Clinical trial NCT05437419
Conditions: Rheumatoid Arthritis
Keywords: Multiple Ascending Dose autoimmune disease Disease modifying antirheumatic drugs (DMARD)
Sponsor: Teijin America, Inc.
Start date: 2022-08-10; Completion date: 2023-07-27
Enrollment: 32 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The study is to evaluate the safety, tolerability, and pharmacokinetic (PK) of multiple orally administered TCK-276 in both males and females with Rheumatoid Arthritis (RA).

Detailed description:
This is a Phase 1, multi-center, double-blind, randomized, placebo-controlled, multiple ascending dose (MAD) study.

The study will consist of a Screening Visit (Days -1 to Day 10), Treatment duration (up to 11 days) and a Follow-up/end of treatment (EOT) visit.

This MAD study will consist of 4 cohorts of 8 patients (6 active treatment and 2 matching placebo, or a 3:1 ratio), each receiving an oral dose of TCK-276 or matching placebo for 7 days (once daily (QD) under fed condition). The first cohort will be divided into 2 subgroups to implement the sentinel dosing approach.

The study duration is approximately 42 days.

Arms: arm 1: The patient will receive Dose A of TCK-276 or matching placebo orally from Day 1 to Day 7 (once daily (QD) under fed conditions). arm 2: The patient will receive Dose B of TCK-276 or matching placebo orally from Day 1 to Day 7 (once daily (QD) under fed conditions). arm 3: The patient will receive Dose C of TCK-276 or matching placebo orally from Day 1 to Day 7 (once daily (QD) under fed conditions). arm 4: The patient will receive Dose D of TCK-276 or matching placebo orally from Day 1 to Day 7 (once daily (QD) under fed conditions).
Interventions: intervention 1: TCK-276 intervention 2: TCK-276 Placebo
Intervention descriptions: intervention 1: Patients will receive an oral dose of TCK-276 QD under fed conditions from Day 1 to Day 7. intervention 2: Patients will receive an oral dose of TCK-276 matching placebo QD under fed conditions from Day 1 to Day 7.

Protocol documents:
Prot_000.pdf: 
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Title Page 
Protocol Title: 
A Phase 1, Randomized, Placebo-controlled, Double-blind, 
Multiple Ascending Dose Study to Investigate Safety, Tolerability, 
and Pharmacokinetics of Oral Doses of TCK-276 in Patients with 
Rheumatoid Arthritis 
Brief Title:  
A Study to Investigate Safety, Tolerability, and Pharmacokinetics 
of Oral Doses of TCK-276 in Patients with Rheumatoid Arthritis 
Compound: 
TCK-276 
Indication: 
Rheumatoid arthritis 
Study Sponsor: 
Teijin America, Inc. 
1 Harbor Drive, Suite 200, Sausalito, CA, USA, 94965 
Protocol Number: 
TCK-276-102 
Study Phase: 
1 
Regulatory Agency 
Identifying 
Number: 
 
Version: 
3.0 
Amendment 
Number: 
Amendment 2 
Amendment Scope; 
Region/Country 
Identifier 
Global 
Approval Date: 
Final, 12 Dec 2022  
Date and Version of 
Previous Protocol: 
; Version: 2.0 
 
Confidentiality Statement 
This document contains confidential information of Teijin America, Inc. Do not copy or distribute without written 
permission from the Sponsor. 
 
 


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Sponsor Signatory: 
 
 
Medical Monitor Name and Contact Information: 
 
 
 






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Table of Contents 
Title Page ........................................................................................................................................ 1 
Protocol Amendment Summary of Changes Table ........................................................................ 3 
Table of Contents ............................................................................................................................ 5 
List of Tables .................................................................................................................................. 9 
List of Figures ................................................................................................................................. 9 
1 
Protocol Summary .................................................................................................................. 10 
1.1 
Synopsis .............................................................................................................................. 10 
1.2 
Schema ............................................................................................................................... 17 
1.3 
Schedule of Activities ......................................................................................................... 18 
2 
Introduction............................................................................................................................. 21 
2.1 
Study Rationale .................................................................................................................. 21 
2.2 
Background......................................................................................................................... 22 
2.2.1 
Summary of Findings from Non-clinical Studies with Potential Clinical Relevance .... 22 
2.2.2 
Summary of Findings from Previous Clinical Studies ................................................... 24 
2.3 
Benefit/Risk Assessment .................................................................................................... 25 
2.3.1 
Risk Assessment ............................................................................................................. 25 
2.3.2 
Benefit Assessment ......................................................................................................... 29 
2.3.3 
Overall Benefit/Risk Conclusion .................................................................................... 29 
3 
Objectives and Endpoints ....................................................................................................... 30 
4 
Study Design ........................................................................................................................... 33 
4.1 
Overall Design .................................................................................................................... 33 
4.2 
Scientific Rationale for Study Design ................................................................................ 36 
4.3 
Justification for Dose .......................................................................................................... 36 
4.4 
End of Study Definition...................................................................................................... 37 
5 
Study Population ..................................................................................................................... 37 
5.1 
Inclusion Criteria ................................................................................................................ 37 
5.2 
Exclusion Criteria ............................................................................................................... 39 
5.3 
Lifestyle Considerations ..................................................................................................... 42 
5.3.1 
Meals and Dietary Restrictions ...................................................................................... 42 
5.3.2 
Caffeine, Alcohol, and Tobacco ...................................................................................... 42 
5.4 
Screen Failures ................................................................................................................... 42 


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5.4.1 
Screening and Enrollment Log and Patient Identification Numbers .............................. 43 
6 
Study Intervention(s) and Concomitant Therapy ................................................................... 43 
6.1 
Study Intervention(s) Administered ................................................................................... 43 
6.2 
Preparation, Handling, Storage, and Accountability .......................................................... 44 
6.3 
Measures to Minimize Bias: Randomization and Blinding ................................................ 45 
6.4 
Study Intervention Compliance .......................................................................................... 46 
6.5 
Dose Modification .............................................................................................................. 46 
6.6 
Continued Access to Study Intervention After the End of the Study ................................. 46 
6.7 
Treatment of Overdose ....................................................................................................... 47 
6.8 
Concomitant Therapy ......................................................................................................... 47 
6.8.1 
Permitted Medications .................................................................................................... 47 
6.8.2 
Prohibited Medications ................................................................................................... 48 
6.8.2.1 
Caution ........................................................................................................................ 48 
7 
Discontinuation of Study Intervention and Patient Discontinuation ...................................... 48 
7.1 
Discontinuation of Study Intervention ............................................................................... 48 
7.1.1 
Overall Study Stopping Criteria ..................................................................................... 49 
7.1.2 
Dose Escalation .............................................................................................................. 50 
7.2 
Patient Discontinuation/Withdrawal from the Study .......................................................... 51 
7.3 
Lost to Follow-Up .............................................................................................................. 53 
8 
Study Assessments and Procedures ........................................................................................ 54 
8.1 
Administrative Procedures ................................................................................................. 55 
8.1.1 
Informed Consent ........................................................................................................... 55 
8.1.2 
Patient Identification Card .............................................................................................. 55 
8.1.3 
Calibration of Equipment ............................................................................................... 55 
8.2 
Screening and Eligibility Assessments ............................................................................... 55 
8.2.1 
Eligibility Criteria ........................................................................................................... 55 
8.2.2 
Demography and Other Baseline Information ............................................................... 56 
8.2.3 
Medical History .............................................................................................................. 56 
8.2.4 
Prior and Concomitant Medications Review .................................................................. 57 
8.2.5 
Screening Assessments ................................................................................................... 57 
8.3 
Safety Assessments ............................................................................................................. 58 
8.3.1 
Physical Examinations .................................................................................................... 58 
8.3.2 
Vital Signs ...................................................................................................................... 58 
8.3.3 
Electrocardiograms ......................................................................................................... 59 
8.3.4 
Cardiac Telemetry ........................................................................................................... 59 


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8.3.5 
Clinical Safety Laboratory Tests .................................................................................... 59 
8.3.6 
Pregnancy Testing ........................................................................................................... 60 
8.4 
Adverse Events, Serious Adverse Events, and Other Safety Reporting ............................. 60 
8.4.1 
Time Period and Frequency for Collecting Adverse Events and Serious Adverse Events 
Information ..................................................................................................................... 61 
8.4.2 
Method of Detecting Adverse Events and Serious Adverse Events ............................... 61 
8.4.3 
Follow-up of Adverse Events and Serious Adverse Events ........................................... 61 
8.4.4 
Regulatory Reporting Requirements for Serious Adverse Event ................................... 62 
8.4.5 
Pregnancy ....................................................................................................................... 62 
8.4.6 
Adverse events of Special Interest ................................................................................. 63 
8.5 
Pharmacokinetics ................................................................................................................ 64 
8.5.1 
Blood Sample Collection ................................................................................................ 64 
8.5.2 
Urine Sample Collection ................................................................................................ 64 
8.6 
Exploratory Assessments .................................................................................................... 64 
8.7 
Genetics .............................................................................................................................. 65 
8.8 
Biomarkers ......................................................................................................................... 65 
8.9 
Health Economics ............................................................................................................... 65 
9 
Statistical Considerations........................................................................................................ 65 
9.1 
Statistical Hypotheses ......................................................................................................... 65 
9.2 
Analysis Populations .......................................................................................................... 65 
9.3 
Statistical Analyses ............................................................................................................. 66 
9.3.1 
General Considerations .................................................................................................. 66 
9.3.1.1 
Protocol Deviations..................................................................................................... 66 
9.3.1.2 
Patient Disposition ...................................................................................................... 66 
9.3.1.3 
Demographic and Anthropometric Information and Baseline Characteristics ........... 67 
9.3.2 
Primary Endpoint(s) Analysis ......................................................................................... 67 
9.3.2.1 
Prior and Concomitant Medication ............................................................................. 67 
9.3.2.2 
Exposure ..................................................................................................................... 67 
9.3.2.3 
Adverse Events ........................................................................................................... 67 
9.3.2.4 
Clinical Laboratory Tests............................................................................................ 68 
9.3.2.5 
Vital Signs................................................................................................................... 68 
9.3.2.6 
Standard 12-lead Electrocardiogram .......................................................................... 68 
9.3.2.7 
Telemetry .................................................................................................................... 68 
9.3.2.8 
Physical Examination ................................................................................................. 68 
9.3.3 
Secondary Endpoint(s) Analysis ..................................................................................... 68 
9.3.3.1 
Pharmacokinetics Analyses ........................................................................................ 68 


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9.3.4 
Other Analyses ................................................................................................................ 69 
9.3.4.1 
Exploratory Analyses .................................................................................................. 69 
9.4 
Sample Size Determination ................................................................................................ 69 
10 Supporting Documentation and Operational Considerations ................................................. 70 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ............................ 70 
10.1.1 
Regulatory and Ethical Considerations .......................................................................... 70 
10.1.2 
Financial Disclosure ....................................................................................................... 71 
10.1.3 
Informed Consent Process .............................................................................................. 71 
10.1.4 
Data Protection ............................................................................................................... 71 
10.1.5 
Committees Structure ..................................................................................................... 72 
10.1.6 
Dissemination of Clinical Study Data ............................................................................ 72 
10.1.7 
Data Quality Assurance .................................................................................................. 72 
10.1.8 
Source Documents .......................................................................................................... 74 
10.1.9 
Study and Site Start and Closure .................................................................................... 74 
10.1.10 Publication Policy ........................................................................................................... 75 
10.1.11 Protocol Approval and Amendment ............................................................................... 76 
10.1.11.1 Access to Source Data ................................................................................................ 76 
10.2 Appendix 2: Clinical Laboratory Tests ............................................................................... 77 
10.3 Appendix 3: Adverse Events and Serious Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ............................................................. 79 
10.3.1 
Definition of Adverse Event ........................................................................................... 79 
10.3.2 
Definition of Serious Adverse Event .............................................................................. 80 
10.3.3 
Recording and Follow-up of Adverse Event, Serious Adverse Event, and Adverse Event 
of Special Interest ........................................................................................................... 81 
10.3.4 
Reporting of Serious Adverse Event and Adverse Event of Special Interest ................. 83 
10.4 Appendix 4: Contraceptive and Barrier Guidance ............................................................. 85 
10.4.1 
Definitions ...................................................................................................................... 85 
10.4.2 
Contraception Guidance ................................................................................................. 85 
10.4.2.1 
Collection of Pregnancy Information ......................................................................... 88 
10.5 Appendix 5: Genetics ......................................................................................................... 89 
10.6 
 
 
 
 ............................................................................................................................ 90 
10.7 Appendix 7: Abbreviations and Definitions ....................................................................... 94 
11 References............................................................................................................................... 98 


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List of Tables 
Table 1-1 
Schedule of Activities ........................................................................................... 18 
Table 2–1 
Risk Assessment.................................................................................................... 25 
Table 3–1 
Objectives and Endpoints ..................................................................................... 30 
Table 6–1 
Study Intervention(s) Administered ...................................................................... 43 
Table 6–2 
Study Cohorts........................................................................................................ 44 
Table 6–3 
Measures to Minimize Bias .................................................................................. 45 
Table 9–1 
Patient Analysis Population .................................................................................. 66 
Table 10–1 
Protocol-required Safety Laboratory Tests ........................................................... 77 
 
List of Figures 
Figure 1–1 
Study Design ......................................................................................................... 17 
Figure 4–1 
Study Flow Chart – Multiple Ascending Dose Design ......................................... 35 
 


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1 Protocol Summary 
1.1 Synopsis 
Protocol Title: A Phase 1, Randomized, Placebo-controlled, Double-blind, Multiple Ascending 
Dose Study to Investigate Safety, Tolerability, and Pharmacokinetics of Oral Doses of TCK-276 
in Patients with Rheumatoid Arthritis 
Brief Title: A Study to Investigate Safety, Tolerability, and Pharmacokinetics of Oral Doses of 
TCK-276 in Patients with Rheumatoid Arthritis 
Sponsor Protocol No.: TCK-276-102 
Study Phase: 1 
Sponsor: Teijin America, Inc. 
Rationale: 
Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial inflammation and 
hyperplasia. Activated lymphocytes and macrophages produce various proinflammatory 
mediators which recruit synovial fibroblasts to the joint and activate them. Proliferation of 
activated synovial fibroblasts further increases production of proinflammatory mediators and 
tissue-degrading proteinase such as matrix metalloproteinase-3 (MMP-3), resulting in 
irreversible destruction of bone and cartilage. The current treatment approaches include 
conventional, biological, and targeted synthetic disease modifying antirheumatic drugs 
(DMARDs). However, a high proportion of patients only show a partial response or fail to 
respond to DMARDs currently on the market even used in combination. Therefore, there is a 
persistent unmet medical need for novel orally active agents with greater efficacy and equivalent 
or better safety with an alternative mechanism of action. 
Teijin America, Inc., (hereafter referred to as Sponsor) has developed TCK-276 (Laboratory 
code number: TEI-T01276) as a novel synthetic DMARD with an alternative mechanism of 
action for the treatment of RA. The Sponsor has conducted the Phase 1 single ascending dose 
(SAD) study using an orally administered capsule containing 5 mg or 50 mg of TCK-276. The 
Sponsor thereafter plans to develop TCK-276 using an orally administered tablet containing 
10 mg or 25 mg of TCK-276. 
TCK-276 is a highly potent, orally active, and selective cyclin dependent kinase 4/6 (CDK4/6) 
inhibitor. Historically, CDK4/6 has been extensively explored as a target for anti-cancer 
therapeutics, however there is also mechanistic evidence to suggest that CDK4/6 contributes to 


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the pathogenesis of RA. Cyclin dependent kinase 4/6 is a key regulator at G1/S phase checkpoint 
in the cell cycle. Cyclin dependent kinase 4/6 forms a complex with D-type cyclins (CycD) and 
phosphorylates retinoblastoma protein (Rb), leading to depression of transcription factor E2F to 
accelerate S phase transition. Thus, inhibition of CDK4/6 leads to G1 arrest, and cell cycle 
progression is attenuated in synovial fibroblasts. In addition to the regulation of cell cycle, 
CDK4/6 has been reported to mediate the production of MMP-3 and monocyte chemoattractant 
protein 1 via Rb-independent and dependent pathways. Cyclin dependent kinase 4/6 likely 
contributes to the pathogenesis of RA by mediating the proliferation of synovial fibroblasts and 
the production of MMP-3. The inhibition of CDK4/6 may serve a useful therapeutic strategy for 
RA patients, particularly those with an inadequate response to existing DMARDs. 
Objectives and Endpoints:  
Objectives 
Endpoints 
Primary 
• 
To evaluate the safety and tolerability 
of multiple oral doses of TCK 276 in 
patients with rheumatoid arthritis (RA) 
• 
Safety and tolerability endpoints: 
The following safety and tolerability variables 
will be recorded at regular intervals during the 
study: 
o 
Vital signs measurements: supine blood 
pressure, pulse, body temperature, and 
respiratory rate 
o 
Cardiac safety for arrythmias, 
abnormalities including PR interval, 
QRS interval, RR interval, QT interval, 
and QT interval corrected for heart rate 
(QTc) (Fridericia’s correction [QTcF]) 
as assessed by 12-lead 
electrocardiogram (ECG) and cardiac 
telemetry 
o 
Incidence of laboratory abnormalities: 
hematology, clinical chemistry, 
coagulation, and urinalysis 
o 
Incidence and severity of adverse event 
(AE) and adverse event of special 
interest (AESI) (i.e., gastrointestinal 
toxicity and pulmonary symptoms 
indicative of interstitial lung disease) 
assessments 
o 
Physical examinations 


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Objectives 
Endpoints 
Secondary 
• 
To evaluate pharmacokinetic (PK) of 
TCK-276 and its metabolite 
(TEI-W00595) in patients with RA 
after multiple ascending dose (MAD) 
administration 
• 
PK endpoints 
The following PK parameters for TCK-276 and 
TEI-W00595 will be determined, if calculable: 
o 
Cmax: Maximum plasma concentration 
determined directly from the 
concentration-time profile (Days 1 and 
7) 
o 
tmax: Time of maximum plasma 
concentration determined directly from 
the concentration-time profile (Days 1 
and 7) 
o 
AUCtau: Area under the plasma 
concentration-time curve over a dosing 
interval, tau = 24 hours (Days 1 and 7) 
o 
AUC0-t: Area under the plasma 
concentration-time curve up to last 
measurable concentration (Days 1 and 
7) 
o 
AUC0-inf: Area under the plasma 
concentration-time curve from pre-dose 
(time 0) extrapolated to infinite time 
(Days 1 and 7) 
o 
MRTlast: Mean residence time up to last 
measurable concentration (Day 1 only) 
o 
MRT0-inf: Mean residence time 
extrapolated to infinity (Days 1 and 7) 
o 
t½: Terminal elimination half-life 
(Days 1 and 7) 
o 
CL/F: Apparent total body clearance 
(Days 1 and 7), determined for parent 
only 
o 
Vz/F: Apparent volume of distribution 
based on terminal phase (Days 1 and 7), 
determined for parent only 
o 
Metabolic ratio (MR) for Cmax: Molar 
metabolic ratio of Cmax calculated as 
(Cmax [metabolite] × molecular weight 
of parent)/(Cmax [parent] × molecular 
weight of metabolite) (Days 1 and 7) 


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Objectives 
Endpoints 
o 
MR for area under the plasma 
concentration-time curve (AUC): Molar 
metabolic ratio of AUC calculated as 
(AUC [metabolite] × molecular weight 
of parent)/(AUC [parent] × molecular 
weight of metabolite) (Days 1 and 7) 
o 
Ctrough: Concentration in a dosing period 
defined as the pre-dose concentration of 
the day 
o 
Racc (Cmax): Accumulation ratio based 
on Cmax: Calculated as Cmax on 
Day 7/Cmax on Day 1 
o 
Racc (AUCtau): Accumulation ratio based 
on AUCtau: Calculated as AUCtau on 
Day 7/AUCtau on Day 1 
The following urinary PK parameters for 
TCK-276 will be determined in this study: 
o 
Ae: Amount of study drug excreted 
unchanged in the urine (Days 1 and 7) 
o 
Fe: Percentage of study drug excreted 
unchanged in the urine (Days 1 and 7) 
o 
CLr: Renal clearance (Days 1 and 7) 
Other PK parameters will be determined if 
needed. 
Exploratory 
• 
To evaluate the effect of TCK-276 on 
disease activity and biomarkers in 
patients with RA 
• 
Exploratory endpoints 
The following exploratory disease activity 
parameters for RA will be assessed: 
o 
American College of Rheumatology 
(ACR) 20/50/70 response criteria 
o 
Disease activity score 28 (DAS28) 
o 
Clinical disease activity index (CDAI) 
o 
Simplified disease activity index 
(SDAI) 
The following exploratory biomarkers will be 
assessed: 
o 
Matrix metalloproteinase-3 (MMP-3) 
o 
Granulocyte macrophage 
colony-stimulating factor (GM-CSF) 


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Objectives 
Endpoints 
o 
C-X-C motif chemokine ligand 10 
(CXCL10) 
o 
C-C motif chemokine ligand 2 (CCL2) 
o 
Cartilage oligomeric matrix protein 
(COMP) 
o 
Tumor necrosis factor (TNF)-alpha 
o 
TNF-R1 
o 
Interleukin-6 (IL-6) 
Overall Design: 
This is a Phase 1, multi-center, double-blind, randomized, placebo-controlled, multiple ascending 
dose (MAD) study to evaluate the safety, tolerability, and pharmacokinetics (PK) of orally 
administered TCK-276 in both males and females with RA. Blood samples for possible future 
pharmacogenetic, possible future metabolite assessments, and possible future pharmacodynamic 
(PD) assessments will be collected. 
A total of thirty-two (32) patients with RA will be enrolled in this clinical study. This MAD study 
will consist of 4 cohorts of 8 patients (6 active treatment and 2 matching placebo, or a 3:1 ratio), 
each receiving an oral dose of TCK-276 or matching placebo for 7 days (once daily [QD] under 
fed condition). The first cohort will be divided into 2 subgroups to implement the sentinel dosing 
approach. Within the cohort, the first subgroup will consist of 2 sentinel patients; one patient will 
receive TCK-276, and one patient will receive matching placebo. The second subgroup will 
consist of 6 patients (5 active treatment, 1 matching placebo). Individual patients in the second 
subgroup will be dosed at least 72 hours after the first dose of the second sentinel patient of the 
first subgroup following a decision by the Investigators based on all available safety data from 
the sentinel patients up to 48 hours post-dose. Subsequent cohorts (cohort 2-4) will not include 
the sentinel dosing approach. 
Patients will be admitted to the site from the morning of Day -1 and sequestered for the duration 
of the treatment (dosing) period. Each patient will receive QD oral doses of either TCK-276 or 
matching placebo administered as tablets under fed condition in the morning of Day 1 to Day 7. 
The patients will be discharged on Day 10. The planned dose levels to be tested are 10 mg 
(Cohort 1), 25 mg (Cohort 2), 75 mg (Cohort 3), and 150 mg (Cohort 4) of TCK-276. Based on 
the results from the SAD study (5 mg to 185 mg dosing) and the projected clinical effective dose 
(i.e., 75 mg), 10 mg is selected as the starting dose level in the MAD study. The dose in 
Cohorts 2, 3, and 4 may be adjusted based on the safety and PK results from the previous 
cohorts, if necessary. The overall exposure to TCK-276 (in terms of geometric mean area under 


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the plasma concentration-time curve over a dosing interval [AUCtau, tau = 24 hours]) on Day 7 
would not be expected to exceed 
 
. 
Dose escalation will only be allowed after blinded assessment of all safety, tolerability, and PK 
data up to Day 10 from each previous cohort evaluated by Investigators, Medical Monitor, and 
Sponsor representatives during the Safety Review Committee (SRC) meeting. 
Brief Summary: 
The purpose of this study is to evaluate the safety, tolerability, and PK of multiple orally 
administered TCK-276 in both males and females with RA. 
Study details include: 
• 
Study duration: approximately 42 days 
• 
Treatment duration: Up to 11 days (Day -1 to Day 10) 
• 
Visit frequency: Screening Visit, Days -1 to 10 Visits; Follow-up/end of treatment (EOT) 
Visit. Following discontinuation of TCK-276, patients will be followed unless they withdraw 
their informed consent for study participation. 
Number of Patients: 
A total of 32 patients with RA are planned for enrollment and randomized into 4 cohorts with 
8 patients per cohort. Within each cohort, 6 patients will be randomized to TCK-276 and 
2 patients will be randomized to matching placebo. 
Note: “Enrolled” means a participant’s, or their legally acceptable representative’s, agreement to 
participate in a clinical study following completion of the informed consent process and 
Screening. Potential participants who are screened for the purpose of determining eligibility for 
the study, but do not participate in the study, are not considered enrolled, unless otherwise 
specified by the protocol. A participant will be considered enrolled if the informed consent is not 
withdrawn prior to participating in any study activity after Screening. 
Intervention Groups and Duration: 
This MAD study will consist of 4 cohorts of 8 patients (6 active treatment and 2 matching 
placebo, or a 3:1 ratio), each receiving an oral dose of TCK-276 or matching placebo for 7 days 
(QD under fed condition). The first cohort will be divided into 2 subgroups to implement the 
sentinel dosing approach. Within the cohort, the first subgroup will consist of 2 sentinel patients; 


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one patient will receive TCK-276, and one patient will receive matching placebo. The second 
subgroup will consist of 6 patients (5 active treatment, 1 matching placebo). Individual patients 
in the second subgroup will be dosed at least 72 hours after the first dose of the second sentinel 
patient of the first subgroup following a decision by the Investigators based on all available 
safety data from the sentinel patients up to 48 hours post-dose. Subsequent cohorts (cohort 2-4) 
will not include the sentinel dosing approach. 
Patients will be admitted to the site from the morning of Day -1 and sequestered for the duration 
of the treatment (dosing) period. Each patient will receive QD oral doses of either TCK-276 or 
matching placebo administered as tablets under fed condition in the morning of Day 1 to Day 7. 
The patients will be discharged on Day 10. The planned dose levels to be tested are 10 mg 
(Cohort 1), 25 mg (Cohort 2), 75 mg (Cohort 3), and 150 mg (Cohort 4) of TCK-276. Based on 
the results from the SAD study (5 mg to 185 mg doses) and the projected clinical effective dose 
(i.e., 75 mg), 10 mg is selected as the starting dose level in the MAD study. The dose in 
Cohorts 2, 3, and 4 may be adjusted based on the safety and PK results from the previous 
cohorts, if necessary. 
Dose Group 
Treatment Assignment 
1 
10 mg TCK-276 (N = 6) 
Placebo (N = 2) 
2 
25 mg TCK-276 (N = 6) 
Placebo (N = 2) 
3 
75 mg TCK-276 (N = 6) 
Placebo (N = 2) 
4 
150 mg TCK-276 (N = 6) 
Placebo (N = 2) 
Data Monitoring/Other Committee: 
A SRC will be appointed for this study. The SRC meeting will take place to review safety and 
PK data during each dose level. The SRC will evaluate the safety and tolerability data up to 
Follow-up/EOT Visit and available PK data up to Day 10 to determine the next dose for the 
subsequent cohort. 


