
Human immunodeficiency virus (HIV)g 
non-HDL-C 
Thyroid Testingb: 
Urinary Biomarkers: 
Triiodothyronine (T3) 
Urinary albumin-to-creatinine ratio (UACR)h 
Thyroxine (T4) 
Kidney injury molecule 1 (KIM-1)i 
Free triiodothyronine (FT3) 
Liver fatty acid binding protein (L-FABP) i 
Free thyroxine (FT4) 
Thyrotropin/Thyroid stimulating hormone (TSH) 
8 hydroxy 2' deoxyguanosine (8-OHdG) i 
N-acetyl-β-D-glucosaminidase (NAG) i 
 
Blood Biomarkers: 
Soluble tumor necrosis factor receptor 1 
(sTNFR1) i 
 
high sensitivity C reactive protein; (hs-CRP) i 
 
Estimated glomerular filtration rate (eGFR)  







SAP_003.pdf: 
Cover page 
 
Statistical Analysis Plan 
 
Study ID: TMX-049DN-201 
Study Title: A Randomized, Placebo-Controlled, Double-Blind, 
Multicenter, Phase 2 Study to Assess Safety, Tolerability, 
and Renal Effects of TMX-049 in Subjects With Type 2 
Diabetes and Albuminuria 
NCT No.: 03449199 
 
Teijin America, Inc. 


 
 
 
ST-AD-008 version 04 
18 September 2017 
Statistical Analysis Plan 
 
Teijin America, Inc. 
TMX-049DN-201 
 
 
 
Document Version: Amendment 1 Final Version 1.0 
Document Date: April 12, 2019 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan  
Teijin America, Inc.                                                                                                                          
TMX-049DN-201                                                                          
  
 
 
 
 
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Table of Contents 
1. 
Source Documents ................................................................................. 7 
2. 
Protocol Details ..................................................................................... 7 
2.1 
Study Objectives................................................................................. 7 
2.2 
Overall Study Design ........................................................................... 7 
2.3 
Sample Size and Power ....................................................................... 9 
3. 
Efficacy and Safety Variables................................................................. 10 
3.1 
Primary Efficacy Endpoint(s)............................................................... 10 
3.2 
Secondary Efficacy Endpoints ............................................................. 10 
3.3 
Safety Variables................................................................................ 10 
4. 
Pharmacokinetic/Pharmacodynamic variables .......................................... 10 
5. 
Analysis populations ............................................................................. 10 
5.1 
All Subjects Population ...................................................................... 11 
5.2 
Randomized Population ...................................................................... 11 
5.3 
Safety Population .............................................................................. 11 
5.4 
Modified Intent-to-treat Population ..................................................... 11 
5.5 
Per-Protocol Population ...................................................................... 11 
5.5.1 
Important Protocol Deviations Leading to Exclusion from the Per-Protocol Population ... 12 
5.6 
Pharmacokinetic Population ................................................................ 13 
6. 
DATA Handling .................................................................................... 13 
6.1 
Time points and Visit Windows ........................................................... 13 
6.2 
Handling of Dropouts, Missing Data, and Outliers .................................. 13 
6.2.1 
Observed Cases Datasets .................................................................................................... 14 
7. 
Statistical Methods ............................................................................... 15 
7.1 
General Principles ............................................................................. 15 
7.2 
Subject Disposition and Data Sets Analyzed ......................................... 15 
7.3 
Protocol Deviations ........................................................................... 16 
7.4 
Demographics and Other Baseline Characteristics ................................. 16 
7.4.1 
Medical History ................................................................................................................... 17 
7.4.2 
Previous and Concomitant Medications ............................................................................. 17 
7.5 
Treatment Compliance and Exposure ................................................... 18 


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Teijin America, Inc.                                                                                                                          
TMX-049DN-201                                                                          
  
 
 
 
 
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7.6 
Efficacy ............................................................................................ 18 
7.6.1 
Primary Efficacy Analysis ..................................................................................................... 18 
7.6.2 
Secondary Efficacy Analysis ................................................................................................ 19 
7.6.3 
Sensitivity Analysis .............................................................................................................. 20 
7.6.4 
Subgroup Analysis ............................................................................................................... 20 
7.6.5 
Secondary Efficacy Endpoints Analysis ............................................................................... 21 
7.7 
Safety ............................................................................................. 23 
7.7.1 
Adverse Events .................................................................................................................... 23 
7.7.2 
Laboratory Evaluations ....................................................................................................... 24 
7.7.3 
Vital Signs ............................................................................................................................ 26 
7.7.4 
Electrocardiograms ............................................................................................................. 27 
7.7.5 
Physical Examination ........................................................................................................... 27 
7.8 
Pharmacokinetic Analysis ................................................................... 27 
7.9 
Interim Analysis................................................................................ 28 
8. 
Changes in Planned Analysis ................................................................. 28 
9. 
References .......................................................................................... 29 
 
 
 










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Teijin America, Inc.                                                                                                                          
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measurements, a standard 12-lead electrocardiogram (ECG), provide blood samples 
for repeat eGFR, and submit 2 consecutive day mid-stream first-morning void urine 
samples for Baseline UACR determination for confirmation of eligibility. Subjects will 
be given study medication to be used during a single-blind, placebo run-in phase 
and instructed to return their study medication to the site at Visit 3. All pre-
randomization study visits will be completed in ≤6 weeks. Study medication will be 
self-administered by the subject qd. Study medication should be taken in the 
morning at about the same time each day, and taken with food (breakfast or a 
snack) rather than on an empty stomach beginning on the day after Visit 2. 
Subjects who meet all eligibility criteria, including UACR 200 to 3000 mg/g and 
eGFR ≥30 ml/min/1.73m2 at both Visit 1 and Visit 2 and who also have ≥80% 
study medication compliance during the 2-week placebo run-in phase, will be 
randomized at Visit 3 in a 1:1:1 ratio to 1 of 3 treatment groups: Placebo, 40 mg of 
TMX-049, or 200 mg of TMX-049. Approximately 132 subjects will be randomized, 
with the expectation that 40 subjects per treatment group will complete 12 weeks 
of treatment and be included in the primary endpoint assessment. Randomization 
will be stratified by sUA (<6.0 versus ≥6.0 mg/dL) and UACR (200 to <300 mg/g 
versus 300 to ≤3000 mg/g) levels obtained at Visit 2. Study medication will be self-
administered by the subject qd in the morning at about the same time each day 
and taken with food (breakfast or a snack), rather than on an empty stomach 
during the randomized treatment phase beginning on the day after Visit 3 and 
continued until the morning prior to Visit 6. The time of dosing and time of any food 
intake will remain consistent during the period of randomized treatment. 
Randomized study subjects will return to the site after 2 (Visit 4), 6 (Visit 5), and 
12 weeks (Visit 6) of double-blind treatment. Study medication compliance will be 
assessed by pill count at each visit. First-morning void urine samples will be 
collected on 2 consecutive days prior to each visit. Urine and blood samples for 
determination of eGFR, sUA levels, and other laboratory tests will be obtained prior 
to and after initiation of randomized treatment. Results of sUA and UACR will not be 
reported to Investigators, subjects, and the Sponsor staff during the randomized 
treatment phase of the study. The time of PK sample acquisition, the time of dosing 
prior to the PK sample acquisition, and whether the subject took study medication 
with or without food will be recorded in the appropriate sections of the case report 
form (CRF) based on verbal communications with the subjects. 
At Visit 4, a sample will be obtained prior to TMX-049 dosing (trough sample). At 
Visit 5, a sample will be obtained 3 ± 1 hours after study medication dosing (tmax 
sample). The timing of dosing can be adjusted to the time of visiting. At Visit 6, a 
sample will be obtained ≥6 hours (the ideal target is ≥8 hours) after study 
medication dosing (elimination phase sample). If a subject cannot visit within the 


