Conditions: Osteoarthritis of the Knee
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 504
Healthy volunteers: no

Brief summary:
Phase 3 randomized, double-blind, placebo- and active comparator-controlled study of TLC599.

Detailed description:
This is a Phase 3 randomized, double-blind, placebo- and active comparator-controlled pivotal study. Approximately 500 adult patients with moderate to severe pain due to OA of the knee will be enrolled and randomized. All patients will be followed for a total of 52 weeks. Efficacy and safety of 2 doses of TLC599 will be evaluated in comparison to Placebo and DSP through Week 52.

Arms:
arm 1: TLC599 (1mL) IA injection arm 2: DSP 4mg (1mL) IA injection arm 3: Normal saline (1mL) IA injection

Interventions: intervention 1: TLC599 intervention 2: DSP intervention 3: Normal Saline
Intervention descriptions: intervention 1: TLC599 is a proprietary (Bioseizer) lipid formulation containing DSP (active ingredient) intervention 2: Dexamethasone sodium phosphate (DSP) is a glucocorticoid widely used in the treatment of joint pain such as gout, osteoarthritis and rheumatoid arthritis via IA injection. intervention 3: 0.9% normal saline

Protocol document:
Prot_SAP_000.pdf: 
tlc~~ 
Delivering Hope for Life 
PROTOCOL AMENDMENT 
PRODUCT NAME/NUMBER: 
TLC599 (Lipid-based Dexamethasone Sodium Phosphate 
Sustained Release Formulation) 
PROTOCOL NUMBER: 
TLC599A3005 
IND NUMBER: 
DEVELOPMENT PHASE: 
PROTOCOL TITLE: 
PROTOCOL DATE: 
AMENDMENT 4 DATE 
SPONSORED BY: 
CONTRACT RESEARCH 
ORGANIZATION: 
Phase 3 
A Phase 3, Randomized, Double-blind, Placebo- and 
Active-controlled Study to Evaluate the Efficacy and Safety 
of TLC599 in Patients with Osteoa1thritis of the Knee 
Final Version 5.0, 09-Mar-2022 
Taiwan Liposome Company, Ltd. 
1lF-1,3 Yuanqu Street, Nangang District, Taipei 11503 
Taiwan 
+886-2-2655-73 77 
This study will be performed in compliance with International Conference on Harmonisation of 
Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Good Clinical 
Practice and applicable regulatory requirements, including the archiving of essential documents. 
Information contained in this protocol is confidential in nature, and may not be used, divulged, 
published, or otherwise disclosed to others except to the extent necessary to obtain approval of the 
institutional review board or Independent Ethics Committee, or as required by law. Persons to 
whom this information is disclosed should be informed that it is confidential and may not be further 
disclosed without the express permission of Taiwan Liposome Company, Ltd. 
Final Version 5.0, 09-Mar-2022 
Page I of JOO 
NCT number:  NCT04123561


Taiwan Liposome Company, Ltd. 
TLC599A3005 
Confidential 
APPROVAL SIGNATURES 
PROTOCOL NUMBER: 
TLC599A3005 
PROTOCOL TITLE: 
A Phase 3, Randomized, Double-blind, Placebo- and Active-
controlled Study to Evaluate the Efficacy and Safety of TLC599 in 
Patients with Osteoarthritis of the Knee 
PROTOCOL VERSION: 
Amendment 4, Version 5.0 (09-Mar-2022) 
I, the undersigned, have read this protocol and confirm that to the best of my knowledge it 
accurately describes the planned conduct of the study. 
SIGNATURE 
DATE: 
Taiwan Liposome Company, Ltd. 
Taiwan Liposome Company, Ltd. 
Final Version 5.0, 09-Mar-2022 
Page 2 of 100 