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1.2 Schema 
Figure 1–1 
Study Design 
 
N = number of patients; PK = pharmacokinetics; SRC = Safety Review Committee. 
 


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1.3 Schedule of Activities 
Table 1-1 
Schedule of Activities 
Evaluation 
Screening 
visit 
Treatment period 
Follow-up/ 
End of 
treatment 
Early termination 
procedures 
Days 
-28 to -2 
-1 
1 
2-7 
8, 9 
10 
14 
 
Informed consent 
X 
 
 
 
 
 
 
 
Admission 
 
X 
 
 
 
 
 
 
In-house stay 
 
X 
X 
X 
X 
X 
 
 
Ambulatory visits 
X 
 
 
 
 
 
X 
X 
Discharge 
 
 
 
 
 
X 
 
 
Inclusion/exclusion criteria 
X 
X 
X 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
Disease activity data (ACR20/50/70, 
DAS28, CDAI, SDAI) 
 
 
X1 
X2 
 
 
 
 
Blood sampling for ESR, assessed as part 
of disease activity data 
 
 
X1 
X2 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Weight and height (height only at 
Screening) 
X 
X 
 
 
 
X 
 
 
Viral serology (HBsAG, anti-HBc, 
anti-HCV, anti-HIV) 
X 
 
 
 
 
 
 
 
Drug, alcohol, and cotinine screen 
X 
X 
 
 
 
 
 
 
SARS-CoV-2 real time RT-PCR 
X 
X 
 
 
 
 
 
 
IGRA-TB test (Quantiferon) 
X 
 
 
 
 
 
 
 
Chest X-ray 
X 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
Study drug administration 
 
 
X 
X 
 
 
 
 


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Evaluation 
Screening 
visit 
Treatment period 
Follow-up/ 
End of 
treatment 
Early termination 
procedures 
Days 
-28 to -2 
-1 
1 
2-7 
8, 9 
10 
14 
 
Urine pregnancy test (females) 
X 
X 
 
 
 
 
X 
X 
FSH (post-menopausal females) 
X 
 
 
 
 
 
 
 
Physical examination3 
X 
X 
 
 
 
X 
X 
X 
Clinical laboratory tests (clinical chemistry, 
hematology, coagulation, and urinalysis)  
X 
X 
X1 
X4 
X 
X 
X 
X 
Vital signs 
X 
X 
X5 
X 
X 
X 
X 
X 
12-lead ECG6 
X6 
X7 
X8 
X8 
X 
X 
X 
X 
Telemetry 
 
 
X9 
X9 
 
 
 
 
PK blood sampling10 
 
 
X 
X 
X 
X 
 
 
PK urine collection11 
 
 
X 
X 
X 
X 
 
 
Biomarker blood sampling 
 
 
X1 
X2 
 
 
 
 
Blood sampling for possible future 
pharmacogenetic assessments 
 
X12 
 
 
 
 
 
 
Blood sampling for possible future 
metabolite assessments10 
 
 
X 
X 
X 
X 
 
 
Blood sampling for possible future PD 
assessments 
 
 
X1 
X2 
 
 
 
 
Prior/concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
AE monitoring13 
X 
X 
X 
X 
X 
X 
X 
X 
ACR = American College of Rheumatology; AE = adverse event; CDAI = clinical disease activity index; DAS28 = disease activity score 28; 
ECG = electrocardiogram; ESR = erythrocyte sedimentation rate; FSH = follicle stimulating hormone; HBc = hepatitis B core; HBsAG = hepatitis B surface 
antigen; HCV = hepatitis C virus; HIV = human immunodeficiency virus; ICF = informed consent form; IGRA-TB = interferon gamma release assay for 
tuberculosis; PD = pharmacodynamic; PK = pharmacokinetics; RT-PCR = reverse transcription polymerase chain reaction; SARS-CoV-2 = severe acute 
respiratory syndrome coronavirus 2; SDAI = simplified disease activity index. 


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1. 
Disease activity data (ACR20/50/70, DAS28, CDAI, SDAI, and blood sampling for ESR), blood for clinical laboratory tests, blood for biomarker 
assessments, and blood for possible future PD assessments will be collected prior to dosing on Day 1. Blood sampling for ESR will be collected and 
assessed at local laboratory. 
2. 
Disease activity data (ACR20/50/70, DAS28, CDAI, SDAI, and blood sampling for ESR), blood for biomarker assessments, and blood for possible future 
PD assessments will be collected prior to dosing on Day 7 only. Blood sampling for ESR will be collected and assessed at local laboratory. 
3. 
A full physical examination will be performed at the Screening Visit, Day 14, and Early termination visit; a brief physical will be performed on Days -1 and 
10. 
4. 
Blood for clinical laboratory tests will be withdrawn once on Days 4 and 7.  
5. 
Vital signs will be collected at pre-dose and 1, 2, 4, 8, and 12 hours after dosing on Day 1. 
6. 
12-lead ECG will be conducted before blood sampling. 
7. 
12-lead ECG will be repeated once for eligibility confirmation at Screening and Day -1. 
8. 
12-lead ECG will be recorded at baseline and at 1, 2, 4, and 8 hours after dosing on Days 1 and 7.  
9. 
Starting 2 hours prior to dosing and until 12 hours after dosing on Days 1 and 7. 
10. Blood for PK sample analysis to determine parent and its metabolite concentrations and for possible future metabolite assessments will be sampled at 
pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours (pre-dose of Day 2) after dosing on Day 1, pre-dose on Days 3, 4, 5, 6, and on 7 at pre-dose 
and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, and 72 hours after dosing on Day 7 (the sampling time points may be adjusted based on the PK results 
obtained from the previous parts or cohorts). The last dose will be administered on Day 7. 
11. Urine for PK sample analysis will be collected at 0 (pre-dose) to 6, 6 to 12, and 12 to 24 hours after dosing on Day 1, and from 0 (pre-dose) to 6, 6 to 12, 12 
to 24, 24 to 48, and 48 to 72 hours after dosing on Day 7. Urine collection intervals may be adjusted based on the PK results obtained from the previous 
parts or cohorts, e.g., if plasma PK sampling times are adjusted, the urine sampling times will be updated. 
12. Sample will be obtained only from patients that consent to pharmacogenomics sampling. 
13. Any AEs occurring after the patient signs the ICF will be collected and monitored throughout the study via safety assessments, observation, and patient 
reporting. 


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2 Introduction 
TCK-276 is a highly potent, orally active, and selective cyclin dependent kinase 4/6 (CDK4/6) 
inhibitor. The Sponsor is planning to develop TCK-276 as a novel synthetic disease modifying 
antirheumatic drug (DMARD) with an alternative mechanism of action for the treatment of 
rheumatoid arthritis (RA).  
The term “study intervention” throughout the protocol, refers to TCK-276. 
2.1 Study Rationale 
Rheumatoid arthritis is an autoimmune disease characterized by synovial inflammation and 
hyperplasia. Activated lymphocytes and macrophages produce various proinflammatory 
mediators which recruit synovial fibroblasts to the joint and activate them. Proliferation of 
activated synovial fibroblasts further increases production of proinflammatory mediators and 
tissue-degrading proteinase such as matrix metalloproteinase-3 (MMP-3), resulting in 
irreversible destruction of bone and cartilage1,2. The current treatment approaches include 
conventional, biological, and targeted synthetic DMARDs. However, a high proportion of 
patients only show a partial response or fail to respond to DMARDs currently on the market even 
used in combination. Therefore, there is a persistent unmet medical need for novel orally active 
agents with greater efficacy and equivalent or better safety with an alternative mechanism of 
action. 
Teijin America, Inc., (hereafter referred to as Sponsor) has developed TCK-276 (Laboratory 
code number: TEI-T01276) as a novel synthetic DMARD with an alternative mechanism of 
action for the treatment of RA. The Sponsor has conducted the Phase 1 single ascending dose 
(SAD) study using an orally administered capsule containing 5 mg or 50 mg of TCK-276. The 
Sponsor thereafter plans to develop TCK-276 using an orally administered tablet containing 
10 mg or 25 mg of TCK-276. 
TCK-276 is a highly potent, orally active, and selective CDK4/6 inhibitor. Historically, CDK4/6 
has been extensively explored as a target for anti-cancer therapeutics, however there is also 
mechanistic evidence to suggest that CDK4/6 contributes to the pathogenesis of RA3. Cyclin 
dependent kinase 4/6 is a key regulator at G1/S phase checkpoint in the cell cycle. Cyclin 
dependent kinase 4/6 forms a complex with D-type cyclins (CycD) and phosphorylates 
retinoblastoma protein (Rb), leading to depression of transcription factor E2F to accelerate 
S phase transition3,4. Thus, inhibition of CDK4/6 leads to G1 arrest, and cell cycle progression is 
attenuated in synovial fibroblasts5. In addition to the regulation of cell cycle, CDK4/6 has been 
reported to mediate the production of MMP-3 and monocyte chemoattractant protein 1 via 


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Rb-independent and dependent pathways6. Cyclin dependent kinase 4/6 likely contributes to the 
pathogenesis of RA by mediating the proliferation of synovial fibroblasts and the production of 
MMP-3. The inhibition of CDK4/6 may serve a useful therapeutic strategy for RA patients, 
particularly those with an inadequate response to existing DMARDs. 
This multiple ascending dose (MAD) study will evaluate the safety, tolerability, and 
pharmacokinetic (PK) of orally administered TCK-276 in both male and female patients with 
RA. 
The study is being conducted to establish a dose range that is well tolerated by the majority of 
study patients with RA and to provide exploratory data on the potential for the treatment of RA. 
The results of the clinical study will inform the design and dose selection of subsequent studies. 
2.2 Background 
2.2.1 
Summary of Findings from Non-clinical Studies with Potential Clinical 
Relevance 
Pharmacodynamic (PD) studies demonstrated that TCK-276 inhibits CDK4/6 and has minimal 
potential for off-target kinase activity (Sections 5.1.1.2 and 5.1.2 of the Investigator’s Brochure 
[IB]7). 
Results of in vitro pharmacology study using rheumatoid arthritis synovial fibroblasts (RASF) 
indicated that TCK-276 inhibited proliferation and MMP-3 production of RASF 
(Section 5.1.1.2.5 and 5.1.1.2.6 of the IB). 
Results of in vivo pharmacology studies using rat and mouse arthritis models, indicated that 
TCK-276 at ≥ 15 mg/kg of tested doses was effective in the treatment of arthritis with no effect 
on bone marrow nucleated cells in rat arthritis model and TCK-276 at doses of ≥ 6.25 mg/kg was 
effective in the treatment of arthritis and bone destruction in mouse arthritis model 
(Sections 5.1.1.3.1 and 5.1.1.3.2 of the IB7). 
Safety pharmacology studies were performed in vitro and in vivo (cardiovascular, central 
nervous, and respiratory systems) in rats and monkeys. No untoward effects were observed in 
these studies.  


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TCK-276 was not genotoxic based on the absence of mutagenic potential in bacterial reverse 
mutation, the absence of potential for inducing chromosomal aberration in human lymphocytes 
in vitro and in rat bone marrow in vivo (Section 5.3.3.2 of the IB7). 
Embryo-fetal development studies have revealed evidence for teratogenicity in rats and rabbits 
and post-implantation loss (embryotoxicity) in rabbits (Section 5.3.5.3 of the IB7). In the male 
fertility study, there were no effects on the reproductive function of males or on early embryonic 
development when treated males were mated with untreated females (Section 5.3.5.1 of the IB7).  
Based on the non-good laboratory practice preliminary phototoxicity study (non-good laboratory 
practice grade), TCK-276 is considered to have no phototoxic potential (Section 5.3.7.1 of the 
IB7). 
In summary, the preclinical program supports the clinical development of TCK-276, as a once 
daily, self-administered, oral product for RA treatment. Collectively, the available data indicate 
that TCK-276 can be useful in the treatment of RA. 
2.2.2 
Summary of Findings from Previous Clinical Studies 
The first-in-human (FIH) Phase 1 SAD study (Study TCK-276-101) evaluating TCK-276 has 
completed 
; 48 subjects have been orally administered capsules ranging from 5 to 
185 mg (geometric mean of AUC0-inf: 39.7 to 2,260 ng·h/mL) once daily (QD). Clinical data 
from the SAD study of TCK-276 showed no drug-related safety signals (i.e., serious adverse 
events [SAEs], adverse events [AEs] leading to discontinuation). The plasma exposure levels for 
TCK-276 linearly increased following escalating TCK-276 administration with the proportion of 
metabolite (TEI-W00595) to parent remaining similar across dose levels. It was noted that no 
clinically meaningful differences in PK parameters were observed between fed or fasting states 
for either TCK-276 or its metabolite. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of TCK-276 is 
provided in the IB. 


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2.3 Benefit/Risk Assessment 
The risks of TCK-276 known to date are outlined in Section 2.3.1 and the benefits are outlined in 
Section 2.3.2. More detailed information about the known and expected benefits and risks and 
reasonably expected AEs of TCK-276 can be found in the IB. 
2.3.1 
Risk Assessment 
Table 2–1 
Risk Assessment 


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Measures to mitigate the additional risks caused by COVID-19 are: 
• This study is going to start enrolling only when the Sponsor and contract research 
organization (CRO) in collaboration deem it is safe to start the study. In addition, the study 
will not start until the local containment measures or other safety restrictions linked to the 
COVID-19 pandemic allow. 
• Current national laws and local recommendations for prevention of pandemic will be strictly 
adhered to. 
• Patients will be closely monitored for any signs and symptoms of COVID-19, including 
fever, dry cough, dyspnea, sore throat, fatigue, and changes of taste and smell throughout the 
study. Once clinical signs of infection are reported by patients, the Investigator needs to 
determine whether samples can be collected, and safety data can be recorded on-site. If not, 
information on AEs and concomitant medications will be obtained via phone calls. 
• Confirmation of COVID-19 infection by available approved laboratory standard testing 
should be conducted at Investigator’s discretion. This would include serology testing at 
Screening and virus testing prior to any Admission. 
• The probability of virus transmission will be controlled as much as possible by: 
o 
Advice for patients to adhere to local requirements for reduction of the public exposure 
while ambulatory. 
o 
Asking the potential patients to self-isolate for at least 5 days prior to admission. 
o 
Contacting patients by phone 1 day prior to every visit for assessing COVID-19 
symptoms and signs, and patients will be asked not to attend the site in case of 
suspected reports. In addition, patients will be asked about any contact with a person 
who has tested positive for SARS-CoV-2. If applicable, patients will be referred to the 
local health care system for further follow-up and treatment. 
o 
Physical distancing and person-to-person contact restrictions will be applied during site 
visits. 
o 
Where physical distancing is not possible, face shields will be used by study patients 
(surgical face mask, and gloves) and staff (for example but not limited to masks, gloves, 
protectors, and medical suits) if deemed appropriate by the Investigators and site staff 
and guided by local requirements. 
o 
Logistical improvements of the site and structural measures of the study site building 
will be implemented to further improve physical distancing. 


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• Patients will follow the site policy to mitigate the additional risks caused by COVID-19. All 
medical measures, risk/benefit, and restrictions associated with COVID-19 screening will be 
explained by the informed consent for COVID-19 screening, and written consent must be 
obtained before participating in the clinical study. Patients will be allowed to receive 
COVID-19 vaccines or boosters during the study period if necessary. 
2.3.2 Benefit Assessment 
TCK-276 is a highly potent, orally active, and selective CDK4/6 inhibitor as a novel synthetic 
DMARD with an alternative mechanism of action for the treatment of RA.  
The protocol has been designed to minimize the risk to research patients. Patients will be 
monitored to detect AEs during the study and followed appropriately to ensure resolution of 
AEs. Sentinel dosing will be employed within the first cohort, and available safety/tolerability 
and PK data will be assessed after each dose level to determine if it is safe to escalate to the next 
planned higher dose. 
Based on CDK4/6 inhibition mechanism of action, the adverse event of special interest (AESI) 
will be monitored as described in Section 2.3.1.  
Given the safety and tolerability profile of TCK-276 in preclinical studies and the SAD study, 
also in view of the short treatment duration of 7 days, the overall risk to the patients in this study 
is deemed to be low and the patients cannot derive benefit from short term treatment. The study 
results will help to further develop TCK-276 as potential treatment for RA patients in future and 
will guide researchers to plan and design future studies. Therefore, the Sponsor considers that it 
is medically and ethically acceptable to perform the proposed study. 
2.3.3 
Overall Benefit/Risk Conclusion 
Taking into account the measures taken to minimize risk to patients participating in this study, 
the potential risks identified in association with TCK-276 are justified by the anticipated benefits 
that may be afforded to patients with RA. 


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3 Objectives and Endpoints 
Study objectives and endpoints are summarized in Table 3–1. 
Table 3–1 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
• 
To evaluate the safety and tolerability 
of multiple oral doses of TCK 276 in 
patients with rheumatoid arthritis (RA) 
• 
Safety and tolerability endpoints: 
The following safety and tolerability variables 
will be recorded at regular intervals during the 
study: 
o 
Vital signs measurements: supine blood 
pressure, pulse, body temperature, and 
respiratory rate 
o 
Cardiac safety for arrythmias, 
abnormalities including PR interval, 
QRS interval, RR interval, QT interval, 
and QT interval corrected for heart rate 
(QTc) (Fridericia’s correction [QTcF]) 
as assessed by 12-lead 
electrocardiogram (ECG) and cardiac 
telemetry 
o 
Incidence of laboratory abnormalities: 
hematology, clinical chemistry, 
coagulation, and urinalysis 
o 
Incidence and severity of adverse event 
(AE) and adverse event of special 
interest (AESI) (i.e., gastrointestinal 
toxicity and pulmonary symptoms 
indicative of interstitial lung disease) 
assessments 
o 
Physical examinations 
Secondary 
• 
To evaluate pharmacokinetic (PK) of 
TCK-276 and its metabolite 
(TEI-W00595) in patients with RA 
after multiple ascending dose (MAD) 
administration 
• 
PK endpoints 
The following PK parameters for TCK-276 and 
TEI-W00595 will be determined, if calculable: 
o 
Cmax: Maximum plasma concentration 
determined directly from the 
concentration-time profile (Days 1 and 
7) 


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Objectives 
Endpoints 
o 
tmax: Time of maximum plasma 
concentration determined directly from 
the concentration-time profile (Days 1 
and 7) 
o 
AUCtau: Area under the plasma 
concentration-time curve over a dosing 
interval, tau = 24 hours (Days 1 and 7) 
o 
AUC0-t: Area under the plasma 
concentration-time curve up to last 
measurable concentration (Days 1 and 
7) 
o 
AUC0-inf: Area under the plasma 
concentration-time curve from pre-dose 
(time 0) extrapolated to infinite time 
(Days 1 and 7) 
o 
MRTlast: Mean residence time up to last 
measurable concentration (Day 1 only) 
o 
MRT0-inf: Mean residence time 
extrapolated to infinity (Days 1 and 7) 
o 
t½: Terminal elimination half-life 
(Days 1 and 7) 
o 
CL/F: Apparent total body clearance 
(Days 1 and 7), determined for parent 
only 
o 
Vz/F: Apparent volume of distribution 
based on terminal phase (Days 1 and 7), 
determined for parent only 
o 
Metabolic ratio (MR) for Cmax: Molar 
metabolic ratio of Cmax calculated as 
(Cmax [metabolite] × molecular weight 
of parent)/(Cmax [parent] × molecular 
weight of metabolite) (Days 1 and 7) 
o 
MR for area under the plasma 
concentration-time curve (AUC): Molar 
metabolic ratio of AUC calculated as 
(AUC [metabolite] × molecular weight 
of parent)/(AUC [parent] × molecular 
weight of metabolite) (Days 1 and 7) 
o 
Ctrough: Concentration in a dosing period 
defined as the pre-dose concentration of 
the day 


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Objectives 
Endpoints 
o 
Racc (Cmax): Accumulation ratio based 
on Cmax: Calculated as Cmax on 
Day 7/Cmax on Day 1 
o 
Racc (AUCtau): Accumulation ratio based 
on AUCtau: Calculated as AUCtau on 
Day 7/AUCtau on Day 1 
The following urinary PK parameters for 
TCK-276 will be determined in this study: 
o 
Ae: Amount of study drug excreted 
unchanged in the urine (Days 1 and 7) 
o 
Fe: Percentage of study drug excreted 
unchanged in the urine (Days 1 and 7) 
o 
CLr: Renal clearance (Days 1 and 7) 
Other PK parameters will be determined if 
needed. 
Exploratory 
• 
To evaluate the effect of TCK-276 on 
disease activity and biomarkers in 
patients with RA 
• 
Exploratory endpoints 
The following exploratory disease activity 
parameters for RA will be assessed: 
o 
American College of Rheumatology 
(ACR) 20/50/70 response criteria 
o 
Disease activity score 28 (DAS28) 
o 
Clinical disease activity index (CDAI) 
o 
Simplified disease activity index 
(SDAI) 
The following exploratory biomarkers will be 
assessed: 
o 
Matrix metalloproteinase-3 (MMP-3) 
o 
Granulocyte macrophage 
colony-stimulating factor (GM-CSF) 
o 
C-X-C motif chemokine ligand 10 
(CXCL10) 
o 
C-C motif chemokine ligand 2 (CCL2) 
o 
Cartilage oligomeric matrix protein 
(COMP) 
o 
Tumor necrosis factor (TNF)-alpha 
o 
TNF-R1 
o 
Interleukin-6 (IL-6) 


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4 Study Design 
4.1 Overall Design 
This is a Phase 1, multi-center, double-blind, randomized, placebo-controlled, MAD study to 
evaluate the safety, tolerability, and PK of orally administered TCK-276 in both males and 
females with RA. Blood samples for possible future pharmacogenetic, possible future metabolite 
assessments, and possible future pharmacodynamic (PD) assessments will be collected. 
A total of thirty-two (32) patients with RA will be enrolled in this clinical study. This MAD study 
will consist of 4 cohorts of 8 patients (6 active treatment and 2 matching placebo, or a 3:1 ratio), 
each receiving an oral dose of TCK-276 or matching placebo for 7 days (QD under fed 
condition) as shown in Figure 1–1. The first cohort will be divided into 2 subgroups to 
implement the sentinel dosing approach. Within the cohort, the first subgroup will consist of 
2 sentinel patients; one patient will receive TCK-276, and one patient will receive matching 
placebo. The second subgroup will consist of 6 patients (5 active treatment, 1 matching placebo). 
Individual patients in the second subgroup will be dosed at least 72 hours after the first dose of 
the second patient of the first subgroup following a decision by the Investigators based on all 
available safety data from the sentinel patients up to 48 hours post-dose. Subsequent cohorts 
(cohort 2-4) will not include the sentinel dosing approach. 
Patients will be admitted to the site from the morning of Day -1 and sequestered for the duration 
of the treatment (dosing) period. Each patient will receive QD oral doses of either TCK-276 or 
matching placebo administered as tablets under fed condition in the morning of Day 1 to Day 7. 
The patients will be discharged on Day 10. The planned dose levels to be tested are 10 mg 
(Cohort 1), 25 mg (Cohort 2), 75 mg (Cohort 3), and 150 mg (Cohort 4) of TCK-276. Based on 
the results from the SAD study (5 mg to 185 mg dosing) and the projected clinical effective dose 
(i.e., 75 mg), 10 mg is selected as the starting dose level in the MAD study. The dose in 
Cohorts 2, 3, and 4 may be adjusted based on the safety and PK results from the previous 
cohorts, if necessary. The overall exposure to TCK-276 (in terms of geometric mean area under 
the plasma concentration-time curve over a dosing interval [AUCtau, tau = 24 hours]) on Day 7 
would not be expected to exceed 
 
. Further details are presented in Figure 4–1. 
Dose escalation will only be allowed after blinded assessment of all safety, tolerability, and PK 
data up to Day 10 from each previous cohort evaluated by Investigators, Medical Monitor, and 
Sponsor representatives during the Safety Review Committee (SRC) meeting.  


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All patients (including patients who terminate the study early) will return to the site 13 days after 
the first TCK-276 or TCK-276 matching placebo administration for follow-up procedures and 
for the end of treatment examination. 
Duration of patient participation from the Screening Visit to the end of treatment examination 
will be approximately 42 days. This includes 27 days for the Screening period, 11 days for the 
in-house Treatment period (patients will be confined from the morning of Day -1 until all safety 
assessments have been completed on Day 10), and 4 days after the end of the Treatment period, 
for the Follow-up/EOT Visit.  
If the Investigator, the Sponsor, or the Medical Monitor becomes aware of conditions or events 
that suggest a possible hazard to patients if the clinical study continues, the clinical study may be 
terminated after appropriate consultation between the involved parties. The clinical study may 
also be terminated at the Sponsor’s discretion in the absence of such a finding. 
 




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4.2 Scientific Rationale for Study Design 
This study evaluates the safety, tolerability, and PK of ascending multiple doses of TCK-276 
administered as oral tablet(s). The design is standard and is considered appropriate to meet the 
objectives of this exploratory study. 
A double-blind, placebo-controlled study is appropriate and standard for an ascending multiple 
dose study. This design will minimize bias and provide reference data (i.e., data from 
placebo-treated patients) which will aid in the interpretation of results. The SRC will review 
available blinded safety, tolerability, and PK data after each cohort to confirm whether it is safe 
to proceed with the next planned dose, whether the dose escalation should be stopped, or if the 
dose should be lowered, repeated or titrated in the subsequent cohort. 
The safety assessments for the study are accepted measures for ensuring safety of patients during 
a clinical study. The PK sampling schedule is considered appropriate given the information 
available. The justification for dose selection is discussed in Section 4.3. 
4.3 Justification for Dose 
In the SAD study, which included dose-levels up to 185 mg (capsule), TCK-276 was generally 
safe and well tolerated in healthy subjects with no reports of SAEs nor discontinuations due to 
AEs. The starting dose for the MAD study (10 mg, tablet) is sufficiently lower than the highest 
dose in the SAD study (185 mg, capsule), and the projected clinical effective dose (75 mg) that 
was calculated from nonclinical pharmacological study using the rat adjuvant-induced arthritis 
model.  
Patients with RA will be enrolled in this MAD study. Given the data for recently approved RA 
drugs, an up to 2-fold increased exposure in patients with RA compared to healthy subjects was 
taken into consideration as a conservative approach. Even if a 2-fold higher exposure in patients 
with RA would occur, the exposure of the 10 mg in the MAD study corresponds to 20 mg in 
healthy subjects, which is sufficiently lower than that of the highest dose in the SAD study 
(185 mg) and the projected clinical effective dose (75 mg). 
Therefore, 10 mg as tablet formulation is considered the appropriate starting dose in the MAD 
study. 
The dosing frequency (i.e., QD) was selected considering the PK characteristics of TCK-276 and 
patient’s convenience. The dosing duration (7 days) was considered sufficient to achieve steady 
state conditions. 