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Teijin America, Inc.                                                                                                                          
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time window, a sample will be obtained when the subject visits, even out of the 
time window. If the trough sample is not obtained at Visit 4, the trough sample 
should be obtained at Visit 6, instead of the elimination phase sample. If the trough 
sample is obtained at Visit 4 and tmax sample is not obtained at Visit 5, the tmax 
sample should be obtained at Visit 6, instead of the elimination phase sample. Sites 
have the option to have a study participant return to the site on a separate day to 
obtain a properly timed Visit 4, 5, or 6 sample for PK analysis. 
Safety assessment will be based on clinical laboratory evaluations, vital signs, 
physical examinations, and 12-lead ECG, which will be obtained prior to and during 
the period of randomized treatment. 
All study subjects will attend an end of study follow-up Visit (Visit 7) 4 weeks after 
the last dose of study medication. Two consecutive day urine samples for UACR 
determination will be submitted by all subjects at this final visit. Urine and blood 
samples for determination of eGFR, sUA levels, and other laboratory safety tests 
will be obtained at Visit 7 or at Visit 6 (or the Early Termination [ET] Visit). 
The study schema is illustrated below: 
 
2.3 Sample Size and Power 
Approximately 132 subjects will be randomized at a 1:1:1 ratio to each of the 3 
treatment groups (40 mg TMX-049, 200 mg TMX-049, and Placebo). Assuming that 
10% of all randomized subjects will not be included in the primary endpoint 
analysis, this would result in approximately 40 subjects per treatment group for 
inclusion in the primary endpoint assessment. 
A sample size of 40 per group will have more than 80% power on the primary 
endpoint assessment to detect a difference in means of 35% reduction (-0.431 for 


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Teijin America, Inc.                                                                                                                          
TMX-049DN-201                                                                          
  
 
 
 
 
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log-transformed value) of UACR assuming that the common standard deviation 
(SD) is 0.670 (log-scale) using a 2-group t-test with a 0.050 two-sided significance 
level. 
3. Efficacy and Safety Variables 
3.1 Primary Efficacy Endpoint(s) 
The primary efficacy endpoint is the change from Baseline to Study Week 12 (Study 
Visit 6) in log-transformed UACR.  
 
3.2 Secondary Efficacy Endpoints 
The secondary efficacy endpoints include: 
 
 
Proportion of subjects with >30% reduction from Baseline to Study Week 12 
(Study Visit 6)  in UACR 
 
Change in eGFR (Baseline compared to Study Weeks  2, 6, 12/ET, and 
Follow-up visit) 
 
Change in UACR (Baseline compared to Study Weeks 2, 6, 12/ET, and 
Follow-up visit) 
 
Change in renal biomarkers (Baseline compared to Study Weeks 2, 6, 12/ET, 
and Follow-up visit) 
 
Change in sUA (Baseline compared to Study Weeks 2, 6, 23/ET, and Follow-
up visit) 
 
3.3 Safety Variables 
The safety endpoints include: 
 
Proportion of subjects with reported adverse events (AEs), discontinuation 
due to AEs and serious adverse events (SAEs) 
 
Proportion of subjects with AEs considered by the Investigator  to be related 
to study drug 
 
Proportion of subjects with mild, moderate, or severe AEs as assessed by the 
Investigator 
 
Changes from Baseline in vital signs, ECGs, and laboratory parameters  
4. Pharmacokinetic/Pharmacodynamic variables 
The Pharmacokinetic endpoint is the plasma concentrations of TMX-049 at Study 
Weeks 2, 6, and 12/ET. 
5. Analysis populations 
Unless otherwise specified, all efficacy analyses will be performed using the 
modified Intention-to-Treat (mITT) population, all sensitivity analyses will be 


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Teijin America, Inc.                                                                                                                          
TMX-049DN-201                                                                          
  
 
 
 
 
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performed using the Per Protocol (PP) population and safety analyses will use 
Safety population.  Pharmacokinetic (PK) analyses will be performed using the PK 
population. 
 
5.1 All Subjects Population 
All subjects who enrolled in the study, ie, signed informed consent, and had study 
assessments recorded in the database per the protocol will be included in the All 
Subjects population. 
5.2 Randomized Population 
All randomly assigned subjects will be included in the Randomized population.  
Randomized subjects are analyzed according to their randomized treatment. 
5.3 Safety Population 
All randomized subjects who received at least 1 dose of study drug will be included 
in the Safety population. Safety subjects are analyzed according to their actual 
treatment received. 
5.4 Modified Intent-to-treat Population 
The mITT population will consist of all randomized subjects who have at least 1 
post randomization UACR assessment. Subjects in the mITT population will be 
analyzed according to their randomized treatment.  
5.5 Per-Protocol Population 
The PP population will consist of all subjects in the mITT population who do not 
experience any important protocol deviations leading to exclusion from the PP 
population.  Subjects in the PP population will be analyzed according to their 
randomized treatment. 
Protocol deviations are defined as any change, divergence, or departure from the 
study design or procedures defined in the study protocol. Important protocol 
deviations are a subset of protocol deviations and may significantly impact the 
correctness, accuracy, and/or reliability of the study data or that may significantly 
affect a subject’s rights, safety, or well-being. Section 5.5.1 details the deviations. 
All protocol deviations that occur during the study will be considered prior to 
database lock (DBL) for their severity and impact.   