Taiwan Liposome Company, Ltd. 
TLC599A3005 
1. 
PROTOCOL SUMMARY 
Confidential 
PRODUCT NAME/NUMBER: TLC599 (Lipid-based Dexamethasone Sodium Phosphate Sustained Release 
Formulation) 
PROTOCOL NUMBER: TLC599A3005 
DEVELOPMENT PHASE: Phase 3 
PROTOCOL T ITLE: A Phase 3, Randomized, Double-blind, Placebo- and Active-controlled Study to 
Evaluate the Efficacy and Safety ofTLC599 in Patients with Osteoarthritis of the Knee 
INDICATION: Osteoarthritis of the knee 
PLANNED STUDY SITES: Approximately 45 to 50 study sites in the United States and Australia 
OBJECTIVES 
Primary Objective: 
• 
To evaluate the efficacy ofa single intra-articular (IA) dose ofTLC599 in patients with osteoarthritis (OA) 
of the knee 
Secondary Objectives: 
• 
To evaluate the efficacy of repeat doses ofTLC599 in patients with OA of the knee 
• 
To evaluate the safety of single and repeat IA doses of TLC599 in patients with OA of the knee 
RATIONALE 
Osteoarthritis is a common degenerative joint disorder of the articular cartilage associated with hypertrophic 
bone changes. Treatment for OA primarily involves a non-pharmacological combination of exercise and lifestyle 
modification, pharmacological treatment, supplementation with glucosamine or chondroitin sulphate, and 
surgical joint replacement. Among pharmacological treatments, corticosteroids have both anti-inflammatory and 
anti-angiogenic properties, and they are routinely given via inject IA injection for the treatment of chronic knee 
joint diseases to relieve pain, reduce inflammation, and improve mobility. 
IA corticosteroid injection is a commonly used treatment with an excellent safety profile. A limitation of IA 
injection with corticosteroids is the modest duration of treatment effect, which often lasts for only 2 to 4 weeks. 
Repeat injections are possible in the same joint, but there are limited data on the safety and duration of the 
effectiveness of this procedure. Thus, there is a pressing need for a more sustained duration of an IA 
corticosteroid injection. 
Taiwan Liposome Company (TLC) is developing TLC599, a sustained release liposomal formulation of 
dexamethasone sodium phosphate (DSP) for the treatment of OA. DSP, an injectable form of dexamethasone, is 
formulated with lipid excipients to allow a sustained release of DSP lo maintain therapeutic concentrations of 
dexamelhasone in the joint space for an extended period of time. The formulation of TLC599 is specifically 
designed to provide both immediate-release DSP and long-acting Iiposomal form of DSP, providing both 
short-term and sustained pain and symptom relief for up to 6 months in patients with knee OA pain. To date, 
TLC has completed 2 studies to evaluate the safety and efficacy of a single-dose IA injection of TLC599 in 
patients with knee OA. Based on data from both trials, TLC599 with 12 mg DSP demonstrated a rapid onset of 
OA pain and symptom relief, with sustained therapeutic benefit up to 6 months with a single IA injection. 
METHODOLOGY 
Study Design: 
• 
This is a Phase 3 randomized, double-blind, placebo- and active comparator-controlled pivotal study . 
• 
Efficacy and safety of 2 doses ofTLC599 will be evaluated in comparison with Placebo and DSP through 
Week 52. 
• 
Approximately 500 adult patients with moderate to severe pain due to OA of the knee will be randomized 
in a 2: I: I ratio to receive TLC599 12 mg (Group A), DSP 4 mg (Group B), or Placebo (normal saline) 
(Group C) via IA injection into the designated index knee at Baseline (Injection I). 
• 
At Week 24, patients will receive blinded Injection 2 per their randomly assigned dosing regimen (Group 
A, B, or C) via IA injection into the index knee. Patients who received TLC599 12 mg (Group A) or DSP 
(Group B) for Injection I will receive blinded TLC599 I 2 mg for Injection 2 and those who received Placebo 
for Injection I (Group C) will receive Placebo for Injection 2. 
Final Version 5.0, 09-Mar-2022 
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Taiwan Liposome Company, Ltd. 
TLC599A3005 
Confidential 
• 
All patients will be fo llowed for a total of 52 weeks, regardless of whether or not they receive Injection 2. 
Patients who do not receive Injection 2 at the Week 24 Visit will be encouraged to continue in the study 
through the entire 52 weeks of follow-up. 
• 
The study design and visit schedule are illustrated in the fo llowing figure: 
Group 
Blinded Injection 1 
Blinded Injection 2 
j TLC599 
i TLC599 
l DSP 
i TLC599 
! 
: 
! 
i Placebo 
: 
! Placebo 
: 
I 
111 I 
I 
I 
I 
I 
I 
I 
W20 
W2~W28 
W32 
W36 
W40 
W44 
W48 
W52 
111 
I 
BLTW4 
' 
I 
I 
I 
SCR 
WS 
W12 
Wl6 
Wl/2 
W25/26 
Abbreviations: BL = Baseline (Day I); DSP = dexamethasone sodium phosphate; Rand = Randomization; 
SCR = Screening; W = Week. 
Study Procedures: 
• 
Patients will be screened for eligibility at Visit I (Screening); procedures will include, but is not limited to, 
medical history and concomitant medication review, knee pain assessments, knee rad iographs, physical 
examination, and clinical laboratory assessments. Initial eligibility for pain in each knee will be assessed 