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Dose Escalation 
In this MAD study, the dose escalation progression will be from 10, 25, 75, and up to 150 mg in 
subsequent cohorts. The overall exposure to TCK-276 (in terms of geometric mean AUCtau) on 
Day 7 is not expected to exceed the predefined AUC cap 
. The exposure at 
150 mg dosing in tablet formulation is assumed to be less than the predefined AUC cap based on 
the results from the SAD study (5 mg to 185 mg, capsule). Therefore, 150 mg is chosen for the 
highest dose. The dose in Cohorts 2, 3, and 4 may be adjusted based on the safety and PK results 
from the previous cohorts, if necessary. Dose escalation will only be allowed after blinded 
assessment of all safety, tolerability, and available PK data up to Day 10 from each previous 
cohort evaluated by Investigators, Medical Monitor, and Sponsor representatives during the SRC 
meeting. 
4.4 End of Study Definition 
The end of the study is defined as the date of the last visit of the last patient in the study or last 
scheduled procedure shown in the Schedule of Activities (SoA) (Table 1-1). 
A patient is considered to have completed the study if he/she has completed all periods of the 
study including the last visit. 
5 Study Population 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
The study population will consist of patients with RA. Patients must be able to provide written 
consent and meet all the inclusion criteria and none of the exclusion criteria. 
5.1 Inclusion Criteria 
Patients who meet the following criteria will be considered eligible to participate in the clinical 
study: 
1. Patient voluntarily agrees to participate in this study and signs an Institutional Review Board 
(IRB) approved informed consent prior to performing any of the Screening Visit procedures. 
2. Patient is able to understand and is willing to comply with all study requirements, and willing 
to follow the instructions of the study staff. 


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3. Diagnosis of RA and meeting the 2010 American College of Rheumatology/European 
League Against Rheumatism classification criteria for RA9(total score 6 or greater/10 
diagnosed at least 3 months prior to the Screening Visit). 
4. Patient between the ages of 18 and 64 years, inclusive, at the Screening Visit.  
5. Female patient must be not pregnant, not breast feeding and one of the following conditions 
need to apply: 
a. Of non-childbearing potential based on documented surgical treatment (hysterectomy, 
bilateral salpingectomy, bilateral oophorectomy) or post-menopausal, meaning patient 
had spontaneous amenorrhea for at least 12 months without alternate medical cause prior 
to Screening Visit and follicle stimulating hormone (FSH) > 40 U/mL at the Screening 
Visit. 
OR 
b. Of childbearing potential and using a highly effective method of contraception (failure 
rate of < 1% per year) and agrees to remain on a highly effective method from the time 
of signing the informed consent form (ICF) until 21 days after the last dose. 
6. Male patient must agree to stay abstinent or must use together with his female partner(s) a 
form of highly effective contraceptive (failure rate of < 1% per year) from the time of signing 
the ICF until up to 3 months after the last dose of the study drug. 
7. Nonsmokers (or other nicotine use) as determined by history (no nicotine use over the past 
one year prior to the Screening Visit) and by negative urine cotinine concentration 
(< 200 ng/mL) at the Screening Visit and at Admission. 
8. Body mass index (BMI) between 18.5 and 32.0 kg/m2, inclusive, at the Screening Visit. 
9. Patient is required to have completed a COVID-19 vaccine regimen within no more than 
5 months prior to screening to be eligible for the study. 
10. Permitted concomitant medications for any reason, must be on a stable dose (12 weeks for 
methotrexate and anti-malarials and at least 30 days for other medications prior to the 
Screening Visit).  
Permitted medications include: anti-malarials; nonsteroidal anti-inflammatory drugs 
including selective cyclooxygenase-2 inhibitors at approved dosage, and low dose oral 
corticosteroids (prednisone ≤ 10 mg/day or equivalent); methotrexate ≤ 25 mg by mouth 
(PO) or subcutaneous (SC) weekly concomitantly with folic acid or folinic acid. 


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5.2 Exclusion Criteria 
Patients who meet one or more of the following criteria will not be considered eligible to 
participate in the clinical study: 
1. Female patients who are breastfeeding or have a positive urine pregnancy test either at the 
Screening Visit or at Admission. 
2. Patients who are unable to eat the prescribed meals during the stay at the site; vegetarian or 
vegan. 
3. Patient has a history of significant drug allergy, as determined by the Investigator. 
4. Patient has used a study drug, any prohibited medication(s) (see Section 6.8.2), 
over-the-counter (OTC) medications, vitamins, dietary and herbal supplements within 
14 days or 5 half-lives if known (whichever is longer) prior to the first dose of study drug. 
5. Patient has a history of active suicidal ideation in the past 6 months prior to the Screening 
Visit, or any psychiatric disorders that will affect the patient’s ability to participate in the 
study as determined by the Investigator. 
6. Patient has a current or recent (within 14 days prior to the Screening Visit) history of 
uncontrolled, clinically significant infectious, hematological, renal, endocrine, pulmonary, 
gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease. 
7. Patient with any of the following laboratory abnormalities either at the Screening Visit or at 
Admission. These assessments may be repeated once at the discretion of the Investigator.  
a. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) ≥ 2 times the upper 
limit of normal (ULN) 
b. Bilirubin ≥ 1.5 times ULN  
c. An estimated glomerular filtration rate (eGFR) according to Cockcroft-Gault 
≤ 60 mL/min  
d. Hematology values below the lower limit of normal: Neutropenia, absolute neutrophil 
count < 1000/mm3, hemoglobin < 9 g/dL, white blood cell < 2.5 × 103/μL 
e. Clinically significant abnormalities, as judged by the Investigator 
8. Patient has a history of alcohol and/or drug abuse within 24 weeks of the Screening Visit. 
9. Patient has positive results for drug testing either at the Screening Visit or at Admission. 
10. Patient has positive breath alcohol test either at the Screening Visit or at Admission. 


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11. Regular consumption of alcohol within 6 months prior to the Screening Visit 
(> 7 drinks/week for females, > 14 drinks/week for males where 1 drink = 5 ounces [150 mL] 
of wine or 12 ounces [360 mL] of beer or 1.5 ounces [45 mL] of hard liquor), or use of drugs 
of abuse (such as marijuana) within 3 months prior to the Screening Visit. 
12. Patient has positive test for hepatitis B surface antigen (HBsAg), anti-hepatitis B core (HBc) 
antibodies, hepatitis C virus (HCV) antibody, and/or human immunodeficiency virus (HIV) 
antibody at Screening Visit. 
13. Patient has QT interval corrected for heart rate (QTc) using Fridericia’s correction (QTcF) 
> 450 ms for males or QTcF > 470 ms for females either at the Screening Visit or Admission, 
based on safety 12-lead electrocardiogram (ECG). Patient has Screening or Admission ECG 
with second- or third-degree atrioventricular block, bundle branch block, arrhythmia (but not 
sinus arrhythmia or supraventricular premature beats), or illegible QT interval. 
14. Patient has history or evidence of cardiopathy, acute coronary syndrome, hypertrophic 
cardiomyopathy, myocarditis or QT prolongation syndrome. 
15. Patient is unwilling to abstain from drinks and foods containing alcohol, grapefruit, or 
caffeine (including coffee, tea, coke, energy drinks, or chocolate) starting 72 hours prior to 
the Admission until Day 14 Follow-up Visit. 
16. Patient has donated blood or experienced acute blood loss (including plasmapheresis) of 
greater than 500 mL within 90 days prior to the first dose of study drug. 
17. Patients with a known immunodeficiency disorder. Have a history of a major organ transplant 
or hematopoietic stem cell/marrow transplant. 
18. Patients with infections requiring treatment or hospitalization within 14 days prior to the 
Screening Visit, parenteral antimicrobial therapy within 60 days prior to the Screening Visit, 
infected joint prosthesis; history of herpes zoster, active herpes simplex, or herpes simplex on 
suppressive therapy. 
19. Patient has a chronic hepatic disease or hepatic impairment. 
20. Patient has a history of Mycobacterium tuberculosis or positive interferon gamma release 
assay for tuberculosis (IGRA-TB) or abnormal chest X-ray (for positive IGRA-TB patients) 
at the Screening Visit. 
21. Patient has a history of any lymphoproliferative disorder. 
22. Patient has a history of COVID-19 unless fully recovered with no sequalae for 14 days. 
23. Patient who had a severe course of COVID-19 (extracorporeal membrane oxygenation, 
mechanically ventilated). 


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24. Patient who has recent (within 14 days prior to the Screening Visit or between the Screening 
Visit and Admission) exposure to someone who has COVID-19 symptoms or positive test 
result. 
25. Patient who has a positive reverse transcription polymerase chain reaction (RT-PCR) test for 
SARS-CoV-2 either at the Screening Visit or at Admission. 
26. Patient who has clinical signs and symptoms consistent with SARS-CoV-2 infection; e.g., 
fever, dry cough, dyspnea, sore throat, fatigue, or positive SARS-CoV-2 test result within 
14 days prior to and including either the Screening Visit or Admission. 
27. Patients may not receive any live/attenuated vaccine from 30 days prior to the Screening 
Visit until Day 14 Follow-up Visit.  
28. COVID-19 vaccine should not be given 1 week prior to the Screening Visit. 
29. Patients treated with any other medications listed under Inclusion Criteria #9 including all 
medications listed in Section 6.8.2. 
30. Patients with malignancy or history of malignancy except adequately treated or excised 
non-metastatic basal cell or squamous cell cancer of the skin or cervical carcinoma in situ. 
Previous treatment with total lymphoid irradiation. 
31. History of recurrent inflammatory joint disease other than RA (e.g., gout, Lyme disease) or 
history of any other autoimmune rheumatic diseases other than Sjogren’s syndrome. 
32. Major surgery within 30 days prior to the Screening Visit or patients with planned surgery. 
33. Patients who have an abnormal chest X-ray for interstitial lung disease (ILD) at the 
Screening Visit and/or patients with history of ILD. 
34. History of fainting or family history of sudden death. 
35. Patient has any disorder that would interfere with the absorption, distribution, metabolism or 
excretion of study drug. 
36. Patient has a history of deep vein thrombosis and/or pulmonary embolism. 
37. Patient has poor venous access. 
38. Patient is an employee of the clinical research team (any Teijin or research site employee) or 
has a family member who is an employee of these organizations. 


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39. Patient is unable to understand the protocol requirements, instructions, study related 
restrictions, nature, scope, and possible consequences of the clinical study. Patient is unlikely 
to comply with the protocol requirements, instructions and study related restrictions; e.g., 
uncooperative attitude, inability to return for Follow-up Visits and improbability of 
completing the clinical study.  
40. Patient is judged as inappropriate for study participation by the Investigator for other reasons. 
5.3 Lifestyle Considerations 
5.3.1 
Meals and Dietary Restrictions 
Refrain from consumption of grapefruit foods or beverages, or Seville-orange containing foods 
(e.g., orange marmalade) or beverages from 72 hours before Admission until Day 14. 
5.3.2 
Caffeine, Alcohol, and Tobacco 
1. During each dosing session, patient will abstain from ingesting caffeine- or 
xanthine-containing products (e.g., coffee, tea, cola drinks, and chocolate) for 72 hours 
before Admission until Day 14. 
2. During each dosing session, patients will abstain from alcohol and alcohol-containing foods, 
medications, or beverages for 72 hours before Admission until Day 14. 
3. Patients who use tobacco products will be instructed that use of nicotine-containing products 
(snuff, chewing tobacco, cigars, pipes, vaping tobacco products or nicotine-replacement 
products such as nicotine chewing gum and nicotine plasters) will not be permitted from 
1 year before the Screening Visit until Day 14. 
5.4 Screen Failures 
A screen failure occurs when a patient who consents to participate in the clinical study is not 
subsequently randomly assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure patients to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to respond 
to queries from regulatory authorities. Minimal information includes demography, reason for 
screen failure (e.g., eligibility requirements failed), and documentation of any medical 
occurrences that qualify as SAEs. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once. Rescreened patients should be assigned a new patient number for every 
Screening/Rescreening event. 






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or will be destroyed locally in agreement with the Sponsor and Certificates of Destruction 
provided to the Sponsor. 
Further guidance and information for the final disposition of unused study intervention are 
provided in the study reference manual or other specified location. 
6.3 Measures to Minimize Bias: Randomization and Blinding 
Table 6–3 
Measures to Minimize Bias 
Study using IRT 
All patients will be centrally randomized using an IRT. Each patient will 
be assigned a unique number (randomization number) that encodes the 
patient’s assignment to a treatment group within one of the 4 cohorts of 
the study, according to the randomization schedule generated by IRT 
using a validated computer program. Details of the procedure are 
described in the IRT Manual provided to all sites. 
Study intervention will be administered/dispensed at the study visits as 
summarized in the SoA (Table 1-1). 
Returned study intervention should not be re-dispensed to the patients. 
Blind break 
(IRT) 
This is a double-blind study in which patients/care 
providers/Investigators/outcomes assessors, are blinded to study 
intervention. The IRT will be programmed with blind-breaking 
instructions. In case of an emergency, the Investigator has the sole 
responsibility for determining if unblinding of a patient’s study 
intervention assignment is warranted. Patient safety must always be the 
first consideration in making such a determination. If the Investigator 
decides that unblinding is warranted, the Investigator should make every 
effort to contact the Sponsor prior to unblinding a patient’s study 
intervention assignment unless this could delay emergency treatment for 
the patient. If a patient’s study intervention assignment is unblinded, the 
Sponsor must be notified within 24 hours of this occurrence. The date and 
reason for the unblinding must be recorded. 


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Blinded study 
with unblinded 
third party who 
is dispensing 
intervention 
Patients will be randomly assigned in a 3:1 ratio to receive study 
intervention. Investigators will remain blinded to each patient’s assigned 
study intervention throughout the course of the study. To maintain this 
blind, an otherwise uninvolved third party will be responsible for the 
reconstitution and dispensation of all study intervention and will endeavor 
to ensure that there are no differences in time taken to dispense following 
randomization. 
This third party will instruct the patient/patient’s LAR to avoid discussing 
the taste, dosing frequency, or packaging of the study intervention with 
the Investigator. 
In the event of a quality assurance audit, the auditor(s) will be allowed 
access to unblinded study intervention records at the site(s) to verify that 
randomization/dispensing has been conducted accurately. 
IRT = Interactive Response Technology; LAR = legally authorized representative. 
Sponsor safety staff may unblind the intervention assignment for any patient with an SAE. If the 
suspected unexpected serious adverse reaction (SUSAR) requires that an expedited regulatory 
report be sent to one or more regulatory agencies, a copy of the report, identifying the patient’s 
intervention assignment, may be sent to Investigators in accordance with local regulations and/or 
Sponsor policy. 
6.4 Study Intervention Compliance 
When patients are dosed at the site, they will receive study intervention directly from the 
Investigator or designee, under medical supervision. The date and time of each dose administered 
in the clinic will be recorded in the source documents. The dose of study intervention and study 
patient identification will be confirmed at the time of dosing by a member of the study site staff 
other than the person administering the study intervention.  
6.5 Dose Modification 
The dosing schedule may be adjusted based on the safety and PK results, if necessary, to expand 
a dosing cohort to further evaluate safety, and/or PK findings at a given dose level or to add 
cohorts to evaluate additional dose levels. The study procedures for these additional 
patient(s)/cohort(s) will be the same as that described for other study patients/cohorts. 
6.6 Continued Access to Study Intervention After the End of the Study 
Study intervention for RA will not continue beyond this study. 


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6.7 Treatment of Overdose 
For this study, any dose of TCK-276 greater than 10 mg (Cohort 1), 25 mg (Cohort 2), 75 mg 
(Cohort 3), and 150 mg (Cohort 4) within a 24-hour time period will be considered an overdose. 
The Sponsor does not recommend specific treatment for an overdose. 
In the event of an overdose, the Investigator should: 
a. Contact the Medical Monitor immediately. 
b. Evaluate the patient to determine, in consultation with the Medical Monitor, whether 
study intervention should be interrupted or whether the dose should be reduced. 
c. Closely monitor the patient for any AE/SAE and laboratory abnormalities until TCK-276 
can no longer be detected systemically. 
d. Obtain a plasma sample for PK analysis if requested by the Medical Monitor (determined 
on a case-by-case basis). 
e. Document the quantity of the excess dose as well as the duration of the overdose. 
6.8 Concomitant Therapy 
Any medication or vaccine (including OTC or prescription medicines, recreational drugs, 
vitamins, and/or herbal supplements) or other specific categories of interest that the patient is 
receiving at the time of enrollment or receives during the study must be recorded along with: 
a. reason for use 
b. dates of administration including start and end dates 
c. dosage information including dose and frequency 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy before the Investigators initiate the therapy. 
6.8.1 
Permitted Medications 
Permitted medication includes anti-malarials nonsteroidal anti-inflammatory drugs including 
selective cyclooxygenase-2 inhibitors at approved dosage, low dose oral corticosteroids 
(prednisone ≤ 10 mg/day or equivalent); methotrexate ≤ 25 mg PO or SC weekly concomitantly 
with folic acid or folinic acid. 


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6.8.2 
Prohibited Medications 
Prohibited medications may include, but are not limited to, those listed in Appendix 6 
(Section 10.6). These listings of prohibited concomitant treatments are not considered all 
inclusive. If the use of these types of medications is medically necessary during the course of the 
study, the Investigator must contact the Sponsor Medical Monitor to discuss further 
administration of TCK-276. A decision to allow the patient to continue in the study will be made 
on a case-by-case basis. 
6.8.2.1 
Caution 
 
 Investigators should recognize potential 
interactions with these drugs and avoid maximum doses, if possible, if these drugs are used. 
Cautioned medications may include, but are not limited to, those listed in Appendix 6 
(Section 10.6). These listings of cautioned concomitant treatments are not considered all 
inclusive. 
7 Discontinuation of Study Intervention and Patient Discontinuation 
7.1 Discontinuation of Study Intervention 
It may be necessary for a patient to permanently discontinue study intervention. If study 
intervention is permanently discontinued, the patient will remain in the study to be evaluated for 
clinical observation and safety monitoring. See the SoA (Table 1-1) for data to be collected at the 


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time of discontinuation of study intervention and follow-up and for any further evaluations that 
need to be completed. 
7.1.1 
Overall Study Stopping Criteria 
The study will be stopped if any of the following occur and are thought to be at least possibly 
related to study intervention agreed upon by the SRC: 
• 
Two patients develop the same Grade 3 AE (grading is based on the Common Terminology 
Criteria for Adverse Events [CTCAE] version 5.0).  
• 
One patient develops ≥ Grade 4 AE (CTCAE version 5.0).  
• 
Death of a patient at any time. 
If any of the following scenarios occur within a cohort with reasonable possibility of a causal 
relationship with study drug, dosing will be stopped, and further dosing will not be initiated. 
• 
One or more patients experience increased alanine ALT or AST > 3 × ULN with total 
bilirubin (TBL) > 2 × ULN or increased AST > 3 × ULN accompanied by alkaline 
phosphatase (ALP) > 1.5 × ULN. 
• 
One or more patients experience a decrease of absolute neutrophil count less than 
1,000/mm3 or white blood cell (WBC) less than 2.5 × 103/μL or platelet count less than 
75,000/μL. 
• 
One or more patients have an increase of more than 60 ms in QTcF compared to the baseline 
QTcF (baseline QTcF = value obtained on Day 1 at pre-dose in the treatment period) or 
QTcF > 500 ms or other clinically significant conduction disturbance or arrhythmia. All 
ECGs for this determination must be performed under strict resting conditions. 
• 
Two or more patients, who receive study intervention, have tachycardia defined as resting 
supine heart rate > 125 beats per minute (bpm) persisting for at least 10 minutes. 
• 
Two or more patients, who receive study intervention, have symptomatic bradycardia 
defined as resting supine heart rate < 40 bpm accompanied with symptoms of bradycardia 
while awake persisting for at least 10 minutes. 
• 
Two or more patients, who receive study intervention, develop hypertension defined as an 
increase in resting supine systolic blood pressure (BP) > 40 mmHg to above a reading of 180 
mmHg and persisting for at least 10 minutes. 
If the criteria were met, the SRC will carefully review the totality of data, considering moderate 
non-serious AEs at least possibly related to the study intervention administration in unblinded 


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fashion, the number of patients in which they occur, concurrency of more than one within the 
same patient. Although changes from normal ranges are most relevant, changes from baseline 
measurements will also considered observing any trends. If consensus among the voting SRC 
members cannot be reached, then the Principal Investigator, who has the ultimate responsibility 
for the safety of the patients, will make the final decision. 
7.1.2 
Dose Escalation  
After each sub-cohort and cohort, the Principal Investigator and the SRC will evaluate the safety, 
tolerability data and available PK data up to Day 10 to determine the next dose. The predefined 
AUCtau 
 level will be used in the SRC as a 
benchmark so that the human exposure can be compared with preclinical exposure data. The 
safety and PK data from all patients in the previous cohort must be reviewed before a decision to 
escalate the dose can be made. Dose escalation will only occur if data from a minimum of 
6 patients have been reviewed from the previous lower dose group, such that data from a 
minimum of 4 patients who have received active treatment will be used to make the dose 
escalation decision (based on the randomization of 6 active treatment:2 matching placebo). 
Doses will not exceed a dose level at which the geometric mean of AUCtau exceeds or would be 
anticipated to exceed the following limits: 
 
 
 
 
 
If PK data indicate that the predefined AUC 
 has 
been achieved or would be exceeded with escalation to the next higher dose, dose escalation will 
be stopped. A dose in which the stopping criteria have been met will not be repeated and further 
dose escalation will not occur. Where stopping criteria have not been met, the decision of the 
SRC may be to give the next intended dose, a smaller than the predefined dose increment, a 
repeated dose or to stop dosing. The SRC will make the decision for the next dose level (to give 
the next intended dose, a greater or smaller dose increment than the intended dose, a repeated 
dose) or whether to stop the study after reviewing all the pertinent safety and any other relevant 
data and decision of the voting members. If consensus among the voting SRC members cannot 
be reached then the Principal Investigators, who have the ultimate responsibility for the safety of 
the patients, will make the final decision on the next dose level or whether to stop the study. In 
any event, dose escalation can only occur if agreed by the Principal Investigators. The decisions 
of the SRC on the next dose level will be documented and provided to all the appropriate parties 


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involved with the study, including the pharmacist to enable study intervention preparation for the 
next scheduled dosing day. 
Initially the data will be reviewed blinded, but if the Principal Investigators or the SRC consider 
it necessary due to a safety concern, either individual patients or the entire cohort may be 
unblinded to enable decision making. Before breaking the code, the potential decisions and 
actions should be determined. The code will be broken according to local standard operating 
procedures (SOPs). Following review of data from a cohort of patients, the timing of assessments 
and/or blood samples may be adjusted for subsequent cohorts. 
Dose escalation will be stopped if any of the following occur and are thought to be at least 
possibly related to study intervention agreed upon by the SRC. It is determined that the limit of 
safety and/or tolerability has been reached as determined by the SRC. 
• Two or more of the patients in a cohort develop ≥ Grade 2 AEs (CTCAE version 5.0) in the 
same category, related to TCK-276, as judged by the Investigator.  
• One or more patients in a cohort develop ≥ Grade 3 AEs (CTCAE version 5.0) in the same 
category, related to TCK-276, as judged by the Investigator. 
7.2 Patient Discontinuation/Withdrawal from the Study 
A patient may withdraw from the study at any time at their own request or may be withdrawn at 
any time at the discretion of the Investigator for safety, behavioral, or compliance reasons. The 
patient will be permanently discontinued from the study intervention and the study at that time. 
If the patient withdraws consent for disclosure of future information, the Sponsor may retain and 
continue to use any data collected before such a withdrawal of consent. 
If a patient withdraws from the study, he/she may request destruction of any samples taken and 
not tested, and the Investigator must document this in the site study records. 
At the time of discontinuing from the study, if possible, an early discontinuation visit should be 
conducted, as shown in the SoA (Table 1-1). Refer to the SoA for data to be collected at the time 
of study discontinuation and follow-up and for any further evaluations that need to be completed. 
In addition to the stopping rules described in Section 7.1.1, a patient will be withdrawn by the 
Investigator or designee from the study and not be allowed to continue with the study if any of 
the following criteria are fulfilled: 
• Any patient who develops an AE ≥ Grade 3 (CTCAE version 5.0).  


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• Patient will be discontinued from further dosing if following toxicities are observed: 
o 
Hematologic: Neutropenia, absolute neutrophil count < 1000/mm3, 
hemoglobin < 9 g/dL, white blood cell < 2.5 × 103/μL 
o 
Renal: serum creatinine > 3 × ULN  
o 
Hepatic: bilirubin elevation > 2 × ULN; AST or ALT elevation > 3.0 × ULN  
o 
QTcF prolongation: mean QTcF ≥ 500 ms or change from the nearest baseline > 60 ms 
o 
ECG abnormalities including ventricular tachycardia or ventricular fibrillation, complete 
heart block (Grade III atrioventricular block) or second degree atrioventricular block 
Mobitz type II  
o 
Hypertension: resting systolic BP ≥ 180 mmHg and ≤ 80 mmHg diastolic BP  
Hypotension: resting systolic BP ≥ 110 mmHg and ≤ 40 mmHg diastolic BP 
o 
Pulse (resting) < 35 or > 110 bpm 
• A patient may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral or 
administrative reasons.  
• If the patient withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
• If a patient withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the Investigator must document this in the site study records.  
• Withdrawn patients may be replaced if patient withdrawal is not due to safety or tolerability 
reasons.  
• Refer to the SoA for assessments to be performed at the time of study discontinuation. 
o 
At the discretion of the Investigator or designee, the patient may continue with study 
assessments after discontinuation until the final Follow-up Visit procedures are 
performed. A reasonable effort will be made to determine the reasons why a patient fails 
to return for the necessary visits or is discontinued from the study. If the patient is 
unreachable by telephone, a registered letter, at the minimum, should be sent to the 
patient requesting him/her to contact the study center. 
While patients are encouraged to complete all study evaluations, they may withdraw from the 
study at any time and for any reason. Every effort will be made to determine why any patient 
withdraws from the study prematurely. All patients who withdraw from the study with an 
ongoing AE must be followed until the event is resolved or deemed stable. If a patient withdraws 
prematurely after dosing, all data to be collected prior to discharge from the clinical site should 
be collected at the time of premature discontinuation or at the scheduled discharge. 