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Teijin America, Inc.                                                                                                                          
TMX-049DN-201                                                                          
  
 
 
 
 
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5.6 Pharmacokinetic Population 
The PK population will consist of all subjects who received at least 1 dose of TMX-
049 and had evaluable PK data. Subjects in the PK population will be analyzed 
according to their actual treatment received. 
6. DATA Handling 
6.1 Time points and Visit Windows 
Day 0 is defined as the Baseline/Randomization visit (Study Visit 3).  Day 1 is the 
first day of treatment. Relative days after Day 1 are calculated as (assessment date 
– Day 1 date) + 1.  Relative days prior to Day 1 are calculated as (assessment date 
– Day 1 date). 
The visit windows defined in the following table will be used for the by-visit 
analyses of the primary, the secondary and other endpoints.  All other analyses will 
use the nominal study visit as defined in the study schedule and eCRF. 
If there are multiple visits (scheduled or unscheduled) within a visit window, the 
measurement closest to the target day of the visit will be used in the analysis. If 
the measurements are equally distant to the target day, then the later one will be 
used in the analysis. 
 
Time Point 
(Target Study Day) 
Study Day 
Range for 
UACR* 
Study Day Range for 
Serum Chemistry, 
Hematology, Lipid 
Panel, Urinalysis, Blood 
and Urine Samples for 
Biomarkers, Vital Signs 
Study Day 
Range for 
ECG, 
Physical 
Examination 
Study Day 
Range for 
HbA1C 
Baseline 
≤ 1 
≤ 1 
< 1 
≤ 1 
Week 2 (Day 14) 
2 – 21 
2 - 21 
 
 
Week 6 (Day 42) 
22 – 63 
22 - 63 
 
 
Week 12/ET (Day 84) 
64 – 104 
64 – 104 
≥ 1 
> 1 
Week 12/ET + 28 
Days (Day 112) 
≥ 105 
≥ 105 
 
 
*: This is for the first morning void UACR sample collection. 
 
6.2 Handling of Dropouts, Missing Data, and Outliers 
Missing data will not be imputed for safety analyses. The safety evaluations will be 
performed on observed data only. 
For AEs with partial or missing onset or stop dates: 


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Teijin America, Inc.                                                                                                                          
TMX-049DN-201                                                                          
  
 
 
 
 
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AE stop date will be imputed first as: 
 
If stop date is complete missing, assume it is ongoing (no imputation); 
 
For a partial AE stop date (day is missing, or both day and month are 
missing): December 31st if both day and month are missing, or last day of 
the month if only day is missing. 
Then AE onset date will be imputed as: 
 
If onset date is complete missing: the first dose date; 
 
For a partial AE onset date (day is missing, or both day and month are 
missing): 
 Partial date < the first dose date: December 31st, or last day of the 
month 
 Partial date = the first dose date: the first dose date 
 Partial date > the first dose date: January 1st if both day and month 
are missing, or first day of the month if only day is missing. 
If the imputed AE onset date is after the AE stop date/imputed AE stop date, then 
the onset date will be set to the AE stop date/imputed AE stop date. 
The imputed dates will not be listed. Study day relative to the first dose of double-
blind study drug associated with missing or partial dates will not be displayed in AE 
listings. 
In the event that a partial date (month/year or year) for concomitant medication is 
available, this information will be used as follows: 
 
When both month and year are available – first day of the month will be used 
for start date and the last day of the month will be used for the stop date. 
 
When only year is available – January 1st will be used for the start date and 
December 31th will be used for the stop date. 
The imputed dates will only be used to determine whether a concomitant 
medication will be classified as prior medication or concomitant medication. 
6.2.1 Observed Cases Datasets 
Mixed-effects model for repeated measurements (MMRM) will be performed based 
on a missing at random (MAR) assumption using data actually observed - observed 
cases (OC) dataset. OC datasets will be used for analysis of the primary efficacy as 
well as all secondary efficacy endpoints. This dataset will not impute any values for 
missing observations. 


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Teijin America, Inc.                                                                                                                          
TMX-049DN-201                                                                          
  
 
 
 
 
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7. Statistical Methods 
7.1 General Principles 
All data processing, summarization and analyses will be performed using the Hosted 
SAS (d-Wise) Environment / Version 9.4 (or later) of the SAS (SAS Institute, Cary, 
NC) statistical software package. 
Unless specified otherwise, data will be displayed using the following treatment 
group labels, in the order presented: 
 
Placebo 
 
TMX-049 40 mg QD 
 
TMX-049 200 mg QD 
 
TMX-049 Overall 
All data collected will be presented in listings by treatment group, center, subject, 
and visit (where applicable), unless otherwise specified. 
Data will be presented in summary tables by treatment group, assessment, and 
visit (where applicable). 
The category “Missing” will be presented if the number missing is greater than zero 
for at least 1 treatment group. 
Descriptive summary statistics for continuous variables will include the number of 
observations (N), mean, standard deviation (SD), median, minimum, and 
maximum. For UACR of original scale, the geometric mean, geometric coefficient of 
variation (CV), and CV will also be provided. 
Descriptive summary statistics for categorical variables will include frequency 
counts and percentages [n (%)]. Unless stated otherwise in the table shells, the 
denominator for percentage calculations will be the number of subjects in the 
pertinent analysis population. 
Dates will be displayed as DDMMMYYYY. 
Analysis and summarization of treatment group comparisons for the primary and 
secondary efficacy endpoints will be reported in their original measurement units 
and converted values to accommodate regulatory review by FDA and external 
authorities, where appropriate. 
All significance tests will be 2-sided and use a 0.05 α-level. 
 
7.2 Subject Disposition and Data Sets Analyzed 
Subject disposition will be listed and summarized by treatment group, and will 
include the number and percentage of subjects: 
• Screened 
• Entered single-blind Placebo run-in period 
• Discontinued single-blind Placebo run-in period 


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Teijin America, Inc.                                                                                                                          
TMX-049DN-201                                                                          
  
 
 
 
 
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• Randomized 
• Treated 
• Included in each study population (All subjects, Randomized, mITT, Safety, PP, 
and PK) 
The number and percentage of subjects who complete the study and those who 
discontinue early (including a breakdown of the primary reasons for 
discontinuation), will be presented for the subjects randomized in each treatment 
group. 
A summary of subject enrollment by site will be provided by treatment group and 
overall. A summary of subject randomized by randomization strata (sUA and UACR 
levels) will also be provided by treatment group. 
 