using a patient-reported numeric rating scale (NRS) (rating of average pai n over the previous 24 hours). 
• 
Patients will be trained on the use of diaries, accurate pain reporting, and appropriate expectations for a 
clinical trial. 
• 
During the screening period, patients will complete daily diaries including assessments of pain in each knee 
by NRS as well as rescue medication use. Every evening, patients must score their average pain in each knee 
by NRS over the previous 24 hours. The diary must be completed for at least 5 of the last 7 days of the 
screening period before returning to the study site for Visit 2 (Baseline/Day I). 
• 
At Visit 2 (Baseline/Day I), after baseline assessments, eligibility will be confirmed and the index knee will 
be determined, and eligible patients will be randomized in a 2: I: I ratio lo receive TLC599 12 mg (Group A), 
DSP 4 mg (Group B), or Placebo (Group C) via IA injection into the index knee (Injection I). 
• 
Patients will return to the study site at Week 1, Week 2. Week 4, and every 4 weeks through Week 24 to 
complete efficacy and safety assessments as applicable. 
• 
At Week 24, patients (see Criteria for Injection 2 [Week 24)) will receive blinded Injection 2 via IA injection 
into the index knee according to their randomly assigned dosing regimen: TLC599 12 mg (Groups A and 
B) or Placebo (Group C). 
• 
Patients will continue to return to the study site every 4 weeks through Week 52 to complete efficacy and 
safety assessments as applicable. 
• 
Patients who receive Injection 2 al Week 24 will also return to the study site at I week (Week 25) and 
2 weeks (Week 26) after Injection 2. 
• 
Patients who do not receive Injection 2 will continue to be followed through Week 52. Patients who do not 
complete the study through Week 52 will complete early termination procedures. 
VISIT STRUCTURE: There will be up to 19 study visits, including Screening (Visit I), Baseline 
(Day I/Visit 2), Week I (Visit 3), Week 2 (Visit 4), and 6 visits occwTing every 4 weeks from Week 4 (Visit 5) 
through Week 24 (Visit 10), Week 25 (Visit 11), Week 26 (V isit 12), and every 4 weeks from Week 28 (Visit 
13) through Week 52 (Visit 19). Week 25 (Visit 11) and Week 26 (Visit 12) will only be required for patients 
who receive Injection 2 at Week 24 (Visit I 0). 
ST UDY DURATION: Duration of patient participation will be up to 56 weeks, including a Screening period 
of up to 4 weeks before randomization, Injection I Period of24 weeks and Injection 2 Period of28 weeks. 
Final Version 5.0, 09-Mar-2022 
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Taiwan Liposome Company, Ltd. 
TLC599A3005 
STUDY POPULATION 
Confidential 
This study wi ll randomize approximately 500 patients, according to the followi ng inclusion and exclusion 
criteria: 
Inclusion Criteria: 
1. 
Male or female ~40 years of age, inclusive. 
2 . 
Body mass index :s40 kg/m2• 
3. 
Has symptoms associated with OA oflhe index knee for al least 6 months before Screening. 
4. 
Documented diagnosis ofOA in the index knee based on American College of Rheumatology Criteria for 
Classirication of Idiopathic OA of the knee (clin ical and radiological including standing rixed-flexion 
posterior-anterior X-ray oflhe knee). 
5. 
OA with Kellgren-Lawrence Grade 2 to 3 severity in the index knee based on the grade per X-ray assessed 
by a central radiologist reader at Screening. 
6. 
Initial patient-reported pain with NRS score ~4 (on a 0-10 scale) in at least I knee (index knee) al Screening 
(rating of average pain over the previous 24 hours). 
7. 
Patient-reported pain with average daily NRS score of 5.0 lo 9.0 (inclusive) in the index knee, AND with 
non-index knee pain score of :s4.0. based on diaries completed daily for at least 5 of the last 7 days of the 
screening period before randomization. 
8. 
Patient-reported WOMAC Pain sub-scale (hereafler referred to as WOMAC Pain) score~6 (combined score 
on a 0-20 scale) in the index knee before dosing at Baseline. 
9. 
a. 
IF FEMALE, must meet all of the following: 
• 
Not breast feeding; 
• 
Not planning to become pregnant during the study; 
• 
If of childbearing potential (defined as non-post-hysterectomy or non-post-menopausal ramenorrheic 
for at least 2 years]), must have a negative pregnancy test result (human chorionic gonadotropin, beta 
subunit [P-hCG]) at Screening and Baseline, a nd must commit to the use of an acceptable and effective 
form of birth control for the duration of the study and until at least 6 months after the last dose of study 
drug. 
b. IF MALE. must be surgically sterile (biologically or surgically) or commit to the use o f a reliable 
method of birth control (must agree to use double-barrier contraception in the event of sexual activi ty), 
or be practicing abstinence for the duration of the study and until at least 6 months aflcr the last dose of 
study drug. 
I 0. Is able to read, understand. and sign the informed consent form (ICF), communicate with the investigator, 
and understand and comply with protocol requirements. 
Exclusion Criteria: 
I. 
Use of any of the following medications within the specified period: 