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Patient participation may be terminated prior to completing the study and the reason recorded as 
follows: 
1. Adverse event  
2. Protocol violation  
3. Loss to follow-up  
4. Patient withdrew consent at own request  
5. Other 
A genuine effort must be made to determine the reasons why a patient fails to return for the 
necessary visits or is discontinued from the study. If the patient is unreachable by telephone, a 
registered letter, at the minimum, should be sent to the patient requesting him/her to contact the 
clinic. 
Patients who are withdrawn after randomization for non-drug-related reasons may be replaced 
following discussion between the Investigator and the Sponsor. Patients withdrawn after 
randomization as a result of AEs thought to be related to the study drug will generally not be 
replaced. 
7.3 Lost to Follow-Up 
A patient will be considered lost to follow-up if they repeatedly fail to return for scheduled visits 
and are unable to be contacted by the study site. 
The following actions must be taken if a patient fails to return to the clinic for a required study 
visit: 
a. The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible (and within the visit window, where one is defined), counsel the patient on the 
importance of maintaining the assigned visit schedule, and ascertain whether the patient 
wishes to and/or should continue in the study. 
b. In cases in which the patient is deemed lost to follow-up, the Investigator or designee 
must make every effort to regain contact with the patient (where possible, 3 telephone 
calls and, if necessary, a certified letter to the patient’s last known mailing address or 
local equivalent methods). These contact attempts should be documented in the patient’s 
medical record/case report form (CRF). 


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c. Should the patient continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
d. Site personnel, or an independent third party, will attempt to collect the vital status of the 
patient within legal and ethical boundaries for all patients randomized, including those 
who did not get study intervention. Public sources may be searched for vital status 
information. If vital status is determined as deceased, this will be documented and the 
patient will not be considered lost to follow-up. Sponsor personnel will not be involved in 
any attempts to collect vital status information. 
8 Study Assessments and Procedures 
Study procedures and their timing are summarized in the SoA (Table 1-1). Protocol waivers or 
exemptions are not allowed. 
A Safety Management Plan (SMP) will be signed between the Sponsor and 
. 
Immediate safety concerns should be discussed with the Sponsor immediately upon occurrence 
or awareness to determine if the patient should continue or discontinue study intervention. 
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential patients 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of all 
patients screened and to confirm eligibility or record reasons for screening failure, as applicable. 
Procedures conducted as part of the patient’s routine clinical management (e.g., blood count) and 
obtained before signing of the ICF may be used for screening or baseline purposes provided the 
procedures met the protocol-specified criteria and were performed within the timeframe defined 
in the SoA. 
Safety/laboratory/analyte results that could unblind the study will not be reported to investigative 
sites or other blinded personnel until the study has been unblinded. 
The maximum amount of blood collected from each patient over the duration of the study, 
including any extra assessments that may be required, will not exceed 600 mL  
Blood samples of approximately 520 mL will be collected for measurement of blood 
concentrations of TCK-276 and TEI-W00595 as specified in the SoA (Table 1-1) throughout the 
study period. A maximum of 30 samples may be collected at additional timepoints during the 


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study if warranted and agreed upon between the Investigator and the Sponsor. The timing of 
sampling may be altered during the course of the study based on newly available data (e.g., to 
obtain data closer to the time of peak plasma concentrations) to ensure appropriate monitoring. 
Instructions for the collection and handling of biological samples will be provided by the 
Sponsor. The actual date and time (24-hour clock time) of each sample will be recorded. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples. 
8.1 Administrative Procedures 
8.1.1 
Informed Consent 
Informed consent must be documented according to Appendix 1 (Section 10.1.3).  
8.1.2 
Patient Identification Card 
All patients will be given a patient identification card identifying them as patients in a research 
study. The card will contain study site contact information (including direct telephone numbers) 
to be used in the event of an emergency. The Investigator or qualified designee will provide the 
patient with a patient identification card immediately after the patient provides written informed 
consent. At the time of intervention allocation/randomization, site personnel will add the 
intervention/randomization number to the patient identification card. 
8.1.3 
Calibration of Equipment 
The Investigator (or qualified designee) is responsible for ensuring that any device or instrument 
used for a clinical evaluation/test during the study that provides information about eligibility 
criteria and/or safety or efficacy parameters is suitably calibrated and/or maintained to ensure 
that the data obtained are reliable and/or reproducible. Documentation of equipment calibration 
must be retained as source documentation at the study site. 
8.2 Screening and Eligibility Assessments 
8.2.1 
Eligibility Criteria 
All inclusion and exclusion criteria (Section 5.1 and Section 5.2) will be reviewed by the 
Investigator or designee to ensure that the patient qualifies for the study. Recheck of clinical 
status will need to be performed before the first dose of study intervention. 


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8.2.2 
Demography and Other Baseline Information 
The following demographic information will be recorded: 
• Age 
• Ethnic origin (Hispanic/Latino or not Hispanic/not Latino) 
• Race (White, American Indian/Alaska Native, Asian, Native Hawaiian or other Pacific 
Islander, Black/African American) 
• Height, without shoes (cm) 
• Body weight, without shoes (kg) 
• Body mass index (BMI) (kg/m2) 
Other baseline characteristics will be recorded as follows: 
• History of drug abuse 
• History of alcohol abuse 
• Smoking history 
• History of caffeine use (or other stimulating beverages) 
• Special diet (vegetarian and vegan) 
• History of blood or plasma donation 
8.2.3 
Medical History 
A medical history will be obtained by the Investigator or qualified designee. The medical history 
will collect all active conditions and any condition diagnosed within the prior 1 year that the 
Investigator considers to be clinically relevant. Details regarding the disease for which the 
patient has enrolled in this study will be recorded separately and not listed as medical history. 
• The medical history comprises: 
• General medical history 
• Medication history 
• Prior and concomitant medication 
• Reproductive history 
• Onset date of RA 


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• Criteria for the classification of RA used for the diagnosis 
• History of surgery of RA 
• Name of the RA treatment drugs used in the past 
8.2.4 
Prior and Concomitant Medications Review 
The Investigator or qualified designee will review prior medication use and record prior 
medications taken by the patient. 
The Investigator or qualified designee will record medication, if any, taken by the patient during 
the study through the last visit. Concomitant medications will be recorded until the last dose of 
study intervention (or longer if related to an SAE). 
8.2.5 
Screening Assessments 
Patients who have signed an informed consent will undergo following procedures and 
assessments: 
• Viral serology to HBsAg, anti-HBc antibodies, anti-HCV antibody, and/or anti-HIV types 1 
and 2 antibodies 
• Blood and urine drug screen to check the levels of amphetamines, barbiturates, 
benzodiazepines, oxycodone, tricyclic antidepressants, cannabinoids, cocaine, opiates, 
phencyclidine, 3,4-Methylenedioxymethamphetamine (MDMA) and propoxyphene  
• Breath alcohol test by breathalyzer 
• Interferon gamma release assay for tuberculosis (IGRA-TB) or abnormal chest X-ray 
• Urine cotinine test 
• SARS-CoV-2 test measured by real time RT-PCR 
• Classification of disease stage/progression of RA 
• For female patients, a urine β-human chorionic gonadotropin test must be used to confirm 
eligibility 
• For female patients who are post-menopausal, FSH levels will be measured 
Laboratory tests are listed in Table 10–1. 


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8.3 Safety Assessments 
Planned timepoints for all safety assessments are provided in the SoA (Table 1-1). 
8.3.1 
Physical Examinations 
Physical examinations will be performed at the time points detailed in the SoA (Table 1-1). 
Full physical examination: 
An assessment of general appearance and a review of systems (dermatologic, head, eyes, ears, 
nose, mouth/throat/neck, thyroid, lymph nodes, respiratory, cardiovascular, gastrointestinal, 
extremities, musculoskeletal, neurologic, and psychiatric systems). 
Brief physical examination: 
An assessment of the general appearance, skin, cardiovascular system, respiratory system, and 
abdomen. 
The brief physical examination may be extended to a full physical examination if considered 
necessary by the Investigators. Other evaluations may be performed as deemed necessary by the 
Investigators. 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
8.3.2 
Vital Signs 
Vital signs will be assessed at the time points detailed in the SoA (Table 1-1). The following vital 
signs will be measured: 
• Blood pressure (systolic and diastolic [mmHg]) 
• Pulse (bpm) 
• Body temperature (tympanic [ear] or non-contact infrared thermometers) (°C) 
• Respiratory rate (breaths per minute) 
Supine BP and pulse recordings will be made after the patient has been recumbent and at rest 
≥ 5 minutes. 


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8.3.3 
Electrocardiograms 
Standard safety 12-lead ECGs will be performed at the time points detailed in the SoA 
(Table 1-1). 
The12-lead ECGs will be performed after the patient has been resting supine for ≥ 5 minutes. 
The ECG will include all 12 standard leads and a Lead II rhythm strip on the bottom of the 
tracing. The ECG will be recorded at a paper speed of 25 mm/sec. The following ECG 
parameters will be collected: PR interval, QRS interval, RR interval, QT interval and QTc 
interval (QTcF). 
All ECGs must be evaluated by a qualified physician for the presence of abnormalities. 
8.3.4 
Cardiac Telemetry 
To allow a real-time assessment of cardiac safety at the study site, patients will be monitored by 
cardiac telemetry (for real-time assessment of cardiac rate and rhythm). Any clinically 
significant change noted on telemetry will be followed up with a 12-lead ECG. Further 
evaluation and treatment will be performed as deemed appropriate by the Investigators. 
Irrespective of the intervention, the ECG and continuous cardiac monitoring will be repeated 
hourly until the event resolves or the patient is deemed clinically stable by the Investigators. 
8.3.5 
Clinical Safety Laboratory Tests 
Refer to Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and the 
SoA (Table 1-1) for the timing and frequency. 
The Investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study as an AE. The laboratory reports must 
be filed with the source documents. 
Abnormal laboratory findings associated with the underlying disease are not considered 
clinically significant unless judged by the Investigator to be more severe than expected for the 
patient’s condition. 
All laboratory tests with values considered clinically abnormal during participation in the study 
or within 2 months after the last dose of study intervention should be repeated until the values 
return to normal or baseline or are no longer considered clinically significant by the Investigator 
or Medical Monitor. 


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a. If clinically significant/any values do not return to normal/baseline within a period of 
time judged reasonable by the Investigator, the etiology should be identified, where 
possible, and the Sponsor notified. 
b. All protocol-required laboratory tests, as defined in Appendix 2 (Section 10.2), must be 
conducted in accordance with the laboratory manual and the SoA (Table 1-1). 
c. If laboratory values from laboratory tests not specified in the protocol and performed at 
the institution’s local laboratory result in the need for a change in patient management or 
are considered clinically relevant by the Investigator (e.g., are considered to be an SAE or 
an AE or require dose modification), then the results must be recorded. 
8.3.6 
Pregnancy Testing 
Women of non-childbearing potential should only be included after a confirmed negative urine 
pregnancy tests at Screening and on Day - 1. 
Women of childbearing potential should only be included after a confirmed negative urine 
pregnancy test at Screening, Days -1 and 14, and Early termination procedures. 
8.4 Adverse Events, Serious Adverse Events, and Other Safety Reporting 
The means of obtaining AE data should be described (volunteered, checklist, or questioning) as 
should any specific rating scales used and any specifically planned follow-up procedures for AEs 
or any planned re-challenge procedures. 
Consider whether there any protocol-specific events that may need expedited reporting, or 
alternatively, are not required to be reported. Provide guidance for Investigators. If there is a 
specific AE that will be of special interest it should be described in Section 8.4.6. 
The definitions of AEs and SAEs can be found in Appendix 3 (Section 10.3). 
AEs will be reported by the patient (or, when appropriate, by a caregiver, surrogate, or a legally 
authorized representative [LAR]). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for following 
up AE that are serious, considered related to the study intervention or the study, or that caused 
the patient to discontinue the study intervention (see Section 7). 


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The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3 
(Section 10.3). 
Screening form including AE questioning will include specific questions regarding symptoms of 
COVID-19: fever, cough, dry throat, difficulty breathing, and potential exposure in the past 
2 weeks. 
Confirmed and suspected SARS-CoV-2 infection and COVID-19 will be recorded in the AE 
fields. 
8.4.1 
Time Period and Frequency for Collecting Adverse Events and Serious 
Adverse Events Information 
All AEs and SAEs will be collected and recorded for each patient from the date for signing of 
ICF until Day 14 Follow-up Visit or early termination visit i.e., the patient has discontinued or 
completed Day 14 visit in the SoA (Table 1-1). 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours of awareness, 
as indicated in Appendix 3 (Section 10.3). The Investigator will submit any updated SAE data to 
the Sponsor within 24 hours of it being available. 
Investigators are not obliged to actively seek information on AEs or SAEs after the conclusion of 
study participation. However, if the Investigator learns of any SAE, including a death, at any 
time after a patient has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the Investigator must promptly 
notify the Sponsor. 
8.4.2 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the patient is the preferred method to inquire about 
AE occurrence. 
8.4.3 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial AE/SAE report, the Investigator is required to proactively follow each patient at 
subsequent visits/contacts. All SAEs, and non-serious AESIs (as defined in Section 8.4), will be 
followed until resolution, stabilization, until the event is otherwise explained, or the patient is 


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lost to follow-up (as defined in Section 7.3). Further information on follow-up procedures is 
given in Appendix 3 (Section 10.3). 
8.4.4 
Regulatory Reporting Requirements for Serious Adverse Event 
Prompt notification (within 24 hours, see Appendix 3 [Section 10.3]) by the Investigator to the 
Sponsor of an SAE is essential so that legal obligations and ethical responsibilities towards the 
safety of patients and the safety of a study intervention under clinical investigation are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, IRB, and Investigators. 
An Investigator who receives an Investigator Safety Report describing an SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the Sponsor will review and then file 
it along with the IB and will notify the IRB, if appropriate according to local requirements. 
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and forwarded to Investigators as necessary. 
8.4.5 
Pregnancy 
Details of all pregnancies in female patients and, if indicated, partners of male patients will be 
collected after the start of study intervention and until time period for reporting pregnancies 
should align with the time period for post-intervention contraception determined in Section 5.1. 
If a pregnancy is reported, the Investigator will record pregnancy information on the appropriate 
form and submit it to the Sponsor within 24 hours of learning of the female patients or partner of 
male patient (after obtaining the necessary signed informed consent from the partner) pregnancy 
and should follow the procedures outlined in Appendix 4 (Section 10.4). 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered to be SAEs and will be reported as such. 
The patient/pregnant partner will be followed to determine the outcome of the pregnancy. The 
Investigator will collect follow-up information on the patient/pregnant partner and the neonate 
and the information will be forwarded to the Sponsor. 


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Any post-study pregnancy-related SAE considered reasonably related to the study intervention 
by the Investigator will be reported to the Sponsor as described in Section 8.4.4. While the 
Investigator is not obligated to actively seek this information in former study patients/pregnant 
partners, he or she may learn of an SAE through spontaneous reporting. 
Any female patient who becomes pregnant while participating in the study will discontinue study 
intervention or be withdrawn from the study. 
Prior to continuation of study intervention following pregnancy, the following must occur: 
a. The Sponsor and the relevant IRB give written approval. 
b. The patient gives signed informed consent. 
c. The Investigator agrees to monitor the outcome of the pregnancy and the status of the 
patient and her offspring. 
8.4.6 
Adverse events of Special Interest 
An AESI (serious or non-serious) is one of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring and rapid communication by the 
Investigator to the Sponsor can be appropriate. Such an event might warrant further investigation 
to characterize and understand it. Depending on the nature of the event, rapid communication by 
the Sponsor to other parties might also be warranted. 
AESIs are required to be reported by the Investigator to the Sponsor immediately (i.e., within 
24 hours after learning of the event) regardless of their causality to the study treatment. The most 
appropriate diagnosis or if a diagnosis cannot be established, the abnormal laboratory values 
should be recorded on the eCRF and reported to the Sponsor immediately (i.e., within 24 hours 
after learning of the event), either as a SAE or an AESI. Based on CDK4/6 inhibition mechanism 
of action, the following AEs will be defined as AESIs:  
• Myelosuppression: Hematology including monitoring for neutropenia, leucopoenia, 
thrombocytopenia, and increased tendency to bleed 
• Embryo-fetal toxicity: highly effective methods of contraception will be used by the patients 
until 21 days after receiving the study drug 
• Interstitial lung disease: Pulmonary symptoms (dyspnea, pyrexia, and cough) 
• Gastrointestinal toxicity: e.g., diarrhea, nausea, vomiting, and abdominal pain 


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8.5 Pharmacokinetics 
8.5.1 
Blood Sample Collection 
Blood samples will be used to evaluate the PK of TCK-276. Each plasma sample will be divided 
into 4 aliquots (1 each for the PK, the possible future metabolite assessments, a backup for the 
PK, and a backup for the possible future metabolite assessments). Samples collected for analyses 
of TCK-276 plasma concentration may also be used to evaluate safety or efficacy aspects that 
address concerns arising during or after the study. 
Genetic analyses will not be performed on these plasma samples. Patient confidentiality will be 
maintained. At visits during which samples for the determination of plasma concentration of 
TCK-276 will be taken, 1 blood draw of sufficient volume can be used. 
Intervention concentration information that may unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded. 
Any changes in the timing or addition of timepoints for any planned study assessments must be 
documented and approved by the relevant study team member and then archived in the Sponsor 
and site study files but will not constitute a protocol amendment. The IRB will be informed of 
any safety issues that require alteration of the safety monitoring scheme or amendment of the 
ICF. 
8.5.2 
Urine Sample Collection 
Urine samples for the analysis of TCK-276 will be collected at the timepoints detailed in the SoA 
(Table 1-1). Urine will be collected at the following time intervals relative to study drug dosing: 
0 to 6 hours, 6 to 12 hours, 12 to 24 hours after dosing on Day 1, and from 0 (pre-dose) to 6, 6 to 
12, 12 to 24, 24 to 48, and 48 to 72 hours after dosing on Day 7. Urine sample collection, 
processing and shipping details will be outlined in a separate laboratory manual. In brief, urine 
will be processed and analyzed by a validated method for concentrations of TCK-276. The PK 
parameters listed in Section 3 will be calculated from the urine concentration and volume of 
urine collected in each urine collection interval. 
8.6 Exploratory Assessments 
The following disease activity parameters will be evaluated in this study; 
• ACR 20/50/70 1991 revised criteria for the classification of global functional status in RA on 
Days 1 and 7 


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• DAS28, CDAI, SDAI scores on Days 1 and 7  
8.7 Genetics 
A blood sample for DNA isolation will be collected from patients who have consented to 
participate in the optional pharmacogenomics component of the study. Patients who do not wish 
to participate in the genetic research may still participate in the study. 
In the event of DNA extraction failure, a replacement pharmacogenomic blood sample may be 
requested from the patient. Signed informed consent will be required to obtain a replacement 
sample. 
The final disposition of samples will be conducted per local regulations. 
See Appendix 5 (Section 10.5) for information regarding genetic research. Details on processes 
for collection and shipment of these samples can be found in a separate laboratory manual. 
8.8 Biomarkers 
Following biomarkers will be evaluated by the central laboratories in this study; 
MMP-3, granulocyte macrophage colony-stimulating factor (GM-CSF), C-X-C motif chemokine 
ligand 10 (CXCL10), C-C motif chemokine ligand 2 (CCL2), cartilage oligomeric matrix protein 
(COMP), tumor necrosis factor (TNF)-α, TNF-RI, and interleukin (IL)-6 . 
8.9 Health Economics 
Health economics are not evaluated in this study. 
9 Statistical Considerations 
Before database lock, a statistical analysis plan (SAP) will be issued as a separate document, 
providing detailed methods for the analyses outlined below. Any deviations from the planned 
analyses will be described and justified in the clinical study report (CSR). 
9.1 Statistical Hypotheses 
Not applicable. 
9.2 Analysis Populations 
For purposes of analysis, the following analysis populations are defined: 




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Patient discontinuations will be listed including the date of study exit, duration of treatment and 
reason for discontinuation. A listing of informed consent response will also be presented. 
A randomization listing will be presented and include the following: each patient’s 
randomization number, site, the treatment to which the patient has been randomized. 
9.3.1.3 
Demographic and Anthropometric Information and Baseline Characteristics 
Demographic and anthropometric variables (age, sex, ethnicity, race, height, weight, and BMI) 
and disease activity data (ACR20/50/70, DAS28, CDAI, and SDAI) will be listed by patient. 
Demographic characteristics (age, sex, ethnicity, and race), anthropometric characteristics 
(height, weight, and BMI) and disease activity data (ACR20/50/70, DAS28, CDAI, and SDAI) 
will be summarized by cohort, treatment and for all patients in the safety analysis population.  
Medical history data will be listed by patient including visit, description of the 
disease/procedure, Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class 
(SOC), MedDRA preferred term (PT), start date, and stop date (or ongoing if applicable). 
9.3.2 
Primary Endpoint(s) Analysis 
9.3.2.1 
Prior and Concomitant Medication 
Prior medications are those that started and stopped prior to the first dose of study drug. 
Concomitant medications are those taken after first dosing (including medications that started 
prior to dosing and continued after). 
Prior and concomitant medication will be listed by patient and will include the following 
information: reported name, PT, the route of administration, dose, frequency, start date/time, 
duration, and indication. 
Prior and concomitant medication will be coded according to the World Health Organization 
Drug Dictionary (WHO-DD) latest version. 
9.3.2.2 
Exposure 
A listing of drug administration will be created and will include the date and time of 
administration.  
9.3.2.3 
Adverse Events 
All AEs will be listed and coded according to the MedDRA. Adverse events will be individually 
listed per patient number, presenting assigned treatment, verbatim term, Primary SOC, PT, 


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treatment emergence (yes or no), date and time of onset, date and time of last study drug 
administration before AE, duration, time from onset since last study drug administration, 
frequency, severity and seriousness, relationship to study drug, the required action taken, 
outcome, if it is a reason for drop out, and if it is AESI or not. The treatment emergent AEs will 
be summarized by MedDRA terms and treatment groups. It will include evaluation of the 
number of AEs and the number of patients reporting these AEs. 
SAEs will be listed separately. 
9.3.2.4 
Clinical Laboratory Tests 
A by-patient listing will be presented. Clinical laboratory tests (observed values and change from 
baseline) will be summarized descriptively in tabular format. Shift tables will be presented for 
select laboratory parameters. 
9.3.2.5 
Vital Signs 
A by-patient listing will be presented. Observed values as well as change from baseline data will 
be summarized descriptively in tabular format. 
9.3.2.6 
Standard 12-lead Electrocardiogram 
Standard 12-lead ECG data (observed and change from baseline) will be listed for each patient 
and time point. Observed values and change from baseline will be summarized descriptively in 
tabular format. A categorical QTc analysis will also be performed. 
9.3.2.7 
Telemetry 
Cardiac telemetry (real-time assessment) will assess the cardiac safety. A by-patient listing will 
be provided.  
9.3.2.8 
Physical Examination 
Abnormal physical examination findings will be listed. 
9.3.3 
Secondary Endpoint(s) Analysis 
9.3.3.1 
Pharmacokinetics Analyses 
Plasma concentrations of TCK-276 and TEI-W00595 will be listed and summarized by 
descriptive statistics and displayed graphically as appropriate. 


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Plasma PK parameters of TCK-276 and TEI-W00595 will be calculated using non-
compartmental methods and tables, figures, and listings for PK parameters will be generated 
using PK population, as detailed in SAP. 
Plasma metabolite (TEI-W00595) to parent (TCK-276) molar ratio based on Cmax and AUC will 
be determined and summarized after first and last dose administration. Molar ratios will be 
calculated based on molecular weight of 
 for TCK-276 and 
 for TEI-W00595. 
Urine PK parameters of TCK-276 will be listed and summarized as detailed in SAP. 
Dose proportionality will be assessed using power model based on Days 1 and 7 Cmax and 
AUCtau values for TCK-276.  
Further details of analysis of PK data will be provided in the SAP before database lock. 
9.3.4 
Other Analyses 
Not Applicable. 
9.3.4.1 
Exploratory Analyses 
Exploratory assessment data will be listed and summarized by descriptive statistics and displayed 
graphically as appropriate. 
9.4 Sample Size Determination 
Formal sample size calculations were not performed. Thirty-two patients were chosen based on 
feasibility and are considered sufficient to meet the study objectives of this exploratory study. 


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10 Supporting Documentation and Operational Considerations 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) international ethical guidelines. 
o Applicable International Council for Harmonisation (ICH) Good Clinical Practice (GCP) 
guidelines. 
o Applicable laws and regulations. 
The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., advertisements) 
must be submitted to an IRB by the Investigator and reviewed and approved by the IRB before 
the study is initiated. 
Any amendments to the protocol will require IRB approval before implementation of changes 
made to the study design, except for changes necessary to eliminate an immediate hazard to 
study patients. 
Protocols and any substantial amendments to the protocol will require health authority approval 
prior to initiation except for changes necessary to eliminate an immediate hazard to study 
patients. 
The Investigator will be responsible for the following: 
o Providing written summaries of the status of the study to the IRB annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/EC. 
o Notifying the IRB of SAE or other significant safety findings as required by IRB 
procedures. 
o Overall conduct of the study at the site and adherence to requirements of 21 Code of 
Federal Regulations (CFR), ICH GCP guidelines, the IRB, and all other applicable local 
regulations. 


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10.1.2 Financial Disclosure 
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the Sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study. 
10.1.3 Informed Consent Process 
The Investigator or their representative will explain the nature of the study, including the risks 
and benefits, to the patient or the patient’s LAR and answer all questions regarding the study. 
Patients must be informed that their participation is voluntary. Patients or the patient’s LAR will 
be required to sign a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, privacy, and data protection requirements, where applicable, 
and the IRB or study center. 
The medical record must include a statement that written informed consent was obtained before 
the patient was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
Patients must be re-consented to the most current version of the ICF(s) during their participation 
in the study. 
A copy of the ICF(s) must be provided to the patient or the patient’s LAR. 
A patient who is rescreened is required to sign a new ICF as a new assigned patient number. 
If a protocol amendment is required, the ICF may need to be revised to reflect the changes to the 
protocol. If the ICF is revised, it must be reviewed and approved by the appropriate IRB and 
signed by all patients subsequently enrolled in the study as well as those currently enrolled in the 
study. 
10.1.4 Data Protection 
Patients will be assigned a unique identifier by the Sponsor. Any patient records or datasets that 
are transferred to the Sponsor will contain the identifier only; patient names or any information 
which would make the patient identifiable will not be transferred. 


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The patient must be informed that their personal study-related data will be used by the Sponsor 
in accordance with local data protection law. The level of disclosure must also be explained to 
the patient who will be required to give consent for their data to be used as described in the 
informed consent. 
The patient must be informed that their medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the Sponsor, by appropriate IRB 
members, and by inspectors from regulatory authorities. 
10.1.5 Committees Structure 
The SRC will consist of the following core members: 
• 
Principal Investigators 
• 
Medical Monitor 
• 
Sponsor Medical Representative 
The SRC may also request to have attendance of or off-line support and input from the following 
functions as required: 
• Study and Sponsor Statisticians 
• Sponsor and/or study Medical Specialists (e.g., Neurologist, ECG Center cardiologists, etc.)  
• Study and Sponsor Pharmacokineticists 
10.1.6 Dissemination of Clinical Study Data 
A summary of the results of the clinical study together with a summary that is understandable to 
a layperson will be provided after the global end (or early termination) of the study in all 
countries concerned to ensure full availability of all clinical data under this protocol, within 
12 months. 
10.1.7 Data Quality Assurance 
All patient data relating to the study will be recorded on printed or electronic case report forms 
(eCRFs) unless transmitted to the Sponsor or designee electronically (e.g., laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF. 
Guidance on completion of eCRFs will be provided in eCRF Completion Instructions. 