7.3 Protocol Deviations 
All the important protocol deviations leading to exclusion from the PP population 
will be listed and summarized by treatment group for the mITT population. 
 
7.4 Demographics and Other Baseline Characteristics 
Demographic and baseline characteristics will be listed and summarized by 
treatment group for the mITT, Safety, and PP population. Standard descriptive 
statistics will be presented for the continuous variables of: 
 
Age at study entry (years) 
 
Weight (kg) 
 
Height (cm)  
 
Body mass index (BMI) (kg/m2) 
 
Supine systolic blood pressure (SBP) (mm Hg) 
 
Supine diastolic blood pressure (DBP) (mm Hg) 
 
Pulse rate (beats/min) 
 
Temperature (oC) 
The total counts and percentages of subjects will be presented for the categorical 
variables of: 
 
Age group (years) (<65;≥65) 
 
Sex (Male; Female) 
 
Race 
 
Ethnicity 
 
BMI categories (≤30 kg/m2; >30 kg/m2) 
 
Tobacco use (Yes, number of cigarettes/day; No) 


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Teijin America, Inc.                                                                                                                          
TMX-049DN-201                                                                          
  
 
 
 
 
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 
Alcohol Drinking (Yes, number of units/week; No) 
Baseline laboratory characteristics for a select number of tests will also be 
summarized by treatment group for the mITT, Safety, and PP population. Standard 
descriptive statistics will be presented for the following laboratory tests: 
 
Urinary albumin-to-creatinine ratio (UACR) (mg/g) 
 
Log-transformed UACR (mg/g) 
 
HbA1C (%) 
 
eGFR (CKD-EPI) (ml/min/1.73m2) 
 
Serum creatinine (mg/dL) 
 
Serum uric acid (mg/dL) 
 
Total cholesterol (mg/dL) 
 
High-density lipoprotein cholesterol (HDL-C) (mg/dL) 
 
Non-HDL-C (mg/dL) 
A summary of physical examination data will be presented by treatment group for 
the mITT, Safety, and PP population. 
No formal tests of statistical significance will be performed on the demographic and 
Baseline data. 
7.4.1 Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) Version 20.5 (or a later version if updated during the study).  All medical 
history will be listed, and the number and percentage of subjects with any medical 
history will be summarized for the mITT population by system organ class (SOC) 
and preferred term (PT) for each treatment group.   
7.4.2 Previous and Concomitant Medications 
Medications received prior to or concomitantly with treatment will be coded by 
 using the World Health Organization (WHO) Drug Dictionary, Version 
September 2017 (or a later version if updated during the study), Anatomical 
Therapeutic Chemical (ATC) Classification codes.  
Prior medications and concomitant medications are defined as follows: 
 
Prior medications are those taken prior to the first dose date of double-blind 
study drug. 
 
Concomitant medications are those with a start date on or after the first dose 
date of double-blind treatment, or those with a start date before the first 
dose date of double-blind treatment and a stop date on or after the first dose 
date of study drug. 
If a medication cannot be classified as “prior” or “concomitant” after applying 
imputation rules for missing/incomplete dates, it will be classified as concomitant. 


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Teijin America, Inc.                                                                                                                          
TMX-049DN-201                                                                          
  
 
 
 
 
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Prior medications, prohibited medications (See Protocol Appendix B for the full list 
of prohibited medications defined in this study) taken during the double-blind 
treatment period, and concomitant medications taken during the double-blind 
treatment Period will be listed and summarized separately for the mITT population. 
The number and percentage of subjects using each medication will be displayed 
together with the number and percentage of subjects using at least one medication 
within each therapeutic class (Anatomical Therapeutic Chemical [ATC]-Level 2), 
chemical subgroup (ATC-Level 4), and generic term. 
 
7.5 Treatment Compliance and Exposure 
Duration of exposure to double-blind study drug is defined as: 
Date of last dose – Date of first dose + 1 
For each subject, percentage of compliance is calculated as: total number of days 
taken study drug / the total number of days exposed to study drug.  The total 
number of days on study drug can be calculated as: total number of days exposed 
to study drug minus the total number of days missing doses.  
The number and percentage of compliant subjects will be presented for the Safety 
population, where compliant is defined as percentage compliance between 80.0% 
and 120.0% inclusive. The following percentage compliance categories will also be 
presented: 
 
<80.0% 
 
80.0% to 120.0% 
 
>120.0% 
Treatment duration (days) and percentage compliance will be summarized 
descriptively by treatment group for the Safety population. 
 
<28 days 
 
≥28 days and <56 days 
 
≥56 days and <84 days 
 
≥84 days 
 
7.6 Efficacy 
7.6.1 Primary Efficacy Analysis 
The primary efficacy endpoint is the change from Baseline to Study Week 12 (Study 
Visit 6) in log-transformed UACR.  The analysis will be based on the mITT 
population.  
 


Statistical Analysis Plan  
Teijin America, Inc.                                                                                                                          
TMX-049DN-201                                                                          
  
 
 
 
 
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The UACR values from Study Visits 2 to 7 are calculated as the mean result from 2 
consecutive day mid-stream, first morning void urine samples that are submitted 
on the morning before and on the day of study visits.  If only 1 sample is available, 
the measurement from that sample is used. 
 
Baseline UACR is defined as the mean of UACR from urine samples collected on 
Study Visit 3 (Randomization day).  
 
For the primary analysis of the primary efficacy endpoint, the last-observation-
carried-forward (LOCF) imputation algorithm will be used, where the last recorded 
post-baseline value for the same subject is carried forward to the missing Study 
Week 12 visit. 
 
The change from Baseline to Study Week 12 in log-transformed UACR will be 
analyzed in an analysis of covariance (ANCOVA) model with randomized treatment, 
randomization strata of sUA (<6.0 vs ≥6.0 mg/dL) and UACR (200 to <300 mg/g 
vs 300 to ≤3000 mg/g) levels as independent variables.  The least square mean 
(LS mean), p-value, and the corresponding 95% confidence limit (CL) for the 
change in log-transformed UACR in each treatment group, and the difference  of 
change in log-transformed UACR between each TMX-049 treatment group versus 
Placebo group will be presented.  The adjusted geometric mean of Week 12 to 
Baseline ratio in UACR with the corresponding 95% CLs for each treatment group, 
and the ratio of the adjusted geometric mean of Week 12 to Baseline ratio achieved 
within each treatment group relative to that achieved with Placebo group with 95% 
CLs will also be provided. 
 
7.6.2 Secondary Efficacy Analysis 
Secondary analysis of the primary efficacy endpoint will use mixed model repeated 
measures (MMRM) and all observed data.  The model will include randomized 
treatment, randomization strata of sUA (<6.0 vs ≥6.0 mg/dL) and UACR (200 to 
<300 mg/g vs 300 to ≤3000 mg/g) levels, timepoint (Study Week), a treatment-
by-timepoint interaction as fixed effects, and subject as a random effect.  All post-
baseline (excluding data collected at Follow-up visit) observations collected will be 
used in the MMRM.  The MMRM statistics will be based on the restricted maximum 
likelihood (REML) method for estimation.  An unstructured (co)variance structure 
will be used to model within-subject errors. The Kenward-Roger approximation will 
be used to approximate the denominator degrees of freedom.  The adjusted mean 
change in log-transformed UACR from Baseline to Study Week 12 for each 
treatment group and the 95% CLs will be estimated in the framework of the this 
model, as well as the between-group difference and  the 95% CLs for the 
difference.  
 
Summarization of the inferential statistics will include the LS means, standard error 
(SE) of the estimates, p-value, and 2-sided CLs.  These statistics will be provided 
for the within treatment group changes from Baseline and for the comparison of 
TMX-049 versus Placebo for the change from Baseline values. The adjusted 


Statistical Analysis Plan  
Teijin America, Inc.                                                                                                                          
TMX-049DN-201                                                                          
  
 
 
 
 
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geometric mean of Week 12 to Baseline ratio in UACR with the corresponding 95% 
CLs for each treatment group, and the ratio of the adjusted geometric mean of 
Week 12 to Baseline ratio achieved within each treatment group relative to that 
achieved within Placebo group with 95% CLs will also be provided. 
 
Figures displaying the mean change from Baseline by study week, LS mean change 
at Week 12 in log-transformed UACR from the ANCOVA model using LOCF, as well 
as the adjusted geometric mean ratio to Baseline at each study week from MMRM 
will be presented by treatment group. 
 
Furthermore, the ANCOVA model specified in Section 7.6.1 will be fitted using 
observed data in order to check the robustness of LOCF in the primary efficacy 
analysis. 
7.6.3 Sensitivity Analysis 
The analyses described in Sections 7.6.1 and 7.6.2 will be performed using the PP 
population. 
In addition, the primary efficacy endpoint, ie, the change from Baseline to Study 
Week 12 in log-transformed UACR will also be analyzed in an analysis of covariance 
(ANCOVA) model with randomized treatment, randomization strata of sUA (<6.0 vs 
≥6.0 mg/dL) and UACR (200 to <300 mg/g vs 300 to ≤3000 mg/g) levels as 
independent variables, Baseline log-transformed UACR as a covariate.  The least 
square mean (LS mean), p-value, and the corresponding 95% confidence limit (CL) 
for the change in log-transformed UACR in each treatment group, and the 
difference of change in log-transformed UACR between each TMX-049 treatment 
group versus Placebo group will be presented.  The adjusted geometric mean of 
Week 12 to Baseline ratio in UACR with the corresponding 95% CLs for each 
treatment group, and the ratio of the adjusted geometric mean of Week 12 to 
Baseline ratio achieved within each treatment group relative to that achieved within 
Placebo group with 95% CLs will also be provided. These analyses will be performed 
in both mITT and PP population, using LOCF and observed data, respectively. 
7.6.4 Subgroup Analysis 
Standard descriptive statistics of UACR (both Log-scale and original scale) and 
change from Baseline to Study Week 12 will be provided for different categories of 
the following Baseline demographics and lab characteristics subgroups. If data 
allowed, the primary efficacy endpoint, ie, the change from Baseline to Study Week 
12 in log-transformed UACR, with LOCF imputation algorithm will be analyzed using 
ANCOVA model described in Section 7.6.1 for each subgroup. The analyses will be 
based on mITT population. 
 
Age at study entry (years) (<65; >=65) 
 
Sex (male; female) 


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Teijin America, Inc.                                                                                                                          
TMX-049DN-201                                                                          
  
 
 
 
 
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 
Race (African American; not African American) 
 
eGFR (CKD-EPI) at Baseline (ml/min/1.73m2) (<60; >=60) 
 
BMI (kg/m2) (below the median; at or above the median) 
 
SBP (mm Hg) (below the median; at or above the median) 
 
sUA (mg/dL) (below the median; at or above the median) 
 
UACR (mg/g) (below the median; at or above the median) 
 
HbA1C (%) (below the median; at or above the median)Oxidative stress 
markers (below the median; at or above the median) 
- 8 hydroxy 2' deoxyguanosine (8-OhdG) 
- high sensitivity C reactive protein (hs-CRP) 
- soluble tumor necrosis factor receptor 1 (sTNFR1) 
7.6.5 Secondary Efficacy Endpoints Analysis 
Analysis of the secondary efficacy endpoints will be based on mITT population and 
PP population. Descriptive statistics for secondary efficacy endpoints will be 
presented by treatment group and by study visit where appropriate.  All post-
baseline data collected will be used in the analyses, including observations 
occurring after discontinuation of study drug.   
7.6.5.1 
Change in eGFR, UACR, and sUA from Baseline to Study 
Weeks 2, 6, 12/ET, and Follow-up Visit 
For each of these secondary efficacy endpoints, the ANCOVA model using LOCF 
described for the primary efficacy endpoint in Section 7.6.1 will be fitted for the 
change from Baseline to each specific timepoint, ie, Study Week 2, Week 6, Week 
12, and Follow-up Visit.  
The MMRM and all observed data (excluding data collected at Follow-up visit) 
described for the primary efficacy endpoint in Section 7.6.2 will be fitted for each 
of these endpoints also.  
Note: In the above ANCOVA and MMRM models, Baseline eGFR will be included as a 
covariate to model change in eGFR from Baseline. 
For each of these endpoints, 3 figures will be generated by treatment group: figure 
to present the mean change from Baseline by visit; figure to present the LS mean 
change from Baseline to Study Week 12 from the ANCOVA model, and figure to 
present the LS mean change from Baseline to each post-baseline study weeks from 
the MMRM.  
In addition, the following scatter plots will be generated by treatment group: 
- 
Change in UACR at Study Week 12 from Baseline versus Baseline UACR 