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The Investigator must permit study-related monitoring, audits, IRB review, and Regulatory 
Agency inspections and provide direct access to source data documents. 
Monitoring details describing strategies, including definition of study critical data items and 
processes (e.g., risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities and 
requirements, including handling of noncompliance issues and monitoring techniques (central, 
remote, or on-site monitoring) are provided in the monitoring plan. 
The Sponsor or designee is responsible for the data management of this study including quality 
checking of the data. 
The Sponsor assumes accountability for actions delegated to other individuals (e.g., CROs). 
Records and documents, including signed ICF, pertaining to the conduct of this study must be 
retained by the Investigator for 2 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the Sponsor. No records may be transferred to 
another location or party without written notification to the Sponsor. 
All data generated by the site personnel will be captured electronically at each study center using 
eCRFs. Data from external sources (such as laboratory data) will be imported into the database. 
Once the eCRF clinical data have been submitted to the central server at the independent data 
center, corrections to the data fields will be captured in an audit trail. The reason for change, the 
name of the person who performed the change, together with the time and date will be logged to 
provide an audit trail. 
If additional corrections are needed, the responsible monitor or data manager will raise a query in 
the electronic data capture (EDC) application. The appropriate staff at the study site will answer 
queries sent to the Investigator. The name of the staff member responding to the query, and time 
and date stamp will be captured to provide an audit trail. Once all source data verification is 
complete and all queries are closed, the monitor will freeze the eCRF page. 
The specific procedures to be used for data entry and query resolution using the EDC 
system/eCRF will be provided to study sites in a training manual. In addition, site personnel will 
receive training on the EDC system/eCRF. 


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10.1.8 Source Documents 
Source documents provide evidence for the existence of the patient and substantiate the integrity 
of the data collected. Source documents are filed at the Investigator’s site. 
Data reported in the eCRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The Investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of patients are being protected; and that the study is being 
conducted in accordance with the currently approved protocol and any other study agreements, 
ICH GCP, and all applicable regulatory requirements. 
10.1.9 Study and Site Start and Closure 
First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
patients. 
The first act of recruitment is considered when the first site is activated and allowed to screen 
patients, which will be the study start date. 
Study/Site Termination 
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study site closure visit has been performed. 
The Investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 


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Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
For study termination: 
• Discontinuation of further study intervention development. 
For site termination: 
• Failure of the Investigator to comply with the protocol, the requirements of the IRB or local 
health authorities, the Sponsor's procedures, or GCP guidelines. 
• Inadequate or no recruitment (evaluated after a reasonable amount of time) of patients by the 
Investigator. 
• Total number of patients included earlier than expected. 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IRBs, the regulatory authorities, and any contract research organization(s) used 
in the study of the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The Investigator shall promptly inform the patient and should assure appropriate 
patient therapy and/or follow-up. 
10.1.10 Publication Policy 
The results of this study may be published or presented at scientific meetings after study 
completion. Before any data from this study are published on the initiative of the Investigator, 
the Investigator must obtain written approval from the Sponsor. If this is foreseen, the 
Investigator agrees to submit all manuscripts or abstracts to the Sponsor at least 60 days prior to 
submission. This allows the Sponsor to protect proprietary information and to provide comments. 
The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating Investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 


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10.1.11 Protocol Approval and Amendment 
Before the start of the study, the study protocol and/or other relevant documents will be approved 
by the IRB/Competent Authorities, in accordance with local legal requirements. The Sponsor 
must ensure that all ethical and legal requirements have been met before the first patient is 
enrolled in the study. 
This protocol is to be followed exactly. To alter the protocol, amendments must be written, 
receive approval from the appropriate personnel, and receive IRB/Competent Authority approval 
prior to implementation (if appropriate). In the USA: Following approval, the protocol 
amendment(s) will be submitted to the Investigational new drug (IND) under which the study is 
being conducted. 
Administrative changes (not affecting the patient benefit/risk ratio) may be made without the 
need for a formal amendment. All amendments will be distributed to all protocol recipients, with 
appropriate instructions. 
10.1.11.1 Access to Source Data 
During the study, a monitor will make site visits to review protocol compliance, compare eCRF 
entries and individual patient’s medical records, assess drug accountability, and ensure that the 
study is being conducted according to pertinent regulatory requirements. eCRF entries will be 
verified with source documentation. The review of medical records will be performed in a 
manner to ensure that patient confidentiality is maintained. 
Checking of the eCRF entries for completeness and clarity, and cross-checking with source 
documents, will be required to monitor the progress of the study. Moreover, regulatory 
authorities of certain countries, IRBs, and/or the Sponsor’s Clinical QA Group may wish to carry 
out such source data checks and/or on-site audit inspections. Direct access to source data will be 
required for these inspections and audits; they will be carried out giving due consideration to 
data protection and medical confidentiality. The Investigator assures the Sponsor, and 
 if 
involved in monitoring/data management, of the necessary support at all times. 
 
 


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10.2 Appendix 2: Clinical Laboratory Tests 
The tests detailed in Table 10–1 will be performed by each local laboratory (for assessments of 
Screening and Day -1) and central laboratory (for assessments from Day 1 to last visit). Note that 
erythrocyte sedimentation rate (ESR) is not included in Table 10–1, and it will be assessed at 
local laboratory as part of disease activity data on Days 1 and 7, not as safety laboratory test. 
Local laboratory results are only required in the event that the central laboratory results are not 
available in time for either study intervention administration and/or response evaluation. If a 
local sample is required, it is important that the sample for central analysis is obtained at the 
same time. Additionally, if the local laboratory results are used to make either a study 
intervention decision or response evaluation, the results must be recorded. 
Protocol-specific requirements for inclusion or exclusion of patients are detailed in Section 5 of 
the protocol. 
Additional tests may be performed at any time during the study as determined necessary by the 
Investigator or required by local regulations. 
Investigators must document their review of each laboratory safety report. 
Table 10–1 
Protocol-required Safety Laboratory Tests 
Hematology 
White blood cell (WBC) count 
Neutrophils (percentage and absolute count) 
Red blood cell (RBC) count 
Lymphocytes (percentage and absolute count)  
Hemoglobin (Hb) 
Monocytes (percentage and absolute count)  
Hematocrit (HCT) 
Eosinophils (percentage and absolute count)  
Mean corpuscular volume (MCV) 
Basophils (percentage and absolute count)  
Mean corpuscular hemoglobin (MCH) 
Platelet count 
Mean corpuscular hemoglobin concentration (MCHC) 
Reticulocytes (count and percentage) 
RBC distribution width  
Coagulation 
Prothrombin time 
International Normalized Ratio (INR) 
Activated partial thromboplastin time (aPTT) 
 
Clinical Chemistry 
Alanine aminotransferase (ALT) 
Gamma glutamyl transferase (GGT) 
Albumin 
Glucose 
Alkaline phosphatase (ALP) 
Lactate dehydrogenase (LDH) 
Aspartate aminotransferase (AST) 
Phosphorus 
Blood urea nitrogen (BUN) 
Potassium 


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Calcium 
Sodium 
Chloride 
Total bilirubin 
Total cholesterol 
Total protein 
Creatinine 
Triglycerides 
Creatine kinase (CK) 
C- reactive protein (CRP) 
Follicle stimulating hormone (FSH) (Screening Visit only; Post-menopausal females only) 
Urinalysis 
Bilirubin 
Blood 
Glucose 
pH and specific gravity 
Ketones 
Protein 
Leukocytes 
Urobilinogen 
Nitrite 
Color and appearance 
Microscopic (only for abnormal urine stick test 
findings)-Hyaline casts, cellular casts, granular casts,  
RBC and WBC 
Urinary creatinine (to exclude dilution effect) 
Viral Serology 
Hepatitis B core antibody (anti-HBc) 
Human immunodeficiency virus (HIV)  
(Types 1 and 2) antibodies 
Anti-hepatitis B surface antigen (HBsAg) 
Hepatitis C virus antibody (anti-HCV) 
 
COVID-19 Testing 
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcription polymerase chain reaction 
(RT-PCR) 
Urine Drug Screening, Cotinine Test, and Alcohol Test 
Amphetamines 
Cocaine 
Barbiturates 
Opiates 
Benzodiazepines 
Phencyclidine 
Oxycodone 
3,4-methylenedioxymethamphetamine (MDMA) 
Tricyclic Antidepressants  
Propoxyphene 
Cannabinoids 
Cotinine 
Alcohol/Ethanol (to be tested using breathalyzer) 
Pregnancy Testing 
Urine human beta chorionic gonadotrophin 
 
 
 












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learns of the event. Additional follow-up (cause of death, autopsy report, and hospital report) 
information should be reported within an additional 8 days (15 days total). 
If the SUSAR is not fatal or life-threatening but is otherwise serious, associated with study 
intervention, and unexpected, regulatory authorities and IECs will be notified within 
15 calendar days after the Sponsor learns of the event. 
The Sponsor will notify the Investigators in a timely fashion of relevant information about 
SUSARs that could adversely affect the safety of patients. Follow-up information may be 
submitted if necessary. 
The Sponsor will also provide annual safety updates to the regulatory authorities and IECs 
responsible for the study. These updates will include information on SUSARs and other 
relevant safety findings. 
AE=adverse event; IEC=Institutional Review Board; SAE=serious adverse event; SUSAR=suspected unexpected 
serious adverse reactions 
Serious Adverse Events Contact Details 
SERIOUS ADVERSE EVENT REPORTING INSTRUCTIONS 
 
 
 
(See SAE Reporting Instructions) 
 
 
 
1. Telephone the 
 to inform him/her that you are emailing/faxing a 
SAE form. If the 
 is not available or you are calling after business 
hours (8:30 am to 5:30 pm Eastern time, Monday to Friday), leave a message in their voice 
mailbox. 
2. Provide the 
 with the Principal Investigator’s name, your name, the 
telephone number where you can be reached, and the protocol number and title. 
3. Email/Fax the SAE form and any supporting documentation to the 
 
within 24 hours of becoming aware of the event. 
4. After business hours, the 
 may be reached through 
 
24-hour answering service at 
. Give the answering service the protocol 
number, the study intervention name, and the Sponsoring pharmaceutical company. 


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10.4 Appendix 4: Contraceptive and Barrier Guidance 
10.4.1 Definitions 
Women of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below).  
Women in the following categories are not considered to be a woman of childbearing potential: 
1. Premenarchal  
2. Premenopausal female with one of the following: 
• Documented hysterectomy  
• Documented bilateral salpingectomy  
• Documented tubal ligation  
• Documented bilateral oophorectomy 
Note: Documentation can come from the site personnel’s review of the patient’s medical records, 
medical examination, or medical history interview.  
3. Post-menopausal female 
• A post-menopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high FSH level in the post-menopausal range (> 40 U/mL) may be used to 
confirm a post-menopausal state in women not using hormonal contraception or hormonal 
replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, a single 
FSH measurement is insufficient. 
10.4.2 Contraception Guidance 
Male patients 
Male patients with female partners of childbearing potential (including partners who are pregnant 
or breastfeeding [including pumping breast milk to feed to a child]) must use contraception if 
any of the following criteria are met: 
• Genotoxic study medication 
• Study medication where reproductive toxicology studies have not yet been conducted 


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• Study medication with demonstrated or suspected human teratogenicity/fetotoxicity at 
subtherapeutic exposure levels if relevant systemic concentrations may be achieved in 
WOCBP from exposure to seminal fluid 
Male patients with female partners of childbearing potential are eligible to participate if they 
agree to ONE of the following during the protocol-defined time frame: 
• Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent 
on a long term and persistent basis) and agree to remain abstinent. 
• Agree to use a male condom plus partner use of a contraceptive method with a failure rate of 
< 1% per year as described in the table below when having penile-vaginal intercourse with a 
WOCBP who is not currently pregnant. 
• Agree to use a male condom when having penile-vaginal intercourse WOCBP who is 
currently pregnant. 
In addition, male patients must refrain from donating sperm for the duration of the study and for 
3 months after the final dose of study medication. 
Male patients with a pregnant or breastfeeding (including pumping breast milk to feed to a child) 
partner must agree to remain abstinent from penile vaginal intercourse or use a male condom 
during each episode of penile penetration during the study and for at least 3 months after the 
final dose of study medication. 
Female patients 
Female patients of childbearing potential are eligible to participate if they agree to use a highly 
effective method of contraception consistently and correctly as described in the table below. If 
the Investigator has another method not listed below but is proven to have a failure rate < 1%, 
then this method may be considered after discussion with the Medical Monitor or Sponsor study 
physician. 
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependent 
• Failure rate of < 1% per year when used consistently and correctly. 
• Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation 
o 
Oral 


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o 
Intravaginal 
o 
Transdermal 
• Progestogen only hormonal contraception associated with inhibition of ovulation 
o 
Oral 
o 
Injectable 
Highly Effective Methods That Are User Independent 
• Implantable progestogen only hormonal contraception associated with inhibition of 
ovulation: 
o 
Intrauterine device (IUD) 
o 
Intrauterine hormone-releasing system (IUS) 
o 
Bilateral tubal occlusion 
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, 
an additional highly effective method of contraception should be used. 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study medication. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the patient. 
• Women of childbearing potential should only be included after a confirmed menstrual period 
and a negative highly sensitive serum pregnancy test. 
• Additional urine pregnancy testing should be performed at monthly intervals during the 
treatment period and at End of Treatment/End of Study, after the final dose of study 
medication and as required locally. 
• Pregnancy testing will be performed when pregnancy is suspected 
• Pregnancy testing will be performed at Screening and at every post-Screening visit before 
study medication application. 
• If a study patient is pregnant and stays in the study for observation no pregnancy testing will 
be performed as long as the pregnancy lasts. 


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10.4.2.1 
Collection of Pregnancy Information 
Male Patients with Female Partners Who Become Pregnant 
• The Investigator will attempt to collect pregnancy information on any male patient’s female 
partner who becomes pregnant while the male patient is in this study. This applies only to 
male patients who receive the study drug. If the study patient is later found to be on placebo, 
then pregnancy data collection can stop. 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The female 
partner will also be followed to determine the outcome of the pregnancy. Information on the 
status of the mother and child will be forwarded to the Sponsor. Generally, the follow-up will 
not be required after birth of the child or elective termination of pregnancy. Any termination 
of the pregnancy will be reported regardless of fetal status (presence or absence of 
anomalies) or indication for the procedure. 
Female Patients Who Become Pregnant 
• The Investigator will collect pregnancy information on any female patient who becomes 
pregnant while participating in this study. This applies only to female patients who receive 
the study drug. If the study patient is later found to be on placebo, then pregnancy data 
collection can stop. Information will be recorded on the appropriate form and submitted to 
the Sponsor within 24 hours of learning of a patient’s pregnancy. The patient will be 
followed to determine the outcome of the pregnancy. The Investigator will collect any 
follow-up information on the patient and the neonate, and the information will be forwarded 
to the Sponsor. Generally, follow-up will not be required after birth of the child or elective 
termination of pregnancy. Any termination of the pregnancy will be reported, regardless of 
fetal state (presence or absence of anomalies) or indication for the procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE. A spontaneous 
abortion is always considered to be an SAE and will be reported as such. Any post-study 
pregnancy-related SAE considered reasonably related to study drugs by the Investigator will 
be reported to the Sponsor as described in Section 8.4.4. While the Investigator is not 
obligated to actively seek this information in former study patients, he or she may learn of an 
SAE through spontaneous reporting. 
• Any female patient who becomes pregnant while participating in the study will discontinue 
the study drugs and will be withdrawn from the study. 
 


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10.5 Appendix 5: Genetics 
Use/Analysis of DNA 
Genetic variation may impact a patient’s response to therapy. Variable response to therapy may 
be due to genetic determinants that impact intervention absorption, distribution, metabolism, and 
excretion; mechanism of action of the intervention; disease etiology; and/or molecular subtype of 
the disease being treated. Therefore, where local regulations and IRB allow, a blood sample will 
be collected for DNA analysis. 
DNA samples will be used for research related to TCK-276 or RA and related diseases. They 
may also be used to develop tests/assays related to study intervention and/or interventions of this 
drug class and RA. Genetic research may consist of the analysis of one or more candidate genes 
or the analysis of genetic markers throughout the genome or analysis of the entire genome (as 
appropriate) in relation to TCK-276 (as appropriate). 
The samples may be analyzed as part of a multi-study assessment of genetic factors involved in 
the response to TCK-276 or study intervention of this class to understand the study disease or 
related conditions. 
The results of genetic analyses may be reported in the CSR or in a separate study summary. 
The Sponsor will store the DNA samples in a secure storage space with adequate measures to 
protect confidentiality. 
 


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10.6 
 
 
 
 
 
 
 
Prohibited or cautioned medications may include, but are not limited to, those listed below. 
These listings of prohibited or cautioned concomitant treatments are not considered all inclusive. 


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10.7 Appendix 7: Abbreviations and Definitions 
Abbreviations 
Definition 
ACR 
American College of Rheumatology 
AE 
Adverse event 
AESI 
Adverse event of special interest 
Ae 
Amount of study drug excreted unchanged in the urine 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration-time curve 
AUC0-inf 
Area under the plasma concentration-time curve from pre-dose (time 0) 
extrapolated to infinite time (AUClast + Clast/λz) calculated using the 
linear-log trapezoidal rule 
AUC0-t 
Area under the plasma concentration-time curve up to last measurable 
concentration  
AUC0-24h 
Area under the plasma concentration-time curve up to 24 hours 
AUCtau 
Area under the plasma concentration-time curve over a dosing interval, 
tau = 24 hours 
 
 
BMI 
Body mass index 
BP 
Blood pressure 
bpm 
Beats per minute 
CCL2 
C-C motif chemokine ligand 2 
CDAI 
Clinical disease activity index 
CDK 
Cyclin dependent kinase 
CFR 
Code of Federal Regulations 
CL/F 
Apparent total body clearance 
CLr 
Renal clearance 
Cmax 
Maximum plasma concentration determined directly from the 
concentration-time profile 
COMP 
Cartilage oligomeric matrix protein 
COVID-19 
Coronavirus disease 2019 
CRF 
Case report forms 
CRO 
Contract research organization 
CSR 
Clinical study report 


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Abbreviations 
Definition 
CTCAE 
Common Terminology Criteria for Adverse Event 
CycD 
D-type cyclins 
 
 
CXCL10 
C-X-C motif chemokine ligand 10 
DAS28 
Disease activity score 28 
DDI 
Drug-drug interaction 
DMARD 
Disease modifying antirheumatic drug 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
FSH 
Follicle stimulating hormone 
ESR 
Erythrocyte sedimentation rate 
GCP 
Good Clinical Practice 
GM-CSF 
Granulocyte macrophage colony stimulating factor 
HBc 
Hepatitis B core 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IGRA-TB 
Interferon gamma release assay for tuberculosis 
ILD 
Interstitial lung disease 
IL-6 
Interleukin-6 
IMP 
Investigational medicinal product 
IRB 
Institutional Review Board 
LAR 
Legally authorized representative 
MAD 
Multiple ascending dose 
 
 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMP-3 
Matrix metalloproteinase-3 
MR 
Metabolic ratio 


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Abbreviations 
Definition 
MRTlast 
Mean residence time up to last measurable concentration 
MRT0-inf 
Mean residence time extrapolated to infinity 
NOAEL 
No observed adverse effect level 
 
 
 
 
OTC 
Over-the-counter 
PD 
Pharmacodynamics 
 
 
PK 
Pharmacokinetics 
PO 
By mouth 
PT 
Preferred term 
QD 
Once daily 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected for heart rate using Fridericia’s correction 
RA 
Rheumatoid arthritis 
RASF 
Rheumatoid arthritis synovial fibroblasts 
Rb 
Retinoblastoma protein 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SC 
Subcutaneous 
SDAI 
Simplified disease activity index 
SoA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard operating procedure 
SRC 
Safety Review Committee 
SUSAR 
Suspected unexpected serious adverse reactions 
tmax 
Time of maximum plasma concentration determined directly from the 
concentration-time profile 
TNF 
Tumor necrosis factor 
t½ 
Terminal elimination half-life calculated 


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Abbreviations 
Definition 
ULN 
Upper limit of normal 
USA 
United States of America 
WOCBP 
Women of childbearing potential 


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11 References 
1. McInnes IB and Schett G. The pathogenesis of rheumatoid arthritis. N Eng J Med. 2011; 
365(23): 2205-2219. 
2. Bottini N and Firestein GS. Duality of fibroblast-like Synoviocytes in RA: passive 
responders and imprinted aggressors. Nat Rev Rheumatol. 2013;9(1):24-33. 
3. Okada Y, Wu D, Trynka G, Raj T, Terao C, Ikari K, et al. Genetics of rheumatoid arthritis 
contributes to biology and drug discovery. Nature. 2014:506(7488):376-381. 
4. Sherr CJ and Roberts JM. CDK inhibitors: positive and negative regulators of G1-phase 
progression. Genes Dev. 1999;13(12):1501-1512. 
5. Nonomura Y, Kohsaka H, Nagasaka K, and Miyasaka N. Gene transfer of a cell cycle 
modulator exerts anti-inflammatory effects in the treatment of arthritis. J Immunol. 
2003;171(9):4913-4919. 
6. Nonomura Y, Nagasaka K, Hagiyama H, Sekine C, Nanki T, Tamamori-Adachi M, et al. 
Direct modulation of rheumatoid inflammatory mediator expression in retinoblastoma 
protein-dependent and -independent pathways by cyclin-dependent kinase 4/6. Arthritis 
Rheum. 2006;54(7):2074-2083. 
7. Investigator's Brochure of TCK-276. Final Edition 2, 
. 
8. FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public 
Health Emergency, March 2020, Updated on January 27, 2021. 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/fda-guidance-
conduct-clinical-trials-medical-products-during-covid-19-public-health-emergency. Accessed 
05 August 2021. 
9. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham lll CO, et al. 2010 
rheumatoid arthritis classification criteria: an American College of Rheumatology/European 
League Against Rheumatism collaborative initiative. Ann Rheum Dis 2010; 
69(9):1580-1588. 

SAP_001.pdf: 
Cover page 
 
Statistical Analysis Plan 
 
 
Study ID: TCK-276-102 
Study Title: A Phase 1, Randomized, Placebo-controlled, Double-blind, Multiple 
Ascending Dose Study to Investigate Safety, Tolerability, and 
Pharmacokinetics of Oral Doses of TCK-276 in Patients with 
Rheumatoid Arthritis 
NCT number: 05437419 
Version: 2.0 
Document Effective Date: September 12, 2023 
 
 
Teijin America, Inc. 


 
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Statistical Analysis Plan 
 
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Teijin America, Inc. 
 