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Teijin America, Inc.                                                                                                                          
TMX-049DN-201                                                                          
  
 
 
 
 
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- 
Change in UACR at Study Week 12 versus change in eGFR at Study Week 12 
from Baseline 
- 
Change in UACR at Study Week 12 from Baseline versus Baseline eGFR 
- 
Change in UACR at Study Week 12 from Baseline versus Baseline sUA  
- 
Change in UACR at Study Week 12 from Baseline versus Change in sUA at 
Study Week 12 
- 
Change in UACR at Study Week 12 from Baseline versus Baseline BMI 
- 
Change in UACR at Study Week 12 from Baseline versus Baseline SBP 
- 
Change in UACR at Study Week 12 from Baseline versus Baseline HbA1C 
- 
Change in UACR at Study Week 12 from Baseline versus Baseline 8-OhdG 
- 
Change in UACR at Study Week 12 from Baseline versus Baseline hs-CRP 
- 
Change in UACR at Study Week 12 from Baseline versus Baseline sTNFR1 
- 
Change in eGFR at Study Week 12 from Baseline versus Baseline eGFR 
- 
Change in eGFR at Study Week 12 from Baseline versus Baseline sUA 
- 
Change in sUA at Study Week 12 versus change in eGFR at Study Week 12 
from Baseline 
7.6.5.2 
Proportion of Subjects with >30% Reduction from Baseline 
to Study Week 12 in UACR 
The frequency and percent of subjects with >30% reduction from Baseline to Study 
Week 12 in UACR will be presented by treatment group.  Subjects with missing 
observations at Study Week 12 are imputed as non-responders for this analysis. 
Fisher’s exact test will be performed between each TMX-049 group and the placebo 
group and the exact p-value from each test will be provided. The difference in the 
percentage of responders between each treatment group and the Placebo group 
and the exact 95% CLs based on Clopper-Pearson method will also be provided. 
Furthermore, the association between having UACR reduction greater than 30% 
from Baseline to Study Week 12 and the treatment group will be assessed by 
Logistic regression model.  The model will use the incidence of subjects with >30% 
reduction as the dependent variable, the randomized treatment group, 
randomization strata of sUA (<6.0 vs ≥6.0 mg/dL), and UACR (200 to <300 mg/g 
vs 300 to ≤3000 mg/g) levels as independent variables, Baseline UACR and 
Baseline sUA levels as covariates. The estimated odds ratio (and 95% CL) of having 
>30% reduction versus not having >30% reduction in URCA in any active TMX-049 
group versus Placebo group, will be provided. 
7.6.5.3 
Exploratory Renal Biomarkers 
Exploratory renal biomarkers include:  
- 
Urinary biomarkers: kidney injury molecule 1 (KIM-1), liver fatty acid binding 
protein (L-FABP), 8-OHdG, and N-acetyl-β-D-glucosaminidase (NAG).  


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Teijin America, Inc.                                                                                                                          
TMX-049DN-201                                                                          
  
 
 
 
 
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- 
Blood biomarkers: sTNFR1, hs-CRP. 
Descriptive statistics for the listed renal biomarkers will be presented by treatment 
group and by study visit where appropriate.  
 
7.7 Safety 
7.7.1 Adverse Events 
All AEs recorded on the eCRF will be coded using the MedDRA dictionary Version 
20.5 (or a later version if updated during the study) and classified as TEAEs as 
follows: 
TEAEs are events with start date on or after the date of first dose of double-blind 
study drug and up to 30 days after date of last dose of double-blind study drug.  
All AE data will be listed by treatment group. Treatment-emergence status, AEs 
leading to discontinuation of double-blind study drug, AEs resulting in death, and 
serious AEs will be presented in the listing. 
Summary tables of TEAEs by treatment group and overall will be produced for the 
Safety population. 
The relationship between an AE and study drug is assessed as related or not 
related.  
An overview table will summarize the number and percentage of subjects with at 
least 1 of the following TEAEs, where subjects with more than 1 TEAE in a particular 
category are counted only once in that category: 
 
Any TEAE 
 
Drug-related TEAE 
 
Severe drug-related TEAE 
 
Treatment-emergent SAE 
 
Treatment-emergent drug-related SAE 
 
TEAE leading to study drug discontinuation 
 
Drug-related TEAE leading to study drug discontinuation 
 
TEAE leading to death 
The number and percentage of subjects reporting each AE will be summarized by 
SOC and PT for the Safety population. Tables will be sorted, as to SOC, by 
Internationally Agreed Order. PTs will be sorted by PT code (variable PTCD). The 
following summaries will be produced: 
 
TEAEs by SOC and PT 
 
TEAEs by onset time period, SOC, and PT (<28 days; ≥28 days and <56 
days; ≥56 days and <84 days; ≥84 days) 


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Teijin America, Inc.                                                                                                                          
TMX-049DN-201                                                                          
  
 
 
 
 
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 
TEAEs by PT 
 
TEAEs reported by at least 5% of subjects in any treatment group, by SOC 
and PT 
 
TEAEs related to treatment, by SOC and PT 
 
TEAEs related to treatment, by PT 
 
TEAEs by relationship to treatment, by SOC and PT 
 
TEAEs by severity, by SOC and PT 
 
TEAEs related to treatment by severity, by SOC and PT 
 
TEAEs causing discontinuation from treatment, by SOC and PT 
 
TEAEs related to treatment causing discontinuation from treatment, by SOC 
and PT 
 
Treatment-emergent SAEs, by SOC and PT 
 
Treatment-emergent SAEs related to treatment, by SOC and PT 
 
TEAEs leading to death, by SOC and PT 
 
SAEs during Single-blind, placebo run-in, by SOC and PT 
In the above summaries, subjects with more than 1 AE within a particular SOC are 
counted only once for that SOC. Similarly, subjects with more than 1 AE within a 
particular PT are counted only once for that PT. For summaries by maximum 
intensity, subjects with multiple AEs within a particular SOC or PT will be counted 
under the category of their most severe AE within that SOC or PT.  
No statistical comparisons of AE related data between treatment groups will be 
performed. 
 