 
 
TCK-276-102 
 
 
A Phase 1, Randomized, Placebo-controlled, Double-blind, Multiple Ascending Dose Study to 
Investigate Safety, Tolerability, and Pharmacokinetics of Oral Doses of TCK-276 in Patients with 
Rheumatoid Arthritis  
 
 
 
Statistical Analysis Plan 
 
 
 
Version:  2.0 
 
 
 
 
 
 


 
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SPONSOR SIGNATURE PAGE 
 
This document has been approved and signed electronically on the final page by the following: 
 
Approved by:  
 
 
 
 
 
 
 
 


 
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TABLE OF CONTENTS 
1 
INTRODUCTION .................................................................................................................... 12 
2 
STUDY OBJECTIVES ............................................................................................................ 12 
2.1 
Primary Objective(s) ........................................................................................................ 12 
2.2 
Secondary Objective(s) .................................................................................................... 13 
2.3 
Exploratory Objective(s) ................................................................................................. 14 
3 
INVESTIGATIONAL PLAN................................................................................................... 15 
3.1 
Overall Study Design and Plan ........................................................................................ 15 
3.2 
Endpoints and Associated Variables ............................................................................... 17 
3.2.1 
Safety Variables .......................................................................................................... 17 
3.2.2 
Pharmacokinetic Variables ......................................................................................... 17 
3.2.3 
Efficacy Variables ....................................................................................................... 22 
3.2.4 
Pharmacodynamic Variables ...................................................................................... 22 
3.2.5 
Immunogenicity Variables .......................................................................................... 22 
3.2.6 
Exploratory Variables ................................................................................................. 22 
4 
STATISTICAL METHODS..................................................................................................... 23 
4.1 
Data Quality Assurance ................................................................................................... 23 
4.2 
General Presentation Considerations ............................................................................... 23 
4.2.1 
Treatment .................................................................................................................... 23 
4.2.2 
Study Day ................................................................................................................... 23 
4.2.3 
End of Study ............................................................................................................... 24 
4.2.4 
Baseline ....................................................................................................................... 24 
4.2.5 
Controlled, Repeat, Retest, Scheduled and Unscheduled Assessment ....................... 24 
4.2.6 
Summary and Representation of Data ........................................................................ 24 
4.2.7 
On-treatment assessment/event ................................................................................... 24 
4.3 
Software 25 
4.4 
Study Patients .................................................................................................................. 25 
4.4.1 
Analysis Sets ............................................................................................................... 25 
4.4.2 
Disposition of Patients ................................................................................................ 25 
4.4.3 
Protocol Deviations ..................................................................................................... 26 
4.4.3.2 Protocol Deviations with PK Implications ................................................................. 26 
4.5 
Demographics and Anthropometric Information and Baseline Characteristics .............. 26 
4.6 
Medical and Surgical History .......................................................................................... 27 
4.7 
Prior and Concomitant Medications ................................................................................ 27 
4.8 
Treatment Exposure and Compliance .............................................................................. 27 
4.8.1 
Treatment Exposure .................................................................................................... 27 
4.8.2 
Compliance ................................................................................................................. 27 
4.9 
Analysis Supporting Primary Objective(s) ...................................................................... 27 
4.10 Analysis Supporting Secondary Objective(s) .................................................................. 27 
4.11 Efficacy Evaluation ......................................................................................................... 27 
4.12 Pharmacokinetic Analysis, Concentration, and Parameter TFLs, and Statistical Analysis of 
Pharmacokinetic Parameters for Final Analysis .............................................................. 28 
4.12.1 
Pharmacokinetic Concentrations ................................................................................ 28 
4.12.2 
Pharmacokinetic Parameters ....................................................................................... 30 
4.12.3 
Statistical Analysis of Pharmacokinetic Parameters ................................................... 34 


 
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4.12.4 
Pharmacodynamic Analysis, Concentration, and Parameter TFLs, and Statistical Analysis 
of Pharmacodynamic Parameters ................................................................................ 36 
4.13 Safety Evaluation ............................................................................................................. 36 
4.13.1 
Adverse Events ........................................................................................................... 36 
4.13.2 
Deaths, Serious Adverse Events, and Other Significant Adverse Events .................. 37 
4.13.3 
Clinical Laboratory Evaluation ................................................................................... 38 
4.13.4 
Vital Signs ................................................................................................................... 39 
4.13.5 
ECG ............................................................................................................................ 39 
4.13.6 
Physical Examination ................................................................................................. 39 
4.13.7 
Other Analysis ............................................................................................................ 40 
4.13.8 
Exploratory Analysis .................................................................................................. 40 
4.13.9 
Daylight Saving Time (DST) ...................................................................................... 43 
4.13.10 Safety Monitoring (Independent Data Monitoring Committee, Data Monitoring 
Committee, Data and Safety Monitoring Board) ........................................................ 44 
4.14 Cardio Dynamic Analyses ............................................................................................... 44 
4.15 Biomarkers....................................................................................................................... 44 
4.16 Adjustments for Covariates ............................................................................................. 45 
4.17 Handling of Dropouts or Missing Data ........................................................................... 45 
4.18 Subgroup Analysis ........................................................................................................... 45 
4.19 Planned Interim Analyses ................................................................................................ 45 
4.20 Determination of Sample Size ......................................................................................... 45 
4.21 Changes in the Conduct of the Study or Planned Analysis ............................................. 45 
5 
REFERENCES ......................................................................................................................... 45 
6 
APPENDICES .......................................................................................................................... 47 
6.1 
Schedule of Assessments ................................................................................................. 47 
6.2 
Imputation Rules for Partial Dates .................................................................................. 50 
6.3 
Laboratory Test Parameters ............................................................................................. 53 
6.4 
ECG Notable Criteria ...................................................................................................... 55 
 
List of Tables 
Table 3-1  Plasma Pharmacokinetic Parameters of TCK-276 and TEI-W00595 After First Dose 
Administration ........................................................................................................... 18 
Table 3-2 Plasma Pharmacokinetic Parameters of TCK-276 and TEI-W00595 After Last Dose of 
Daily Dose Administration ........................................................................................ 20 
Table 3-3 Urine Pharmacokinetic Parameters ................................................................................... 22 
Table 4-1 Pharmacokinetic Parameter and Estimation ...................................................................... 31 
Table 4-2 Dose Proportionality Assessments in 2 round as shown below ........................................ 35 
Table 4-3 Companion aids/devices items for HAQ-DI categories .................................................... 42 
Table 6-1 Schedule of Assessments ................................................................................................... 47 
Table 6-2 Algorithm for Treatment-Emergent Adverse Events: ....................................................... 50 
Table 6-3 Algorithm for Prior/Concomitant Medications Categorization: ........................................ 52 
 
List of Figures 
Figure 3-1 Study Design .................................................................................................................... 16 
Figure 3-2 Study Flow Chart – Multiple Ascending Dose Design .................................................... 16 


 
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Figure 3-1 Study Design .................................................................................................................... 16 
Figure 3-2 Study Flow Chart – Multiple Ascending Dose Design .................................................... 16 
 


 
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REVISION HISTORY 
 
Version No. 
Effective Date 
Summary of Change(s) 
1.0 
 
New document 
1.1 
 
Updated dose strength to 175 mg throughout the document 
Update the unit of CRP from mg/dL to mg/L, accordingly, 
SDAI = SJC + TJC +PGA + EGA + 0.1*CRP 
DAS 28 CRP = 0.56× √(TJC) ＋0.28× √(SJC) ＋
0.36×LN((CRP)+1) ＋0.14*×(PGA)＋0.96 
Added line in section 4.13.8 “If any of the elements are missing, 
then the corresponding parameter will be considered as 
missing.” to handle the parameter in case of missing elements. 
Removed inactive URL link of DAS28 ESR 
20 
Date 
of 
last 
signature 
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1 
INTRODUCTION 
This Statistical Analysis Plan (SAP) describes all planned analyses for the Clinical Study Report 
(CSR) of Study TCK-276-102, A Phase 1, Randomized, Placebo-controlled, Double-blind, Multiple 
Ascending Dose Study to Investigate Safety, Tolerability, and Pharmacokinetics of Oral Doses of 
TCK-276 in Patients with Rheumatoid Arthritis. 
The content of this SAP is based on following study documents: 
• Study TCK-276-102 protocol Final Version 3.0 12 Dec 2022. 
• Electronic Case Report Form (eCRF) Version 27.0 
.  
This SAP will be finalized prior to database lock. Any changes after the finalization of this SAP will 
be documented in Statistical Method Modification Form. 
2 
STUDY OBJECTIVES 
2.1 
Primary Objective(s) 
 
Objectives 
Endpoints 
• To evaluate the safety and tolerability of 
multiple oral doses of TCK 276 in patients 
with rheumatoid arthritis (RA) 
• Safety and tolerability endpoints: 
The following safety and tolerability variables 
will be recorded at regular intervals during the 
study: 
o Vital signs measurements: supine blood 
pressure, pulse, body temperature, and 
respiratory rate 
o Cardiac 
safety 
for 
arrythmias, 
abnormalities including PR interval, 
QRS interval, RR interval, QT interval, 
and QT interval corrected for heart rate 
(QTc) (Fridericia’s correction [QTcF]) 
as 
assessed 
by 
12-lead 
electrocardiogram (ECG) and cardiac 
telemetry 
o Incidence of laboratory abnormalities: 
hematology, 
clinical 
chemistry, 
coagulation, and urinalysis 
o Incidence and severity of adverse event 
(AE) and adverse event of special 
interest (AESI) (i.e., gastrointestinal 
toxicity 
and 
pulmonary 
symptoms 
indicative of interstitial lung disease) 
assessments 
o Physical examinations 
 
 


 
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2.2 
Secondary Objective(s) 
Objectives 
Endpoints 
• To evaluate pharmacokinetic (PK) of TCK-
276 and its metabolite (TEI-W00595) in 
patients with RA after multiple ascending 
dose (MAD) administration 
• PK endpoints 
The following PK parameters for TCK-276 and 
TEI-W00595 will be determined, if calculable: 
o Cmax: Maximum plasma concentration 
determined 
directly 
from 
the 
concentration-time profile (Days 1 and 
7) 
o tmax: 
Time 
of 
maximum 
plasma 
concentration determined directly from 
the concentration-time profile (Days 1 
and 7) 
o AUCtau: 
Area 
under 
the 
plasma 
concentration-time curve over a dosing 
interval, tau = 24 hours (Days 1 and 7) 
o AUC0-t: 
Area 
under 
the 
plasma 
concentration-time curve up to last 
measurable concentration (Days 1 and 7) 
o AUC0-inf: 
Area under the plasma 
concentration-time curve from pre-dose 
(time 0) extrapolated to infinite time 
(Days 1 and 7) 
o MRTlast: Mean residence time up to last 
measurable concentration (Day 1 only) 
o MRT0-inf: 
Mean 
residence 
time 
extrapolated to infinity (Days 1 and 7) 
o t½: Terminal elimination half-life (Days 
1 and 7) 
o CL/F: Apparent total body clearance 
(Days 1 and 7), determined for parent 
only 
o Vz/F: Apparent volume of distribution 
based on terminal phase (Days 1 and 7), 
determined for parent only 
o Metabolic ratio (MR) for Cmax: Molar 
metabolic ratio of Cmax calculated as 
(Cmax [metabolite] × molecular weight of 
parent)/(Cmax 
[parent] 
× 
molecular 
weight of metabolite) (Days 1 and 7) 
o MR 
for 
area 
under 
the 
plasma 
concentration-time curve (AUC): Molar 
metabolic ratio of AUC calculated as 
(AUC [metabolite] × molecular weight 
of parent)/(AUC [parent] × molecular 
weight of metabolite) (Days 1 and 7) 


 
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o Ctrough: Concentration in a dosing period 
defined as the pre-dose concentration of 
the day 
o Racc (Cmax): Accumulation ratio based on 
Cmax: Calculated as Cmax on Day 7/Cmax 
on Day 1 
o Racc (AUCtau): Accumulation ratio based 
on AUCtau: Calculated as AUCtau on Day 
7/AUCtau on Day 1 
The following urinary PK parameters for TCK-
276 will be determined in this study: 
o Ae: Amount of study drug excreted 
unchanged in the urine (Days 1 and 7) 
o Fe: Percentage of study drug excreted 
unchanged in the urine (Days 1 and 7) 
o CLr: Renal clearance (Days 1 and 7) 
 
Other PK parameters will be determined if 
needed. 
 
2.3 
Exploratory Objective(s) 
Objectives  
Endpoints 
• To evaluate the effect of TCK-276 on 
disease activity and biomarkers in patients 
with RA 
• Exploratory endpoints 
The following exploratory disease activity 
parameters for RA will be assessed: 
o American College of Rheumatology 
(ACR) 20/50/70 response criteria 
o Disease activity score 28 (DAS28) 
o Clinical disease activity index (CDAI) 
o Simplified disease activity index (SDAI) 
The following exploratory biomarkers will be  
assessed: 
o Matrix metalloproteinase-3 (MMP-3) 
o Granulocyte 
macrophage 
colony-
stimulating factor (GM-CSF) 
o C-X-C motif chemokine ligand 10 
(CXCL10) 
o C-C motif chemokine ligand 2 (CCL2) 
o Cartilage oligomeric matrix protein 
(COMP) 
o Tumor necrosis factor (TNF)-alpha 
o TNF-R1 
o Interleukin-6 (IL-6) 
 
 


 
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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is a Phase 1, multi-center, double-blind, randomized, placebo-controlled, multiple ascending 
dose (MAD) study to evaluate the safety, tolerability, and pharmacokinetics (PK) of orally 
administered TCK-276 in both males and females with RA. Blood samples for possible future 
pharmacogenetic, possible future metabolite assessments, and possible future pharmacodynamic 
(PD) assessments will be collected. 
 
A total of thirty-two (32) patients with RA will be enrolled in this clinical study. This MAD study 
will consist of 4 cohorts of 8 patients (6 active treatment and 2 matching placebo, or a 3:1 ratio), each 
receiving an oral dose of TCK-276 or matching placebo for 7 days (once daily [QD] under fed 
condition). Each cohort will be divided into 2 subgroups to implement the sentinel dosing approach. 
Within each cohort, the first subgroup will consist of 2 sentinel patients; one patient will receive 
TCK-276, and one patient will receive matching placebo. The second subgroup will consist of 6 
patients (5 active treatment, 1 matching placebo). Individual patients in the second subgroup will be 
dosed at least 72 hours after the first subgroup following a decision by the Investigators based on all 
available safety data from the sentinel patients up to 48 hours post-dose. 
 
Dose group 
Treatment Assignment 
1 
10 mg TCK-276 (N = 6) 
Placebo (N = 2) 
2 
25 mg TCK-276 (N = 6) 
Placebo (N = 2) 
3 
75 mg TCK-276 (N = 6) 
Placebo (N = 2) 
4 
175 mg TCK-276 (N = 6) 
Placebo (N = 2) 
 
Patients will be admitted to the site from the morning of Day -1 and sequestered for the duration of 
the treatment (dosing) period. Each patient will receive QD oral doses of either TCK-276 or matching 
placebo administered as tablets under fed condition in the morning of Day 1 to Day 7. The patients 
will be discharged on Day 10. The planned dose levels to be tested are 10 mg (Cohort 1), 25 mg 
(Cohort 2), 75 mg (Cohort 3), and 175 mg (Cohort 4) of TCK-276. Based on the results from the SAD 
study (5 mg to 185 mg dosing) and the projected clinical effective dose (i.e., 75 mg), 10 mg is selected 
as the starting dose level in the MAD study. The dose in Cohorts 2, 3, and 4 may be adjusted based 
on the safety and PK results from the previous cohorts, if necessary. The overall exposure to TCK-
276 (in terms of geometric mean area under the plasma concentration-time curve over a dosing 
interval [AUCtau, tau = 24 hours]) on Day 7 would not be expected to exceed 2,355 ng·h/mL, which 
is set taking monkey testicular toxicity into consideration. 
 
Dose escalation will only be allowed after blinded assessment of all safety, tolerability, and PK data 
up to Day 10 from each previous cohort evaluated by Investigators, Medical Monitor, and Sponsor 
representatives during the Safety Review Committee (SRC) meeting. 
 




 
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3.2 
Endpoints and Associated Variables 
3.2.1 Safety Variables 
The following safety and tolerability variables will be recorded at regular intervals during the study: 
 
• 
Vital signs (supine blood pressure [BP] and pulse rate, tympanic (ear) body temperature, 
respiratory rate) 
• 
Cardiac safety for arrythmias, abnormalities including PR interval, QRS interval, RR interval, 
QT interval, and QT interval corrected for heart rate (QTc) (Fridericia’s correction [QTcF]) as 
assessed by 12-lead electrocardiogram (ECG) and cardiac telemetry. 
• 
Incidence of laboratory abnormalities: hematology, clinical chemistry, coagulation, and 
urinalysis 
• 
Incidence and severity of adverse event (AE) and adverse event of special interest (AESI) (i.e., 
gastrointestinal toxicity and pulmonary symptoms indicative of interstitial lung disease) 
assessments 
• 
Physical examinations 
 
3.2.2 Pharmacokinetic Variables 
Pharmacokinetic concentration data will be obtained at time point(s) described in the protocol version 
2.0 
 as follows: 
Blood sample for PK sample analysis to determine parent (TCK-276) and its metabolite (TEI-
W00595) concentrations and for possible future metabolite assessments will be collected at the time 
points detailed in the Schedule of Assessments Each plasma sample will be divided into 4 aliquots (1 
each for the PK, the possible future metabolite assessments, a backup for the PK, and a backup for 
the possible future metabolite assessments). 
Blood for the PK sample analysis and for possible future metabolite assessments will be sampled at 
pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours (pre-dose of Day 2) after dosing on 
Day 1, pre-dose on Days 3, 4, 5, 6, and on 7, and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, and 72 
hours after dosing on Day 7. The sampling time points may be adjusted based on the PK results 
obtained from the previous cohorts. The last dose will be administered on Day 7.  
Urine samples for the analysis of TCK-276 will be collected at the following time intervals relative 
to study drug dosing: 0 to 6 hours, 6 to 12 hours, 12 to 24 hours after dosing on Day 1, and from 0 
(pre-dose) to 6, 6 to 12, 12 to 24, 24 to 48, and 48 to 72 hours after dosing on Day 7. Volumes of 
urine collected in each time window will also be recorded in the clinical database. Urine collection 
intervals may be adjusted based on the PK results obtained from the previous cohorts, e.g., if plasma 
PK sampling times are adjusted, the urine sampling times will be updated. 


 
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Derivation of PK parameters will be the responsibility of Clinical Pharmacology, Modeling and 
Simulation (CPMS) group, 
.   
If calculable, the following PK Day 1 parameters listed in Table 3-1 will be determined for parent, 
TCK-276 and metabolite, TEI-W00595, in plasma following first oral dose administration. 
 
Table 3-1  Plasma Pharmacokinetic Parameters of TCK-276 and TEI-W00595 After First Dose 
Administration  
Parameter 
WNL  
Name 
CDISC Name 
Definition 
Cmax 
Cmax 
CMAX 
Maximum observed concentration 
determined directly from the 
concentration-time profile 
DNCmax 
CmaxD 
CMAXD 
Dose-normalized Cmax 
tmax 
Tmax 
TMAX 
Time of maximum plasma concentration 
corresponding to occurrence of Cmax 
λz 
Lambda_z 
LAMZ 
Terminal elimination rate constant 
AUCtau 
AUC_TAU 
AUCTAU 
Since dosing interval or tau equals 24 
hours, area under the curve from time 0 
to 24 hours (AUC0-24h) will be calculated 
and will be referred to AUCtau for Day 1  
DNAUCtau 
AUC_TAUD 
AUCTAUD 
Dose normalized AUCtau 
AUC0-t 
AUClast 
AUCLST 
AUC from time zero to the last 
quantifiable concentration 
DNAUC0-t 
AUClast_D 
AUCLSTD 
Dose-normalized AUC0-t 
AUC0-inf 
AUCINF_obs 
AUCIFO 
AUC from time zero extrapolated to 
infinity 
%AUCex 
AUC_%Extrap_obs AUCPEO 
Percentage of AUC0-inf obtained by 
extrapolation beyond tlast 
DNAUC0-inf 
AUCINF_D_obs 
AUCIFOD 
Dose-normalized AUC0-inf 
MRTlast 
 MRTlast 
MRTEVLST 
Mean residence time up to last 
measurable concentration 
MRT0-inf 
MRTINF_obs 
MRTEVIFO 
Mean residence time extrapolated to 
infinity 


 
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Parameter 
WNL  
Name 
CDISC Name 
Definition 
t½ 
HL_Lambda_z 
LAMZHL 
Apparent terminal elimination half-life 
CL/F 
Cl_F_obs 
CLFO 
Apparent clearance following oral 
administration, determined for parent 
only 
Vz/F 
Vz_F_obs 
VZFO 
Apparent volume of distribution during 
terminal phase, determined for parent 
only 
MRCmax 
MRCmax 
MRCMAX 
Molar metabolic ratio based on Cmax of 
parent and metabolite 
MRAUCtau 
MRAUCtau 
MRAUC 
Molar metabolic ratio based on AUCtau 
of parent and metabolite 
MRAUC0-t 
MRAUClast 
MRAUCLS 
Molar metabolic ratio based on AUC0-t 
of parent and metabolite 
MRAUC0-inf 
MRAUCINF 
MRAUCIN 
Molar metabolic ratio based on AUC0-inf 
of parent and metabolite 
 
If calculable, the PK Day 7 parameters listed in Table 3-2 will be calculated for parent, TCK-276 and 
metabolite, TEI-W00595 in plasma following once daily oral dose administration after last dose 
administration on Day 7: 


 
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Table 3-2 Plasma Pharmacokinetic Parameters of TCK-276 and TEI-W00595 After Last Dose 
of Daily Dose Administration 
Parameter 
WNL  
Name 
CDISC 
Name 
Definition 
Cmax 
Cmax 
CMAX 
Maximum observed concentration 
determined directly from the 
concentration-time profile 
DNCmax 
CmaxD 
CMAXD 
Dose-normalized Cmax 
tmax 
Tmax 
TMAX 
Time of maximum plasma 
concentration corresponding to 
occurrence of Cmax 
λz 
Lambda_z 
LAMZ 
Terminal elimination rate constant 
AUCtau 
AUC_TAU 
AUCTAU 
Since dosing interval or tau equals 
24 hours, area under the curve from 
time 0 to 24 hours (AUC0-24h) will 
be calculated and will be referred to 
AUCtau for Day 7 
DNAUCtau 
AUC_TAUD 
AUCTAUD 
Dose-normalized AUCtau 
AUC0-t 
AUClast 
AUCLST 
AUC from time zero to the last 
quantifiable concentration 
DNAUC0-t 
AUClast_D 
AUCLSTD 
Dose-normalized AUC0-t 
AUC0-inf 
AUCINF_obs 
AUCIFO 
AUC from time zero extrapolated to 
infinity 
%AUCex 
AUC_%Extrap_obs 
AUCPEO 
Percentage of AUC0-inf obtained by 
extrapolation beyond tlast 
DNAUC0-inf 
AUCINF_D_obs 
AUCIFOD 
Dose-normalized AUC0-inf 
MRT0-inf 
 MRTINF_obs 
MRTEVIFO 
Mean residence time extrapolated to 
infinity 
t½ 
HL_Lambda_z 
LAMZHL 
Apparent terminal elimination 
half-life 
CL/F 
Cl_F_obs 
CLFO 
Apparent clearance following oral 
administration, determined for 
parent only 


 
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Parameter 
WNL  
Name 
CDISC 
Name 
Definition 
Vz/F 
Vz_F_obs 
VZFO 
Apparent volume of distribution 
during terminal phase, determined 
for parent only 
MRCmax 
MRCmax 
MRCMAX 
Molar metabolic ratio based on Cmax 
of parent and metabolite 
MRAUCtau 
MRCAUCtau 
MRCAUC 
Molar metabolic ratio based on 
AUCtau of parent and metabolite 
MRAUC0-t 
MRAUClast 
MRAUCLS 
Molar metabolic ratio based on 
AUC0-t of parent and metabolite 
MRAUC0-inf 
MRAUCINF 
MRAUCIN 
Molar metabolic ratio based on 
AUC0-inf of parent and metabolite 
Ctrough 
Ctrough 
CTROUGH 
Concentration in a dosing period 
defined as pre-dose concentration of 
the day on Day 2 to Day 7, and 24 
after Day 7 dosing 
Racc(Cmax) 
 ARCMAX 
ARCMAX 
Accumulation ratio based on Cmax 
Racc(AUCtau) 
 ARAUC 
ARAUC 
Accumulation ratio based on AUCtau 
 
Additional PK parameters will be determined and reported as needed. 
 
The concentration of TCK-276 as well as volume of urine collected in each collection interval (Vur) 
will be used to calculate amount of TCK-276 in each collection interval and to determine the urine 
PK parameters listed in Table 3-3. 
  


 
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Table 3-3 Urine Pharmacokinetic Parameters 
Protocol 
Parameter 
WNL Name 
CDISC 
Name 
Definition 
Ae 
Amount Recovered 
RCAMINT 
Amount of unchanged drug excreted in 
urine in each interval collection (e.g. 
Ae0-6, Ae6-12, Ae12-24 after Day 1 and 
Day 7 dosing, additionally Ae24-48  and 
Ae48-72 following Day 7 dosing). In 
addition, cumulative amount excreted 
after each collection interval will also 
be determined (e.g. Ae0-6, Ae0-12, Ae0-24 
after Day 1 and Day 7 dosing, 
additionally Ae0-48 and Ae0-72 following 
Day 7 dosing) 
Fe  
Percent_Recovered 
RCPCINT 
Urinary cumulative excretion as % of 
unchanged drug up to 24 hours 
following Day 1 and Day 7 dosing, and 
additionally up to 72 hours following 
Day 7 dosing (e.g. Fe0-6, Fe0-12, Fe0-24 
after Day 1 and Day 7 dosing, 
additionally Fe0-48 and Fe0-72 following 
Day 7 dosing). 
CLr 
CLR@ 
RENALCL 
Renal clearance of the drug from 
plasma following Day 1 and Day 7 
dosing 
3.2.3 Efficacy Variables 
Not Applicable 
3.2.4 Pharmacodynamic Variables 
Not Applicable 
3.2.5 Immunogenicity Variables  
Not Applicable 
3.2.6 Exploratory Variables 
The following exploratory disease activity parameters for RA will be assessed on day 1 and day 7: 
• American College of Rheumatology (ACR) 20/50/70 response criteria 
• Disease activity score 28 (DAS28) 
• Clinical disease activity index (CDAI) 
• Simplified disease activity index (SDAI) 


 
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The following exploratory biomarkers will be assessed: 
• Matrix metalloproteinase-3 (MMP-3) 
• Granulocyte macrophage colony-stimulating factor (GM-CSF) 
• C-X-C motif chemokine ligand 10 (CXCL10) 
• C-C motif chemokine ligand 2 (CCL2) 
• Cartilage oligomeric matrix protein (COMP) 
• Tumor necrosis factor (TNF)-alpha 
• TNF-R1 
• Interleukin-6 (IL-6) 
 
4 
STATISTICAL METHODS 
4.1 
Data Quality Assurance 
All tables, figures, and data listings to be included in the report will be independently checked for 
consistency, integrity, and in accordance with 
. 
4.2 
General Presentation Considerations 
This section is not applicable to PK data. 
4.2.1 Treatment 
Cohort 1: 10 mg TCK-276  
Cohort 2: 25 mg TCK-276  
Cohort 3: 75 mg TCK-276  
Cohort 4: 175 mg TCK-276  
Pooled Placebo 
Dose Group 
Treatment Assignment 
1 
10 mg TCK-276 (N = 6) 
Placebo (N = 2) 
2 
25 mg TCK-276 (N = 6) 
Placebo (N = 2) 
3 
75 mg TCK-276 (N = 6) 
Placebo (N = 2) 
4 
175 mg TCK-276 (N = 6) 
Placebo (N = 2) 
 
4.2.2 Study Day 
Study days will be numbered relative to the first day of study drug administration. 
• 
If the date of event is before the study drug administration, then: 
Study day = (Date of measurement – Date of study drug administration [i.e. Day 1]) 


 
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• 
If the date of event is on or after the study drug administration, then:  
Study day = (Date of measurement – Date of study drug administration [i.e. Day 1]) + 1 
4.2.3 End of Study 
The end of the study is defined as the date of the last visit of the last patient in the study or last 
scheduled procedure shown in the Table 6-1 Schedule of Assessments.  
A patient is considered to have completed the study if he/she has completed all periods of the study 
including the last visit. 
4.2.4 Baseline 
Baseline value is defined as the last non-missing observation before the first administration of study 
drug. 
No imputation will be done for missing baseline value for derivation of change from baseline or 
summary tables and shift tables. 
4.2.5 Controlled, Repeat, Retest, Scheduled and Unscheduled Assessment  
Repeat, retest, and unscheduled assessment will not be considered for the calculation of summary 
statistics and figures, unless assessment qualifies as baseline. 
Average of controlled and planned (scheduled) assessment will be considered for the calculation of 
summary statistics and figures, if more than one controlled/planned assessment will be performed at 
a specific time point.  
4.2.6 Summary and Representation of Data  
Continuous data will be summarized by cohort and treatment group using descriptive statistics 
(number, mean, standard deviation, minimum, median, and maximum).  
 
Categorical data will be summarized by cohort and treatment group using frequency tables (number 
and percentage. 
 
The minimum and maximum will be reported to the same number of decimal places as the raw data 
recorded in the database. The mean and median will be reported to one more decimal place than the 
raw data recorded in the database. The SD will be reported to two more decimal places than the raw 
data recorded in the database. In general, the maximum number of decimal places reported shall be 
four for any summary statistics. 
Percentages will be presented to one decimal place for safety outputs and two decimal places for 
exploratory outputs. Percentages will not be presented for zero counts.  Percentages will be calculated 
using N as the denominator.  If sample sizes are small, the data displays will show the percentages, 
but any textual report will describe frequencies only. Percentage will be presented as whole number 
if count is 100.  
4.2.7 On-treatment assessment/event  
The overall observation period will be divided into three mutually exclusive segments:  
1. pre-treatment period: from day of patient’s informed consent to before date of admission 


 
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2. on-treatment period: from date of admission (Day -1) to discharge from site (11 days i.e., 
from Day -1 to Day 10)  
3. post-treatment period: from after date of discharge from the Site up to follow-up/End of 
treatment visit. (7 days after the last dose) 
4.3 
Software 
All report outputs will be produced using SAS® version 9.4 or later in a secure and validated 
environment.  
The PK analyses will be conducted using Phoenix® WinNonlin (WNL) version 8.3 or later in a secure 
and validated environment.  
All report outputs will be provided to the Sponsor in Microsoft Word document/RTF format.   
4.4 
Study Patients 
4.4.1 Analysis Sets 
Randomized Population (RAN): All patients that signed informed consent form and assigned 
randomization number. 
Safety Population (SAF): All randomized patients who received at least one dose of study drug 
(active/placebo). 
PK Population (PKAS): All randomized patients with at least one quantifiable TCK-276 
concentration. 
Exploratory population: All randomized patients who received at least one dose of study drug 
(active/placebo) and have at least one of the evaluable exploratory assessment data. 
 