7.7.2 Laboratory Evaluations 
Data for the following hematology, blood chemistry, lipid profile, and urinalysis 
received from central laboratory will be listed and summarized by treatment group 
and visit. If data for any additional analytes are also received then these will be 
listed only. 
All summaries of laboratory test results will be presented in International System of 
Units (SI) and conventional units. Out-of-reference-range values will be flagged as 
high (H) or low (L) in the listings. 
For analysis purposes, values preceded by a “<” or a “>”sign (ie, those below or 
above the limits of quantification) will be considered equal to the lower or upper 
limit of quantification, respectively. 
Laboratory evaluations measured on a continuous scale will be summarized by visit 
using standard descriptive statistics for the Safety population. Changes from 
Baseline will also be summarized. For analysis by visit, the nominal study visits will 
be utilized.  


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Teijin America, Inc.                                                                                                                          
TMX-049DN-201                                                                          
  
 
 
 
 
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Qualitative urinalysis laboratory results will be summarized for Baseline and all 
scheduled post-baseline study weeks as the number and percentage of patients 
having either positive or negative results.  Missing category will be reported if there 
is more than 1 patient reported in any treatment group. 
For each laboratory analyte, the Baseline value will be defined as last scheduled or 
unscheduled value collected prior to the first dose of treatment. 
For hematology and serum chemistry, shift tables presenting movement in and out 
of reference range from Baseline to each scheduled post-Baseline visit will be 
provided for each treatment group. 
Mean change from Baseline with standard deviation bars will be plotted by visit for 
select laboratory parameters for the Safety Analysis Set. 
The lab parameters collected are presented in the following table: 
 


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Teijin America, Inc.                                                                                                                          
TMX-049DN-201                                                                          
  
 
 
 
 
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7.7.3 Vital Signs 
The following vital signs will be listed and summarized by treatment group and visit. 
• Supine SBP and DBP (mm Hg) 
Serum Chemistry: 
Complete Blood Count 
Aspartate aminotransferase (AST) 
White blood cell count (WBC) 
Alanine aminotransferase (ALT) 
Red blood cell count (RBC) 
Alkaline phosphatase 
Hemoglobin 
Gamma glutamyl transferase (GGT) 
Hematocrit (PCV) 
Lactate dehydrogenase (LDH) 
Mean cell volume (MCV) 
Sodium 
Mean cell hemoglobin (MCH) 
Potassium 
MCH concentration (MCHC) 
Chloride 
Platelet count 
Calcium 
Differential WBC 
Bicarbonate 
Urinalysis: 
Inorganic phosphate 
Microscopic examination 
Glucose 
Specific gravity 
Urea 
pH 
Uric acid (sUA) 
Protein 
Total bilirubin 
Glucose 
Direct bilirubin 
Ketones 
Creatinine 
Blood 
Blood urea nitrogen (BUN) 
Urobilinogen 
Total protein 
 
Albumin 
For Females Only: 
Creatinine phosphokinase (CPK) 
Urine pregnancy test 
Glycosylated hemoglobin (HbA1c) 
 
 
For Postmenopausal Females Only: 
Lipid Panel: 
Follicle-stimulating hormone (FSH)  
Total cholesterol 
Serology: 
High-density lipoprotein cholesterol (HDL-C) 
Hepatitis B surface antigen (HBsAg) 
Hepatitis C antibody 
Human immunodeficiency virus (HIV) 
non-HDL-C 
Thyroid Testing: 
Urinary Biomarkers: 
Triiodothyronine (T3) 
Urinary albumin-to-creatinine ratio 
(UACR) 
Thyroxine (T4) 
Kidney injury molecule 1 (KIM-1) 
Free triiodothyronine (FT3) 
Liver fatty acid binding protein (L-FABP)  
Free thyroxine (FT4) 
Thyrotropin/Thyroid 
stimulating 
hormone 
(TSH) 
8 hydroxy 2' deoxyguanosine (8-OHdG)  
N-acetyl-β-D-glucosaminidase (NAG)  
 
Blood Biomarkers: 
Soluble tumor necrosis factor receptor 1 
(sTNFR1)  
 
high sensitivity C reactive protein (hs-
CRP)  
 
Estimated glomerular filtration rate 
(eGFR)  


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Teijin America, Inc.                                                                                                                          
TMX-049DN-201                                                                          
  
 
 
 
 
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• Pulse rate (beats/min) 
• Respiration rate (breaths/min) 
• Body temperature (°C) 
Vital signs data and changes from Baseline in vital signs will be summarized by visit 
using standard descriptive statistics for the Safety population.  
The Baseline value will be defined as last scheduled or unscheduled value collected 
prior to the first dose of treatment. For analysis by visit, nominal study visits will be 
used. 
 
7.7.4 Electrocardiograms 
The following quantitative ECG measurements will be listed and summarized by 
treatment group and visit for the Safety population: 
 
heart rate (beats/min); 
 
PR interval (ms); 
 
QRS interval (ms); 
 
QT interval (ms); 
 
Fridericia corrected QT (QTcF) interval (ms)  
An overall Investigator assessment of ECG will be summarized and listed using 
categories reported in the eCRF. 
 
7.7.5 Physical Examination 
Physical examination results (normal or abnormal) and details of abnormalities will 
be listed for each subject. 
For each physical examination body system, the number and percentage of subjects 
with abnormalities at Baseline and post-Baseline will be summarized by treatment 
group for the Safety Population. 
 
7.8 Pharmacokinetic Analysis 
The population pharmacokinetic analysis was described in a separate analysis plan: 
Final Population Pharmacokientic Analysis and Report Plan, dated as of February 22, 
2019.  
Pharmacokinetic plasma concentration of TMX-049 will be summarized and listed by 
treatment group using descriptive statistics (including geometric mean and CV%, 
arithmetic mean, SD, arithmetic CV%, median, observed maximum, minimum, and 
N). No formal statistical tests are planned. 


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Teijin America, Inc.                                                                                                                          
TMX-049DN-201                                                                          
  
 
 
 
 
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The following rules will be applied if there are values that are below the limit of 
quantification (BLQ) or if there are missing values (eg, no result [NR]) in a plasma 
concentration data sets to be summarized. 
 
For the calculation of summary statistics, BLQ values will be set to zero. 
 
If an embedded BLQ value is considered anomalous within the concentration 
time profile, this value will be excluded from the summary statistics. 
 
Where there is NR, these will be set to missing. 
 
If values are obtained from more than or equal to 50% subjects, the summary 
statistics will be calculated. 
 
If values are obtained from less than 50% subjects, all arithmetic and geometric 
summary statistics will be denoted as NC. 
7.9 Interim Analysis 
No interim analysis is planned for this study. 
8. Changes in Planned Analysis 
Not applicable. 
 