A summary table with the number of patients in each of the analysis population will be provided and 
this table will be displayed by cohort/treatment group and overall, for randomized population. A 
listing of patients excluded from analysis population will also be provided including reason of 
exclusion for randomized population. 
4.4.2 Disposition of Patients 
A clear accounting of the disposition of all patients who enter the study will be provided, from 
randomization to study and treatment completion. 
Patient disposition will be summarized and will include the following information: number of patients 
randomized and dosed, number and percentage of patients completing the study and treatment, and 
the number and percentage of patients who were withdrawn (including reasons for withdrawal) from 
study and treatment. Disposition data will be presented based on RAN. 
A by-patient listing of randomizations will be presented and include the following: each patient’s 
randomization number, site, the treatment to which the patient has been randomized. 
A by-patient listing of study and treatment discontinuation will be presented for the RAN. The listing 
will include the date of study exit, duration of treatment and reason for study treatment 
discontinuation.  
A by-patient listing of informed consent response will be provided. 


 
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4.4.3 Protocol Deviations 
All protocol deviations are predefined in the separate document, Protocol Deviation Specification. 
4.4.3.1 Protocol Deviations with Non-PK Implications 
The defined protocol deviations will be collected during the study period by site monitor/clinical team 
and programming team. All deviations related to study inclusion or exclusion criteria, conduct of the 
study, patient management or patient assessment, and handling of the patient’s rights will be 
described.  
4.4.3.2 Protocol Deviations with PK Implications 
 
Protocol deviations that may potentially impact PK parameter derivations include, but are not limited 
to: 
• Emetic episode in case of orally administered study drug 
• Missed PK samples that impact estimation of PK parameter(s) 
• Concomitant medications not authorized by protocol 
• PK samples obtained out of allowance window that may impact the estimation of PK 
parameter(s) 
• Food intake deviations (not completely consumed or consumed outside of time allowed)  
Protocol deviations (mentioned in Sections 4.4.3.1 and 4.4.3.2) and analysis population will be 
reviewed in the blinded data review meeting (BDRM) to decide inclusion or exclusion of patient(s) 
from analyses sets. Decisions regarding the exclusion of patients and/or patient data from analyses 
will be made prior to database lock and will be documented and approved, however, exclusion of 
patients or individual PK parameters will be decided after database lock after review of the calculable 
PK parameters, and any PK data excluded from summary tables/plots will be appropriately 
commented upon in the PK Listings. 
A by-patient listing of major and minor protocol deviations will be provided including patient 
identifier; exclusion from specific analysis sets; and protocol deviation classification, and protocol 
deviation description and exclusion from specific analysis sets. 
 
Protocol deviations related to Covid-19 will be listed separately. 
 
4.5 
Demographics and Anthropometric Information and Baseline Characteristics 
The demographic and anthropometric variables (age, race, ethnicity, sex, height, body weight, body 
mass index [BMI] will be summarized for all patient by cohort, treatment and overall. 
Demographic and anthropometric variables (age, sex, ethnicity, race, height, weight, and BMI) will 
be listed by patient for the SAF. 
Age, height, BMI, weight will be summarized using the n, mean, SD, minimum, median, and 
maximum. The count and percentage will be computed for sex, race, and ethnicity.  
A by-patient listing of history of substance abuse and history of RA and related surgical history will 
be provided. 


 
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4.6 
Medical and Surgical History 
Medical and surgical history will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA®), Version 25.0 and assigned to a System Organ Class (SOC) and Preferred Term (PT). 
A by-patient listing for medical and surgical history including visit, description of the 
disease/procedure, Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class 
(SOC), MedDRA preferred term (PT), start date, and stop date (or ongoing if applicable) will be 
provided, and summarized for the SAF.  
4.7 
Prior and Concomitant Medications 
Prior and Concomitant Medication: 
Medications will be considered as prior if it is started and stopped prior to the first dose of study drug.  
Medications will be considered as concomitant if they are taken after first dosing (including 
medications that started prior to dosing and continued after) 
Prior and concomitant medication will be coded according to the World Health Organization Drug 
Dictionary (WHO-DD) latest version. 
By-patient listings of prior and concomitant medications including the following information: 
reported name, PT, the route of administration, dose, frequency, start date/time, duration, and 
indication will be provided, by WHO DD terms for the SAF. 
 
Prior Medications and concomitant medication will be summarized by WHO DD terms for the SAF. 
 
4.8 
Treatment Exposure and Compliance 
4.8.1 Treatment Exposure  
A by-patient listing of patient exposure to study drug will be generated. The listing will include date 
and time of administration. 
4.8.2 Compliance  
A by-patient listing of treatment compliance will be provided.  
Overall Treatment Compliance (%) will be defined as percentage of total dose taken during the study 
divided by the expected total dose in mg. 
4.9 
Analysis Supporting Primary Objective(s) 
Not Applicable 
4.10 Analysis Supporting Secondary Objective(s) 
Not Applicable 
4.11 Efficacy Evaluation 
Not Applicable 


 
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4.12 Pharmacokinetic Analysis, Concentration, and Parameter TFLs, and Statistical Analysis 
of Pharmacokinetic Parameters for Final Analysis 
4.12.1 Pharmacokinetic Concentrations 
Concentration Listings:  
Pharmacokinetic Plasma concentration data for TCK-276 and TEI-W00595, will be listed by 
cohort/treatment/Day and patient for the PKAS. Concentration listings will include nominal PK 
sampling time, actual sampling times relative to dose administration, deviation from nominal time, 
and percent deviation from nominal time, and concentrations. Plasma concentrations below the lower 
limit of quantification (LLOQ) will be presented as below the limit of quantification (BLQ) in the 
listings and the LLOQ value presented as a footnote. Missing PK samples will be reported as no 
sample (NS) or not reportable (NR) as appropriate and considered excluded from PK analysis.  
Concentration Summary Tables: 
Source data as reported from the laboratory will be used for calculation of concentration summary 
statistics.  Tabular summaries for concentration-time data will report N (number of patients in PKAS), 
n (number of patients with non-missing values), and n(BLQ) (the number of patients with BLQ 
samples). 
Concentration for TCK-276 and TEI-W00595 will be summarized by cohort/treatment/Day, and 
nominal timepoint for the PKAS.  The following descriptive statistics will be presented for plasma 
concentrations obtained at each nominal time point: N, n, n(BLQ), arithmetic mean, SD, coefficient 
of variation (CV%), geometric mean, geometric CV% (calculated as: gCV% =SQRT(es²-1)*100; 
where s is the SD of the log-transformed values), median, minimum, and maximum values. 
For summary concentration tables, all BLQs will be considered zero, and the number of BLQs and 
quantifiable concentrations at each scheduled time point will be reported.  Summary Statistics will 
not be calculated if quantifiable concentrations at a scheduled time point is <3 and will be reported 
as not calculated (NC). 
The rules followed for calculation and presentation of concentration data with regards to the number 
of decimal places/significant digits for the listings of patient level concentrations and summary tables 
of concentration are as follows:  
Concentration Listings and Tables 
Rounding 
Individual concentrations (Listings) 
n s f. as supplied by bioanalytical laboratory 
Minimum and Maximum 
n s f. as supplied by bioanalytical laboratory  
Mean/SD/Median/Geomean 
3 s.f.  
CV%/gCV% 
1 d.p. 
N/n 
Whole number 
s f = significant figures, d.p. = decimal place 
   
For the final plasma concentration PK summary tables and figures, if the 0.25 and 0.5 h samples are 
collected outside +/- 5 minutes time window, the concentration will be flagged and not included in 
the concentration summary tables and mean concentration-time plots. For 1 to 48 h sample, if the 
sample is collected outside 10% time deviation of the scheduled time or outside +/- 30 minutes time 
window, it will be flagged and not included in the concentration summary tables and mean 


 
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concentration-time plots. For 72 h sample, if the sample is collected outside +/- 60 minutes time 
window, it will be flagged and not included in the concentration summary tables and mean 
concentration-time plots. 
 
Concentration Figures: 
For arithmetic mean linear/linear graphs, all BLQ values will be substituted with zero for calculation 
of arithmetic mean. The arithmetic mean will not be calculated if quantifiable concentrations at a 
scheduled time point is <3 and will not be plotted in Figures. For log/linear graphs the log 
transformed arithmetic mean will be displayed (this should not include zero). 
For individual linear/linear and log/linear graphs, all BLQ values will be substituted as follows: 
• BLQs at the beginning of a patient profile (i.e., before the first incidence of a measurable 
concentration) will be assigned to zero. When using log/linear scale, these timepoints will be 
considered missing. 
• BLQs at the end of a patient profile (i.e., after the last incidence of a measurable 
concentration) will be set to missing. 
• Single BLQs which fall between two measurable concentrations will be set to missing.  
• Consecutive BLQs which fall between measurable concentrations will be set to missing. 
• If there are quantifiable concentrations following consecutive BLQs in the apparent terminal 
phase, these values will be evaluated. If these values are considered to be anomalous, they 
will be set to missing. 
To visualize patient-level concentrations and the comparison between cohort/treatment, the 
descriptive PK graphs listed below will be generated. 
• 
Figure x.x.x: Individual patient profiles for TCK-276 and TEI-W00595 Plasma Concentration 
Time Data for Day 1 and Day 7 dosing by Dose – (Linear Scale and Semi-Logarithmic Scale) 
(PKAS) [4 profiles for every individual, Day 1 parent, Day 7 parent, Day 1 metabolite, Day 7 
metabolite)] 
• 
Figure x.x.x : Overlaid individual patient profiles for TCK-276 Plasma Concentration Time Data 
for Day 1 and Day 7 dosing by Dose – (Linear Scale and Semi-Logarithmic Scale) (PKAS) [Plots 
for Dose 1 Days 1-2, Dose 7 Days 7-10)] 
• 
Figure x.x.x : Overlaid individual patient profiles for TEI-W00595 Plasma Concentration Time 
Data for Day 1 and Day 7 dosing by Dose – (Linear Scale and Semi-Logarithmic Scale) (PKAS) 
[Plots with Dose 1 Days 1-2, Dose 7 Days 7-10] 
• 
Figure x.x.x: Overlaid individual patient profiles for TCK-276 Plasma Trough Concentration 
Time Data by Dose – (Linear Scale and Semi-Logarithmic Scale) (PKAS) [Plots for  Day 2 – 
Day 8] 
• 
Figure x.x.x: Overlaid individual patient profiles for TEI-W00595 Plasma Trough Concentration 
Time Data by Dose – (Linear Scale and Semi-Logarithmic Scale) (PKAS) [Plots for  Day 2 – 
Day 8]  


 
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• 
Figure x.x.x : Mean (+ SD) TCK-276 Trough Plasma Concentration Time Data –– (Linear Scale 
and Semi-Logarithmic Scale) (PKAS) [Plots for  Day 2 – Day 8 for all doses on one plot) 
• 
Figure x.x.x : Mean (+ SD) TEI-W00595  Trough Plasma Concentration Time Data – (Linear 
Scale and Semi-Logarithmic Scale) (PKAS) [Plots for  Day 2 – Day 8 for all doses on one plot) 
• 
Figure x.x.x : Mean (+ SD) TCK-276 Plasma Concentration Time Data for Day 1 and Day 7 by 
Dose – (Linear Scale and Semi-Logarithmic Scale) (PKAS) – [Plots for Day 1 all doses, Day 7 
all doses and Plots for from Day 1 to Day 7) 
• 
Figure x.x.x : Mean (+ SD) TEI-W00595 Plasma Concentration Time Data for Day 1 and Day 7 
by Dose – (Linear Scale and Semi-Logarithmic Scale) (PKAS) [Plots for Day 1 all doses, Day 7 
all doses and Plots for from Day 1 to Day 7) 
• 
Figure x.x.x : Mean (+ SD) TCK-276 Plasma Concentration Time Data for Day 1 and Day 7 by 
cohort – (Linear Scale and Semi-Logarithmic Scale) (PKAS) – [Plots for Day 1; Day 7; Day 1, 
Day 7 and trough day 3-6 ) 
• 
Figure x.x.x : Mean (+ SD) TEI-W00595 Plasma Concentration Time Data for Day 1 and Day 7 
by cohort – (Linear Scale and Semi-Logarithmic Scale) (PKAS) [Plots for Day 1; Day 7; Day 1, 
Day 7 and trough day 3-6) 
Figures will be generated in black and white using unique line style and marker for each plot in the 
graph. For all PK concentration-time plots, linear scale will be used for x-axis (i.e. do not use an 
ordinal scale).  
4.12.2 Pharmacokinetic Parameters 
PK parameters will be provided by CPMS group. PK parameters will be calculated by NCA methods 
from the concentration-time data using Phoenix® WinNonlin® Version 8.3 or higher following these 
guidelines: 
• 
Actual time from dose will be used in the calculation of all derived pharmacokinetic parameters, 
except when parameters are calculated for safety/dose escalation meetings when nominal times 
may be used to calculate PK parameters.   
• 
There will be no imputation of missing data.  
• 
Handling of BLQ samples for derivation of plasma PK parameters after multiple dose 
administration 
o BLQs for Day 1 at the beginning of a patient profile (i.e., before the first incidence of a 
measurable concentration) will be assigned to zero 
o BLQs on subsequent dosing days, and BLQs in the absorption phase will be substituted 
by zero before the calculation of the PK parameters 
o BLQ values between non-BLQ concentrations will be considered missing 
o Terminal BLQs (at the end of patient profile) will be set to missing 
• If urinary concentration is BLQ or if urine volume is not collected, amount of unchanged drug 
recovered in urine (Ae) will be defined as NC 
Pharmacokinetic parameters will be estimated according to the guidelines presented in Table 4-1. 


 
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Table 4-1 Pharmacokinetic Parameter and Estimation 
Parameter 
Guideline for Derivation 
Cmax, tmax, Ctrough,  
Obtained directly from the observed concentration-time data. If multiple tmax values are 
observed the earliest value will be reported. 
AUC0-t  
The AUC from zero time (pre-dose) to the time of last quantifiable concentration will be 
calculated by the linear trapezoidal linear interpolation rule.  
The AUC0-t is the sum of areas up to the time of the last quantifiable sample: 
 
AUC0-t=∫𝐶last ∗𝑑𝑡
 t
0
 
where Clast is the last observed quantifiable concentration. 
AUCtau 
The AUC over the dosing interval (24 hours) will be determined for multiple dose studies 
using the trapezoidal rule, as stated above.  
AUC0-inf 
The area from zero time extrapolated to infinite time will be calculated as follows:  
AUC0-inf = AUC0-t+
𝐶last
𝜆𝑧 
where Clast is the last observed quantifiable concentration.  
%AUCex 
The percentage of AUC0-inf obtained by extrapolation will be calculated as follows:  
%AUCex =
AUC0-inf  ꟷ 𝐴𝑈𝐶0-t 
AUC0-inf
x100 .  
λz and t½ 
1. 
The apparent terminal phase rate-constant (λz) will be estimated by linear 
regression of concentration versus time data presented in a log-linear scale. 
2. 
Data are primarily monotonically decreasing in magnitude and are 
representative of the actual decline in the log concentration-time curve. 
3. 
Only those data points that are judged to describe the terminal log-linear 
decline will be used in the regression.  
4. 
A minimum number of three data points in the terminal phase will be used 
in calculating λz with the line of regression starting at any post-Cmax data point 
(Cmax should not be part of the regression slope). Lambda z (λz) and other λz-related 
parameters (i.e. t½, AUC0-inf, CL/F, MRT0-inf, and Vz/F) will be flagged in listings 
and excluded accordingly from summary tables and statistical analysis of PK 
parameters, if the adjusted correlation coefficient (R2 adjusted) is <0.8, and/or the 
interval used to determine λz is <1.3 times the half-life and/or %AUCex  is >30%, 
unless otherwise determined by PK Scientist’s best knowledge and judgment or if 
instructed by the Sponsor. 
6. 
The t½ will be calculated as follows:  
 
 
 
t½ =  ln2/λz = 0.693/ λz 
7. 
Data points may be dropped from the linear regression if the PK Scientist 
considers the reported values to be anomalous.  Any data points so designated 
should remain in the listings with a footnote and be identified in the study report 
with a rationale for exclusion. 
CL/F 
Apparent clearance after 1st dose will be calculated as follows:  
CL/F  = 
Dose
AUC0-inf 
Apparent clearance (CL/F) following oral dosing will be calculated similarly for Day 7 
where AUCtau will be the denominator, assuming steady state has been achieved then. 


 
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Parameter 
Guideline for Derivation 
MRTlast 
MRTlast will be calculated as follows:  
MRTlast = AUMClast/AUClast (Day 1 only) 
MRT0-inf 
MRT0-inf will be calculated as follows:  
Day 1: AUMC0-inf /AUC0-inf 
Day 7: (AUMCtau + τ*(AUC0-inf – AUCtau))/ AUCtau 
Where AUMC is the area under the moments curve and τ is the dosing interval. 
 
Vz/F 
Volume of distribution at terminal phase on Day 1will be calculated as follows: 
 
 
Vz/F = 
Dose
λz×AUC0-inf = (CL/F)/ z 
Likewise, if derived for Day 7 or steady, AUCtau will be used. 
CLr 
Renal clearance will be calculated from the ratio of the appropriate values for 
urinary recovery and area under the concentration-time curve, where x will be 24  
(Day 1) and 72 (Day 7) hours: 
CLr = 
)
0
(
)
0
(
x
x
AUC
Ae
−
−
 
Racc 
Accumulation ratio, calculated from comparison of single dose (Day 1) and steady 
state (Day 7) data: 
Racc(AUCtau) = Steady state AUCtau
Single dose AUCtau  
 
 
 
Racc(Cmax) = Steady state Cmax/ Single dose Cmax 
Ae 
Amount of unchanged drug recovered in urine is calculated as  
 
Ae = Urine drug concentration * urine volume 
This is calculated for each urine collection interval and then summed for the cumulative 
Ae. 
Fe% 
The percent of drug recovered in urine is calculated as  
 
 
Fe = 100 * Ae/Dose 
This is calculated for each urine collection interval and then summed for the cumulative 
Fe%. 
MR for AUC 
Metabolite molar ratio for Day 1 and Day 7 will be calculated as  
MR for AUC0-inf= (AUC0-inf metabolite/AUC0-inf parent) * (MWparent/MWmetabolite) 
Similarly, metabolite molar ratios will be collected for other AUCs defined earlier in this 
SAP. 
Metabolite molar ratios will be calculated based on molecular weight of 
 for 
parent, TCK-276 and 
 for metabolite TEI-W00595. 


 
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Parameter 
Guideline for Derivation 
MR for Cmax 
Metabolite molar ratio for Day 1 and Day 7 will be calculated as  
MR for Cmax = (Cmax metabolite/ Cmax parent) * (MWparent/MWmetabolite) 
Metabolite molar ratios will be calculated based on molecular weight of 
 for 
parent, TCK-276 and 
 for metabolite TEI-W00595. 
DNCmax, DNAUC0-t, 
DNAUC0-inf, DNAUCtau 
Parameter value divided by dose 
 
PK Parameters Listings:  
PK parameters will be listed by patient for the PK Population. PK parameters that will be flagged 
and/or excluded from summary tables and statistical analyses of PK parameters will be flagged and 
footnoted with the reason for flagging/exclusion.  
PK Parameter Summary Tables: 
Biostatistics group will consider the derived PK parameters as source data and will use this data 
without rounding for calculation of PK parameters summary statistics tables.   
PK parameters will be summarized by cohort/treatment and Day for the PK population. Tabular 
summaries for PK parameters will report N (number of patients who received treatment) and n 
(number of patients with non-missing PK parameter). Descriptive statistics for calculated PK 
parameters will include N, n, arithmetic mean, SD, CV%, geometric mean, gCV%, median, 
minimum, and maximum values. For tmax, only N, n, arithmetic mean, SD, CV%, median, minimum, 
and maximum values will be presented. No descriptive statistics will be determined when fewer than 
three individual PK parameters are available. 
The rules followed for presentation of PK parameters data with regards to the number of decimal 
places/significant digits for the listings of patient level PK parameters and summary tables of PK 
parameters are as follows:  
PK Parameter Listings and Tables 
Rounding  
Derived Individual parameters 
3 s f. 
Directly Derived Individual parameters (e.g., 
Cmax, Ctrough) 
n s f. as supplied by the analytical laboratory but not 
more than 3 s f. 
Minimum and Maximum 
3 s f. 
Mean/SD/Median/Geomean 
3 s f. 
CV%/gCV% 
1 d.p. 
CI  
3 s f. 
p-values 
4 d.p. 
N/n 
Whole number 
Exceptions for PK Tables 
  
tmax individuals and min/max 
2 d.p 
tmax median only 
2 d.p 
s f = significant figures, d.p. = decimal place 


 
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PK Parameter Figures: 
Following figures will be created: 
• Dose-normalized TCK-276 Plasma PK Parameter (dose-normalized Cmax, all dose-
normalized AUC) against Dose of TCK-276 scatter plot of individual values and line plot of 
geometric mean values 
• Log-transformed TCK-276 PK Parameter (Cmax, all AUCs) against the Log transformed Dose 
of TCK-276 based on power model 
• Overlaid Individual Urinary Cumulative Excretion Rate (%) of TCK-276 versus End of 
Collection Interval Time Point for Day 1 and Day 7 by Dose [Plots for Day 1 all doses and 
Day 7 all doses] 
• Mean (+ SD) Urinary Cumulative Excretion Rate (%) of TCK-276 versus End of Collection 
Interval Time Point for Day 1 and Day 7 [Plots for Day 1 all doses and Day 7 all doses] 
 
4.12.3 Statistical Analysis of Pharmacokinetic Parameters 
❖ Assessment of Dose Proportionality  
Power model is used for assessment of dose proportionality. 
▪ Power model: 
• Power model using linear regression method: 
Dose proportionality will be assessed for Cmax, AUC tau , AUC0-inf, and AUC0-t on Day 1 and Day 7 
using the PKAS who received single or multiple doses of TCK-276.  PK parameters will be used to 
perform a LS linear regression analysis, using the formula ln_pkvar=A ln_dose + B, where ‘ln 
pkvar’ represents the natural log transformed Cmax AUCtau, AUC0-inf, and AUC0-t parameters and 
‘ln_dose’ represents the natural log-transformed dose.  An estimate of the slope and intercept of the 
regression line and corresponding 95% CI will be obtained. 
The following SAS code will be used: 
ODS OUTPUT parameterestimates=est FitStatistics=fit; 
PROC REG DATA = PP ALPHA=0.05 PLOTS=ALL; 
BY PARAMCD PARAM; 
MODEL LNAVAL=LNDOS/CLB; 
RUN; 
where: 
LNAVAL: natural log-transformed PK parameter  
LNDOS: natural log-transformed dose level of <drug>  
PARAM: PK parameter  
  
 


 
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If the 95% confidence interval (CI) range for the slope includes 1 and the lack of fit test is not 
significant (p-value < 0.05), the relationship between dose and the PK parameter will be concluded 
to be dose proportional for the dose range studied. 
 
If the 95% CI range for the slope does not include 1 or the lack of fit test is significant (p-value < 
0.05), then additional dose proportionality assessments using above power model with narrower dose 
range will be performed by sequentially decreasing the number of doses either from higher or lower 
end of dose range studied as shown in below tabular manner for the respective assessments and 
combinations. The doses for the assessments must be sequential and include at least 3 doses. All the 
possible combinations of sequential ascending doses in a certain number of doses will be applied for 
the assessments. The additional proportionality assessments will be repeated until dose 
proportionality is found in any dose ranges (minimum 3 doses) and the lack of fit test is not 
significant. 
 
Table 4-2 Dose Proportionality Assessments in 2 round as shown below 
Round 
Combination 
Range of Doses  
(in mg) 
Assessment 
1st 
With 
all 
four-dose 
studied 
10, 25, 75, 175 
If no dose proportionality is shown, 
perform 2nd Round 
 
2nd 
1st – with 3 doses 
10, 25, 75 
Stop the assessment at this round 
even if none of the combinations 
shows dose proportionality. 
 
2nd – with 3 doses 
25, 75, 175  
Note: If all 4 doses cannot be administered because of protocol defined dose escalation stopping criteria, dose 
proportionality will be appropriately updated.


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4.12.4 Pharmacodynamic Analysis, Concentration, and Parameter TFLs, and Statistical 
Analysis of Pharmacodynamic Parameters 
Not Applicable 
4.13 Safety Evaluation 
All safety summaries and analyses will be based upon the SAF as defined in Section 4.4.1. 
All summaries will be provided by cohort and treatment. 
Placebo across cohorts will be pooled. 
4.13.1 Adverse Events 
All outputs for AEs/treatment-emergent adverse events (TEAEs) will be based on the SAF unless 
specified separately in TLF shells. AEs are to be classified by using Medical Dictionary for Regulatory 
Activities (MedDRA®), Version 25.0 or higher and assigned to a System Organ Class (SOC) and Preferred 
Term (PT). 
All AE will be summarized by MedDRA terms and treatment groups. It will include evaluation of 
the number of AEs and the number and percentage of patients reporting at least one AEs. 
 Summaries of AEs will include the following: 
• Incidence of AEs - Overview (by cohort/treatment and overall) 
• Incidence of TEAEs (by cohort/treatment and overall, SOC, and PT) 
• Incidence of TEAEs by relationship (by cohort/treatment and overall, SOC, and PT) 
• Incidence of TEAEs by maximum severity (mild/moderate/severe, by cohort/treatment and 
overall, SOC, and PT) 
• Incidence of TEAEs leading to discontinuation of study treatment 
• Incidence of SAEs  
• Incidence of TEAEs Related to IMP by maximum severity (mild/moderate/severe, by 
cohort/treatment and overall, SOC, and PT) 
Summary tables will contain counts of patients, percentages of patients in parentheses, and the 
number of events where applicable. A patient who has multiple events in the same SOC and PT 
will be counted only once in the patient counts, but all events will be included. 
All Adverse Events (AEs) 
Adverse events will be individually listed per patient number, presenting assigned treatment, 
verbatim term, Primary SOC, PT, treatment emergence (yes or no), date and time of onset, date 
and time of last study drug administration before AE, time from onset since last study drug 
administration, severity and seriousness, relationship to study drug, the required action taken, 
outcome, if it is a reason for drop out, and if it is AESI or not. 
 