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Teijin America, Inc.                                                                                                                          
TMX-049DN-201                                                                          
  
 
 
 
 
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9. References 
The schedule of study 
procedures (from the 
Protocol) is attached for 
reference. 
Screen
ing 
 
Single-Blind, 
Placebo, 
Run-in Phase 
 
Double-Blind Treatment Phase Follow- 
up 
 
Visit 1 
Visit 
2 
 
Visit 
3 
Start of 
study 
drug 
Visit 
4 
Visit 
5 
Visit 
6/ET 
Visit 7 
Study days and visit 
window guidelines 
Day -
42 to 
Day -
15 
Day -
14 ± 4 
days  
Day -14  ± 4 
days to Day 0 
Day 0 
Day 1 
Day 
14 
± 4 d
ays 
Day 
42 
± 7 d
ays 
Day 84 
± 7 da
ys 
Visit 
6/ET+28
 ± 7 days 
Administrative Procedures 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Assignment of Screening 
number 
X 
 
 
 
 
 
 
 
 
Contact IXRS 
X 
X 
 
X 
 
X 
X 
X 
X 
Check of eligibility based on 
inclusion/ exclusion criteria 
X 
X 
 
X 
 
 
 
 
 
Assignment of 
randomization number 
 
 
 
X 
 
 
 
 
 
Pre-visit telephone  
reminder for urine and PK1 
 
X 
 
X 
 
X 
X 
X 
X 
Trial Compliance 
 
 
 
 
 
 
 
 
 
Prior/concomitant 
medication review 
X 
X 
 
X 
 
X 
X 
X 
X 
Dispense urine collection 
supplies 
X 
X 
 
X 
 
X 
X 
X 
 
Investigational Product 
 
 
 
 
 
 
 
 
 
Dispense study drug 
(placebo) for single-blind 
run-in 
 
X 
 
 
 
 
 
 
 
Administration of placebo 
 
 
qd dosing for 2 
weeks 
 
 
 
 
 
 
Assess single-blind 
compliance 
 
 
 
X 
 
 
 
 
 
Dispense double-blind study 
drug (placebo or TMX-049) 
 
 
 
X 
 
X 
X 
 
 
Administration of TMX-049 
or placebo 
 
 
 
 
                 qd 
dosing 
for 
12 
weeks 
 
Assess double-blind 
compliance 
 
 
 
 
 
X 
X 
X 
 
Clinical 
Procedures/Assessments 
 
 
 
 
 
X 
X 
X 
 
Demographics and medical 
history 
X 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
Body weight 
X 
 
 
X 
 
 
X 
X 
X 
Vital signs (blood pressure2, 
pulse rate, and body 
temperature) 
X 
X 
 
X 
 
X 
X 
X 
X 
Physical examination 
 
X 
 
 
 
 
 
X 
 


Statistical Analysis Plan  
Teijin America, Inc.                                                                                                                          
TMX-049DN-201                                                                          
  
 
 
 
 
Page 30 of 31 
ST-AD-008 version 04 
The schedule of study 
procedures (from the 
Protocol) is attached for 
reference. 
Screen
ing 
 
Single-Blind, 
Placebo, 
Run-in Phase 
 
Double-Blind Treatment Phase Follow- 
up 
 
Visit 1 
Visit 
2 
 
Visit 
3 
Start of 
study 
drug 
Visit 
4 
Visit 
5 
Visit 
6/ET 
Visit 7 
Study days and visit 
window guidelines 
Day -
42 to 
Day -
15 
Day -
14 ± 4 
days  
Day -14  ± 4 
days to Day 0 
Day 0 
Day 1 
Day 
14 
± 4 d
ays 
Day 
42 
± 7 d
ays 
Day 84 
± 7 da
ys 
Visit 
6/ET+28
 ± 7 days 
12-lead ECG 
 
X 
 
 
 
 
 
X 
 
AE monitoring 
X 
X 
X 
X 
 
 
 
 
 
TEAE monitoring 
 
 
 
 
X 
X 
X 
X 
X 
Laboratory Assessment 
 
 
 
 
 
 
 
 
 
UACR3 
X 
 
 
 
 
 
 
 
 
First morning void UACR 
 
X4 
 
X4,5 
 
X4,5 
X4,5 
X4,5 
X4,5 
Complete blood count 
(CBC) 
X 
 
 
X 
 
X 
X 
X 
X 
Serum chemistry profile 
(including sUA and serum 
creatinine to calculate eGFR) 
X 
X 
 
X5 
 
X5 
X5 
X5 
X5 
Serology: HIV, hepatitis B, 
and hepatitis C 
 
X 
 
 
 
 
 
 
 
Thyroid hormones 
 
X 
 
X 
 
X 
X 
X 
X 
Lipid panel 
 
X 
 
X 
 
X 
X 
X 
X 
HbA1c 
X 
 
 
X 
 
 
 
X 
 
Urine pregnancy (females of 
childbearing potential) 
X 
 
 
X 
 
 
 
X6 
X 
FSH (females of non-
childbearing potential) 
X 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
X 
 
X 
X 
X 
X 
Blood and urine samples for 
biomarkers7 
 
 
 
X 
 
X 
X 
X 
X 
Pharmacokinetic sampling 
 
 
 
 
 
X8 
X9 
X10 
 
Pharmacogenomics sampling 
 
 
 
X11 
 
 
 
 
 
Note: 
AE = adverse event; CRF = Case Report Form; ECG = electrocardiogram; eGFR = estimated 
glomerular filtration rate; ET = early termination; FSH = follicle-stimulating hormone; HbA1c = 
glycosylated hemoglobin; HIV = human immunodeficiency virus; IXRS = interactive voice/web 
response system; KIM 1 = kidney injury molecule 1; L FABP = liver fatty acid binding protein; NAG = 
N-acetyl-β-D-glucosaminidase; PK = pharmacokinetic; 8 OHdG = 8 hydroxy 2' deoxyguanosine; qd = 
once-daily; sUA = serum uric acid; TEAE = treatment emergent adverse event; tmax = time of 
maximum observed plasma concentration; UACR = urinary albumin to creatinine ratio. 
1Telephone contact around 3 days prior to scheduled visits. 
2Average of triplicate measurements. 
3Urine sample for assessment of UACR to be collected at the study site once subjects have signed the 
informed consent form. 
4The average of the 2 consecutive day mid stream, first morning void UACR results will be used. The 2 
consecutive day first morning void urine samples will be collected at the subject’s home the morning 
before and the morning of each visit.