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Treatment-emergent Adverse Event 
A TEAE will be defined as any AE that emerge during treatment (i.e., AE which started after study 
drug administration or pre-existed that worsened in severity after study drug administration) and 
those will be analyzed for the purpose of safety analysis. 
TEAEs will be summarized by SOC and PT, including the number and percentage of patients 
experiencing events, separately. 
Severity 
TEAEs will be summarized by SOC, PT, and severity, including the number and percentage of 
patients experiencing events. If a patient reports the same TEAE more than once within that SOC 
and PT, the TEAE with the highest severity will be used in the corresponding severity summaries. 
In summaries including severity, the following intensity categories will be summarized: ‘Mild’, 
‘Moderate’, ‘Severe’. Subjects who experience the same event multiple times will be included in 
the most severe category. Events with missing intensity will be considered as ‘Severe’ events for 
summary purposes but recorded as missing in the listings. 
If severity is reported by Common Terminology Criteria for Adverse Events (CTCAE) grade, then 
summary of severity will be presented using CTCAE grade. 
Relationship (Causality) 
TEAEs will be summarized by SOC, PT, and causality, including the number and percentage of 
patients experiencing events. Relationship to study drug will be tabulated respectively. If a patient 
reports the same TEAE more than once within that SOC and PT, the TEAE with the worst-case 
relationship to study drug will be in summaries including relationship to study treatment, the 
following relationships will be summarized: ‘Not related’, ‘Related’. Patients who experience the 
same event multiple times will be included in the most related category. Events with missing 
relationship will be considered as ‘Related’ to the last given study drug for summary purposes but 
recorded as missing in the listings. 
Adverse Events of Special Interest (AESI) 
Based on CDK4/6 inhibition mechanism of action, the following AEs will be defined as AESIs:  
• Myelosuppression: Hematology including monitoring for neutropenia, leucopoenia, 
thrombocytopenia, and increased tendency to bleed 
• Embryo-fetal toxicity:  
• Interstitial lung disease: Pulmonary symptoms (dyspnea, pyrexia, and cough)   
• Gastrointestinal toxicity: e.g., diarrhea, nausea, vomiting, and abdominal pain. 
Adverse events of special interest (AESI) will be summarized by SOC and PT, including the 
number and percentage of patients experiencing events. Listing of AESI will be provided. 
4.13.2 Deaths, Serious Adverse Events, and Other Significant Adverse Events 
Describe the listings that are to be provided.  These may include the following listings: 
• 
A by-patient listing of all SAEs 


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• 
A by-patient listing of all AES leading to discontinuation of study treatment 
Listings should follow the format described for AEs in Section 4.13.1 if appropriate. 
 
4.13.3 Clinical Laboratory Evaluation 
Clinical laboratory test results of hematology, clinical chemistry, urinalysis, urinary drug screening, 
coagulation and serology will be provided by patient. 
All TLFs will display only the standard international (SI) units after conversion by means of 
standard conversion factors.  
Quantitative clinical laboratory variables, i.e., hematology, clinical chemistry, coagulation and 
urinalysis will be summarized using descriptive statistics (n, mean, SD, minimum, maximum and 
median) by cohort, treatment group and time-point. Additionally, a within-patient change will be 
calculated as the post-baseline measurement minus the baseline measurement and summarized in 
the same way.  
Baseline definition is defined in section 4.2.4. 
Any quantitative laboratory parameters that are given as '<xx' or '>xx' in the database will be 
imputed with the absolute value of the number without the sign (e.g., <2.2 will be imputed as 2.2) 
for the calculation of the changes from baseline and for the descriptive statistics. In the listings, no 
imputations will be performed, and all data will be displayed as recorded in the database. 
Each laboratory result will be classified as low (L), normal (N), or high (H) at each time point 
according to the laboratory supplied reference ranges. For hematology , clinical chemistry, 
coagulation and urinalysis, shift tables will be presented showing the number and percentage of 
patients with shifts from baseline to each post dose time point. Tabulations will be presented by 
cohort and treatment group.  
Measurements obtained at Screening will not be included in the shift tables and in the tabulations 
of descriptive statistics.  
Measurements obtained prior to dosing in each period will be included in the tabulations for the 
treatment received in that specific treatment period. 
Frequency tabulations of qualitative clinical laboratory variables (urinalysis) will be presented by 
cohort, treatment group and time-point. 
All laboratory data will be displayed in listings. 
Laboratory abnormalities that are considered clinically significant (CS) are recorded in the 
database as AEs. Therefore, no tabulation of laboratory values meeting any CS criteria (except 
liver chemistry) will be presented as all relevant information will be presented in the AE 
summaries. 
Results of pregnancy tests (females only), viral serology, covid-19 test, urine drug screening, 
cotinine test, and alcohol tests will be listed in other laboratory test. 


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4.13.4 Vital Signs 
A by-patient listing of all vital sign measurements (including weight) and change from baseline 
will be presented.  
Baseline is defined in section 4.2.4. 
Measured (observed) values including changes from baseline will be summarized by cohort/ 
treatment and time point and by vital sign parameter (BP (systolic and diastolic [mmHg]), pulse 
rate(bpm), respiratory rate (breaths per minute), and body temperature (tympanic [ear] or non-
contact infrared thermometers) (°C)). 
Measurements obtained at screening will not be included in the tabulations of descriptive statistics.  
4.13.5 ECG 
Standard safety 12-lead ECGs will be performed as shown in the section 6.1. 
The following ECG parameters will be recorded: 
PR interval (msec) 
QRS interval (msec) 
RR interval (msec) 
QT interval (msec) 
QT interval corrected using the Fridericia correction formula (QTcF) (msec). 
The ECG will be evaluated by the Investigator as ‘Normal’, ‘Abnormal, NCS’ or ‘Abnormal, CS’. 
All ECG parameters will be listed by each patient and time point including changes from baseline.  
Baseline is defined in section 4.2.4. 
Descriptive statistics for observed values and changes from baseline will be presented by cohort 
and treatment group. A categorical QTc analysis will also be performed. 
Measurements obtained at Screening will not be included in the shift tables and in the tabulations 
of descriptive statistics.  
Measurements obtained prior to dosing in each period will be included in the tabulations for the 
treatment received in that specific treatment period. 
A summary of the number and percentage of patients with QT/QTc intervals exceeding some 
predefined upper limits (eg, >450 msec, >480 msec, >500 msec for measured values as well as. 
>30 msec, >60 msec for changes from baseline) of ECG parameters (QT interval, QTcF and 
QTcB) will be displayed in a frequency table. 
The listing of ECG abnormality will be presented separately. 
 
4.13.6 Physical Examination 
Physical examinations will be performed as shown in the section 6.1. 


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The full physical examination includes an assessment of general appearance and a review of 
systems (dermatologic, head, eyes, ears, nose, mouth/throat/neck, thyroid, lymph nodes, 
respiratory, cardiovascular, gastrointestinal, extremities, musculoskeletal, neurologic and 
psychiatric systems). 
The brief physical examination includes an assessment of the general appearance, skin, abdomen, 
cardiovascular system and respiratory system. 
Abnormal physical examination findings will be listed. 
4.13.7 Other Analysis 
Not Applicable 
 
4.13.8  Exploratory Analysis 
The following disease activity parameters for RA will be listed and summarized by descriptive 
statistics and displayed graphically as appropriate. 
• American College of Rheumatology (ACR) 20/50/70 response criteria 
• Disease activity score 28 (DAS28) 
• Clinical disease activity index (CDAI) 
• Simplified disease activity index (SDAI) 
 
The derivation of the above endpoints is as follow: 
 
elements 
CDAI 
SDAI 
DAS28 
CRP 
DAS28 
ESR 
ACR 
Swollen Joint Count (SJC) 
X 
X 
X 
X 
X 
Tender Joint Count (TJC) 
X 
X 
X 
X 
X 
Patient Global Assessment (PGA 
or Patient global score) 
X 
X 
X 
X 
X 
Evaluator 
Global 
Assessment 
(EGA or Provider global score) 
X 
X 
 
 
X 
CRP (mg/L) 
 
X 
X 
 
x (or 
ESR) 
ESR (mm/hr) 
 
 
 
X 
x (or 
CRP) 
Pain VAS 
 
 
 
 
X 
HAQ 
 
 
 
 
X 
 
Baseline (Day 1), Current value (Day 7) and CFB (Day 1 - Day 7) and %CFB ((Day 1- 
Day7)/Day1*100) of Disease activity data elements (numbers of SJC and TJC, PGA, EGA, CRP, 
ESR, pain VAS and HAQ-DI) scores will be summarized using the n, mean, SD, minimum, 


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median, and maximum by cohort, treatment and overall, on Exploratory Population. %CFB will 
be presented only for two decimal places. 
 
A by-patient disease activity data elements (numbers of SJC and TJC, PGA, EGA, CRP, ESR, 
pain VAS and HAQ-DI) scores will be listed based on Exploratory population 
 
American College of Rheumatology 
 
ACR CRP Response Criteria: A Patient is considered as ACR 20 (50/70) responder if  
• At least 20%(50% / 70%) improvement in SJC(28 Joint count)  
compared to baseline, AND 
• At least 20%(50% / 70%) improvement in TJC(28 Joint count)  
compared to baseline, AND 
• At least 20%(50% / 70%)  improvement in 3 out of following five 
measures 
1. Patient’s assessment of pain on VAS(0-10) 
2. Patient’s global assessment (PGA or Patient global score) of the 
disease (0-10) 
3. Evaluator global assessment (EGA or provider global score) of 
the disease (0-10) 
4. Patient’s assessment of disability on HAQ 
5. Acute phase reactant (C-reactive Protein (CRP)) 
 
ACR ESR Response Criteria: A Patient is considered as ACR 20 (50/70) responder if  
• At least 20% (50% / 70%) improvement in SJC(28 Joint count)  
compared to baseline, AND 
• At least 20% (50% / 70%)  improvement in TJC(28 Joint count)  
compared to baseline, AND 
• At least 20%(50% / 70%)  improvement in 3 out of following five 
measures 
1. Patient’s assessment of pain on VAS(0-10) 
2. Patient’s global assessment (PGA or Patient global score) of the 
disease (0-10) 
3. Evaluator global assessment (EGA or provider global score) of 
the disease (0-10) 
4. Patient’s assessment of disability on HAQ 
5. Acute phase reactant (Erythrocyte sedimentation rate (ESR)) 
 
ACR 20/50/70 (ESR and CRP) will be summarized using count and percentage of responders by 
cohort and treatment on Exploratory Population. The percentages of ACR20, (50, or 70) 
responders are calculated by the equation, “number of ACR20 (50, or 70) responders / number of 
subjects on each cohort x 100 (%)” by each cohort. 
 


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A by-patient listing of percentage of responders of ACR 20/50/70 (ESR and CRP) will be 
presented on Exploratory Population 
 
Health Assessment Questionnaire - Disability Index (HAQ-DI) 
 
The HAQ-DI consists of eight categories of functioning expressed through 20 questions. Activities 
are organized under the categories of Dressing & Grooming, Arising, Eating, Walking, Hygiene, 
Reach, Grip, and Activities. Each item is scored on a 4-point scale from 0 to 3, representing 
Without ANY Difficulty [0], With SOME Difficulty [1], With MUCH difficulty [2], and 
UNABLE to do [3]. 
 
Scoring for the eight functional categories and overall disability index scoring will be performed 
as follows: 
There are eight categories including 20 items; first score within each category:  
• 
Dressing and Grooming, includes 2 items  
• 
Arising, includes 2 items  
• 
Eating, includes 3 items  
• 
Walking, includes 2 items  
• 
Hygiene, includes 3 items  
• 
Reach, includes 2 items  
• 
Grip, includes 3 items  
• 
Activities, includes 3 items  
 
The score for each category will be the single response within the category with the highest score 
(greatest difficulty). 
For example, in the "Eating" category, there are two answers (one for each item). If " Use 
chopsticks by yourself" is marked as "3" and "Lift a full cup or glass to your mouth" is marked as 
"0", then the score for the "Eating" category would be "3" (the response indicating the greatest 
difficulty within the category). If a component question is left blank or the response is too 
ambiguous to assign a score, then the score that that category will be determined by the remaining 
completed question(s). However, if any "aids or devices" and/or "help from another person" items 
at the bottom of each page are checked with the exception of “other”, the category to which they 
apply will be adjusted upward to "2". If the basic score is already "2" or "3", the score remains 
unchanged. "Aids or devices" and "help from another person" can only change a category's score 
to "2"; they do not change the score to a "1" or a "3". Companion aids/devices items for HAQ-DI 
categories are presented in Table 4-3. No score will be adjusted, if only other is ticked, regardless 
of the specification. 
The score for the disability index will be the mean of the eight category scores. If more than two 
of the categories, or 25%, are missing, scale will not be scored. If fewer than 2 of the categories 
are missing, divide the sum of the categories by the number of answered categories. The higher 
score indicates greater disability. 
Table 4-3 Companion aids/devices items for HAQ-DI categories 
HAQ-DI 
Companion Item 


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Dressing & Grooming 
Devices used for dressing (button hook, zipper 
pull, long-handled shoe horn, etc.) 
Arising 
Special or built up Chair 
Eating 
Built up or special utensils 
Walking 
Cane, Walker, Crutches, Wheelchair 
Hygiene 
Raised toilet seat, Bathtub seat , Bathtub bar, 
Long-handled appliances in bathroom 
Reach 
Long-handled appliances for reach 
Grip 
Jar opener (for jars previously opened) 
 
Disease activity score 28 (DAS28) 
 
o DAS28 ESR 
▪ 0.56×√(TJC)＋0.28×√(SJC)＋0.7×LN(ESR)＋0.14*×(PGA) 
o DAS28 CRP 
▪ 0.56×√(TJC)＋0.28×√(SJC)＋0.36×LN((CRP)+1) ＋0.14*×(PGA)
＋0.96 
 *Because PGA data in this study are collected with 0-10 scale, instead of 0-100 scale, this coefficient is 0.14, not 0.014 usually 
found in the formula. LN means log natural. 
 
Clinical disease activity index (CDAI) 
 
o CDAI = SJC + TJC +PGA + EGA 
 
Simplified disease activity index (SDAI) 
 
o SDAI = SJC + TJC +PGA + EGA + 0.1*CRP 
 
Baseline (Day 1), Current value (Day 7), CFB (Day 1 - Day 7) and %CFB ((Day 1 – 
Day7)/Day1*100) of DAS28 ESR, DAS28CRP, CDAI, and SDAI will be summarized using the 
n, mean, SD, minimum, median, and maximum by cohort, treatment and overall, on Exploratory 
Population. %CFB will be presented only for two decimal places. 
 
If any of the elements are missing, then the corresponding parameter will be considered as missing. 
 
A by-patient disease activity data parameters (DAS28 ESR, DAS28CRP, CDAI, and SDAI) scores 
will be listed based on Exploratory population. 
 
For Exploratory Biomarker refer section 4.15. 
 
4.13.9  Daylight Saving Time (DST) 
Not Applicable 
 


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4.13.10 Safety Monitoring (Independent Data Monitoring Committee, Data Monitoring 
Committee, Data and Safety Monitoring Board)  
A SRC will be appointed for this study. The SRC meeting will take place to review safety and PK 
data during each dose level. The SRC will evaluate the safety and tolerability data up to Follow-
up/EOT Visit and available PK data up to Day 10 to determine the next dose for the subsequent 
cohort. 
The SRC will review available blinded safety, tolerability, and PK data after each cohort to confirm 
whether it is safe to proceed with the next planned dose, whether the dose escalation should be 
stopped, or if the dose should be lowered, repeated or titrated in the subsequent cohort. 
4.14 Cardio Dynamic Analyses 
Not Applicable 
4.15 Biomarkers 
 
Descriptive statistics for observed values, changes from baseline and % changes from baseline, 
and a by-patient listing will be provided for the following biomarkers based on Exploratory 
Population.  This data will also be displayed graphically as appropriate.  
 
Biomarker  
Description 
Read out* 
MMP-3 
Matrix metalloproteinase-3 
GM-CSF 
Granulocyte 
macrophage 
colony 
stimulating factor 
CXCL10 
C-X-C motif chemokine ligand 10 
CCL2 
C-C motif chemokine ligand 2 
COMP 
Cartilage oligomeric matrix protein 
TNF-α 
Tumor necrosis factor - α 
TNF-RI 
Tumor necrosis factor-RI 
IL-6 
Interleukin-6 
* Biomarker name exactly as it will appear in the dataset 
 
 
Handling of LLOQ and ULOQ 
Biomarker data are reported as concentration results, measured using a specific assay with a 
working range defined by the two limits: Lower limit of quantification (LLOQ) and Upper limit 
of quantification (ULOQ). Values which fall below the LLOQ or above the ULOQ are reported as 
< LLOQ * dilution factor (dilution factor: if sample diluted and concentration measured still below 
LLOQ) and > ULOQ * dilution factor, respectively. 
To ensure that biomarkers only have numerical values, censored values will be imputed as follows 
• Values below the LLOQ are replaced by LLOQ/2. 
• Values above the ULOQ are replaced by ULOQ. 
 
Imputed values are used for summary statistics, inferential analyses and plots (with a special 
symbol). Values below LLOQ and values above ULOQ are shown as such in the listings. In the 


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summary table, the frequency (n, %) of values below the LLOQ and above the ULOQ, 
respectively, will be included.  
If the proportion of imputed data is more than 20% for any treatment group at any time point, a 
footnote is added to the summary statistics table stating that the proportion of values outside the 
limits of quantification is more than 20% for some treatment groups at some time points and that 
in such cases summary statistics may be heavily biased. 
 
If the proportion of imputed data for a given biomarker, across all treatment groups and time points, 
is more than 50%, no summary statistics will be provided, and the data are only listed. 
 
4.16 Adjustments for Covariates 
Not Applicable 
4.17 Handling of Dropouts or Missing Data 
No imputation of missing data will be performed except for partial dates imputation mention in 
Section 6.2. 
4.18 Subgroup Analysis 
Not Applicable 
4.19 Planned Interim Analyses 
Not Applicable  
4.20 Determination of Sample Size 
No formal sample size calculations were performed. Thirty-two patients were chosen based on 
feasibility and are considered sufficient to meet the study objectives of this exploratory study. 
4.21 Changes in the Conduct of the Study or Planned Analysis 
Exploratory population definition is more elaborately defined as per study need.  
5 
REFERENCES 
[1] SAS® Version 9.4 of the SAS System for Personal Computers. Copyright © 2002-2003. 
SAS Institute Inc. SAS and all other SAS Institute Inc. product or service names are registered 
trademarks or trademarks of SAS Institute Inc., Cary, NC, USA. 
 
[2] Phoenix®WinNonlin®  Software Version 8.3. https://www.certara.com 
 
[3] CDAI: Clinical Disease Activity Index for RA (CDAI) (medscape.com) 
 
[4] SDAI: Simplified Disease Activity Index for RA (SDAI) (medscape.com) 
 


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[5] DAS28 ESR: https://www.4s-dawn.com/DAS28/ 
 
[6] DAS28 CRP : https://www.4s-dawn.com/DAS28/ 
 
 


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6 
APPENDICES 
6.1 
Schedule of Assessments 
Table 6-1 Schedule of Assessments 
Evaluation 
Screening 
visit 
Treatment period 
Follow-up/ 
End of 
treatment 
Early 
termination 
procedures 
Days 
-28 to -2 
-1 
1 
2-7 
8, 9 
10 
14 
 
Informed consent 
X 
 
 
 
 
 
 
 
Admission 
 
X 
 
 
 
 
 
 
In-house stay 
 
X 
X 
X 
X 
X 
 
 
Ambulatory visits 
X 
 
 
 
 
 
X 
X 
Discharge 
 
 
 
 
 
X 
 
 
Inclusion/exclusion criteria 
X 
X 
X 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
Disease activity data 
(ACR20/50/70, DAS28, 
CDAI, SDAI) 
 
 
X1 
X2 
 
 
 
 
Blood sampling for ESR, 
assessed as part of disease 
activity data 
 
 
X1 
X2 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Weight and height (height 
only at Screening) 
X 
X 
 
 
 
X 
 
 
Viral serology (HBsAG, anti-
HBc, anti-HCV, anti-HIV) 
X 
 
 
 
 
 
 
 
Drug, alcohol, and cotinine 
screen 
X 
X 
 
 
 
 
 
 
SARS-CoV-2 real time 
RT-PCR 
X 
X 
 
 
 
 
 
 
IGRA-TB test (Quantiferon) 
X 
 
 
 
 
 
 
 
Chest X-ray 
X 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
Study drug administration 
 
 
X 
X 
 
 
 
 
Urine pregnancy test 
(females) 
X 
X 
 
 
 
 
X 
X 
FSH (post-menopausal 
females) 
X 
 
 
 
 
 
 
 
Physical examination3 
X 
X 
 
 
 
X 
X 
X 


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Evaluation 
Screening 
visit 
Treatment period 
Follow-up/ 
End of 
treatment 
Early 
termination 
procedures 
Days 
-28 to -2 
-1 
1 
2-7 
8, 9 
10 
14 
 
Clinical laboratory tests 
(clinical chemistry, 
hematology, coagulation, and 
urinalysis)  
X 
X 
X1 
X4 
X 
X 
X 
X 
Vital signs 
X 
X 
X5 
X 
X 
X 
X 
X 
12-lead ECG6 
X6 
X7 
X8 
X8 
X 
X 
X 
X 
Telemetry 
 
 
X9 
X9 
 
 
 
 
PK blood sampling10 
 
 
X 
X 
X 
X 
 
 
PK urine collection11 
 
 
X 
X 
X 
X 
 
 
Biomarker blood sampling 
 
 
X1 
X2 
 
 
 
 
Blood sampling for possible 
future pharmacogenetic 
assessments 
 
X12 
 
 
 
 
 
 
Blood sampling for possible 
future metabolite 
assessments10 
 
 
X 
X 
X 
X 
 
 
Blood sampling for possible 
future PD assessments 
 
 
X1 
X2 
 
 
 
 
Prior/concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
AE monitoring13 
X 
X 
X 
X 
X 
X 
X 
X 
ACR = American College of Rheumatology; AE = adverse event; CDAI = clinical disease activity index; 
DAS28 = disease activity score 28; ECG = electrocardiogram; ESR = erythrocyte sedimentation rate; FSH = follicle 
stimulating hormone; HBc = hepatitis B core; HBsAG = hepatitis B surface antigen; HCV = hepatitis C virus; 
HIV = human immunodeficiency virus; ICF = informed consent form; IGRA-TB = interferon gamma release assay 
for tuberculosis; PD = pharmacodynamic; PK = pharmacokinetics; RT-PCR = reverse transcription polymerase 
chain reaction; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; SDAI = simplified disease activity 
index. 
1. 
Disease activity data (ACR20/50/70, DAS28, CDAI, SDAI, and blood sampling for ESR), blood for clinical 
laboratory tests, blood for biomarker assessments, and blood for possible future PD assessments will be 
collected prior to dosing on Day 1. Blood sampling for ESR will be collected and assessed at local laboratory. 
2. 
Disease activity data (ACR20/50/70, DAS28, CDAI, SDAI, and blood sampling for ESR), blood for biomarker 
assessments, and blood for possible future PD assessments will be collected on Day 7 only. Blood sampling for 
ESR will be collected and assessed at local laboratory. 
3. 
A full physical examination will be performed at the Screening Visit, Day 14, and Early termination visit; a 
brief physical will be performed on Days -1 and 10. 
4. 
Blood for clinical laboratory tests will be withdrawn once on Days 4 and 7.  
5. 
Vital signs will be collected at pre-dose and 1, 2, 4, 8, and 12 hours after dosing on Day 1. 
6. 
12-lead ECG will be conducted before blood sampling. 
7. 
12-lead ECG will be repeated once for eligibility confirmation at Screening and Day -1. 


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8. 
12-lead ECG will be recorded at baseline and at 1, 2, 4, and 8 hours after dosing on Days 1 and 7.  
9. 
Starting 2 hours prior to dosing and until 12 hours after dosing on Days 1 and 7. 
10. Blood for PK sample analysis to determine parent and its metabolite concentrations and for possible future 
metabolite assessments will be sampled at pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours (pre-
dose of Day 2) after dosing on Day 1, pre-dose on Days 3, 4, 5, 6, and on 7, at pre-dose and 0.25, 0.5, 1, 1.5, 2, 
3, 4, 6, 8, 12, 16, 24, 48, and 72 hours after dosing on Day 7 (the sampling time points may be adjusted based 
on the PK results obtained from the previous parts or cohorts). The last dose will be administered on Day 7. 
11. Urine for PK sample analysis will be collected at 0 (pre-dose) to 6, 6 to 12, and 12 to 24 hours after dosing on 
Day 1, and from 0 (pre-dose) to 6, 6 to 12, 12 to 24, 24 to 48, and 48 to 72 hours after dosing on Day 7. Urine 
collection intervals may be adjusted based on the PK results obtained from the previous parts or cohorts, e.g., if 
plasma PK sampling times are adjusted, the urine sampling times will be updated. 
12. Sample will be obtained only from patients that consent to pharmacogenomics sampling. 
13. Any AEs occurring after the patient signs the ICF will be collected and monitored throughout the study via 
safety assessments, observation, and patient reporting. 










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Leukocytes 
Nitrite 
Microscopic (only for abnormal urine stick test 
findings)-Hyaline casts, cellular casts, granular 
casts, RBC and WBC 
Blood 
pH and specific gravity 
Protein 
Urobilinogen 
Color and appearance 
Urinary creatinine (to exclude dilution effect) 
Viral Serology 
Hepatitis B core antibody (anti-HBc) 
Anti-hepatitis B surface antigen (HBsAg) 
Hepatitis C virus antibody (anti-HCV) 
Human 
immunodeficiency 
virus 
(HIV)  
(Types 1 and 2) antibodies 
COVID-19 Testing 
Severe acute respiratory syndrome coronavirus 
2 
(SARS-CoV-2) 
reverse 
transcription 
polymerase chain reaction (RT-PCR) 
Urine Drug Screening, Cotinine Test, and 
Alcohol Test 
Amphetamines 
Barbiturates 
Benzodiazepines 
Oxycodone 
Tricyclic Antidepressants  
Cannabinoids 
Alcohol/Ethanol 
(to 
be 
tested 
using 
breathalyzer) 
Cocaine 
Opiates 
Phencyclidine 
3,4-methylenedioxymethamphetamine 
(MDMA) 
Propoxyphene 
Cotinine 
Pregnancy Testing 
Urine human beta chorionic gonadotrophin 
 
 


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6.4 
ECG Notable Criteria  
ECG Parameters 
Definition/threshold 
 
New value <= 450 msec 
QT, QTcF 
 
New value of > 450 msec and ≤ 480 msec 
 
New value of > 480 msec and ≤ 500 msec 
 
New value of > 500 msec 
 
Increase from baseline <= 30 msec 
 
Increase from baseline of > 30 msec to ≤  60 msec 
 
Increase from baseline of > 60 msec 
 
 
QTcF = QT corrected using Fridericia’s formula 


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