a. 
IA corticosteroid in any joint within 3 months before Screeni ng, or triamcinolone acetate 
extended-release injectable suspension (Zilretta®) within 6 months before Screening 
b. 
IA hyaluronic acid in any knee joint within 6 months before Screening 
c. 
Systemic corticosteroids within 4 months before Screening or chronic use within I year before 
Screening 
d. 
NSAIDs (except topical use on regions other than the index knee) within 14 days before the Baseline 
visit 
c. 
Platelet-rich plasma or other prolotherapy within 6 months before Screening 
f. 
Chronic opioid use (use exceeding 4 days per week) within the last 30 days before Screening. 
g. 
Any chemotherapeutic or systemic immunosuppressant agents for inflammatory diseases within 
6 months before Screening 
h. 
Anti-coagulants, including warfarin. heparin, low molecular weight heparin. or dabigatran within 
I week of Screening and the Baseline visit. Low-dose acetylsalicylic acid or other anti-platelet 
medications are allowed 
1. 
Live atten uated vaccine within 3 months before Screening 
j . 
Any investigational therapy within 4 weeks or within 5 half-lives before Screening, whichever is longer 
2. 
Patient who is not ambulatory. 
3. 
Any surgery or arthroscopy in the index knee within 12 months before Screening. 
Final Version 5.0, 09-Mar-2022 
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Taiwan Liposome Company, Ltd. 
TLC599A3005 
Confidential 
4. 
Unstable index knee joint as determined by the investigator based on physical examination (with or without 
buckling or giving way) because of an acute injury (de fined as injury within 6 months of Screening, 
e.g., anterior cruciate ligament injury or tear). 
5. 
History of infective arthritis in the index knee. 
6. 
Suspected/concurrent infection in either knee at Screening or Baseline before study drug administration. 
7. 
Any skin lesion/breakdown at the anticipated injection site or any condition that impairs penetration of the 
index knee joint space. 
8. 
Documented gout attack in index knee within 6 months before Screening or presence of tophus in index 
knee. 
9. 
Patient with any amputation in any lower limb. 
10. Documented history and confirmed autoimmune disease including but not limited to, reactive a11hritis, 
systemic lupus erythematosus, Sjogren' s syndrome, systemic sclerosis, inflanunatory myositis, mixed 
connective tissue disease, palindromic rheumatism, reactive arthritis, rheumatoid arthritis, psoriatic arthritis, 
ankylosing spondy litis, Behcet' s disease, arthritis associated with inflammatory bowel disease, sarcoidosis, 
vasculitis, cryoglobulinemia, or amyloidosis. 
I I. Any condition that could possibly confoLmd the patient's assessment of index knee pain per the 
investigator' s judgment (i.e., ipsilateral hip OA, radicular low back pain, and hip pain referred to the index 
knee). 
12. Substance abuse disorder, or positive urine drug test for illegal drug substances or non-prescribed controlled 
substances including amphetamines, barbiturates, benzodiazepines, cocaine, opiates, phencyclidine, and 
tetrahydrocannabinol; or positive alcohol breath test. 
13. History of primary or secondary adrenal insufficiency. 
16. History of bleeding disorders. 
17. History of acquired or congenital immunodeficiency diseases, or pos1t1ve test results for human 
immunodeficiency virus (HI V), hepatitis B virus (HBV), or hepatitis C virus (I-ICY) current infection al 
Screening. 
18. Any active in fection requiring treatment with antibiotics. 
19. History of treated malignancy which is disease free for ::;5 years before Screening, except basal cell 
carcinoma of skin or carcinoma in situ of the uterine cervix. 
20. Stroke or myocardial infarction within 12 months before Screening. 
2 1. Uncontrolled and unstable concurrent med ical or psychiatric illness, including but not limited to, poorly 
controlled diabetes, poorly controlled hypertension, dementia, schizophrenia, or bipolar disorder that will 
jeopardize the safety of the patient, interfere with the objectives of the protocol, or affect the patient 
compliance with study requirements, as determined by the investigator. 
22. Abnormalities of the following laboratory parameters at Screening: 
a. 
HbA le >9.0% 
b. 
platelet count <80,000/µL 
c. 
hemoglobin <8.0 g/dL 
d. 
total white blood cell count <4000/µ L 
e. 
serum bilirubin/alanine aminotransferase/ aspartate aminotransferase >2 times upper limit of nom1al 
(ULN) for the laboratory reference ranges 
f. 
serum creatinine level > l .5X ULN 
g. 
prothrombin time/International Normalized Ratio > ULN for the laboratory reference range 
23. Known allergy or hypersensitivity to the study drugs or their components. 
24. ls an immediate family member (spouse, parent, child, or sibling; biological or legally adopted) of personnel 
directly affi liated with the study at the clinical study site. 
25. Employed by sponsor (i.e., is an employee, temporary contract worker, or designee responsible for the 
conduct of the study). 
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Taiwan Liposome Company, Ltd. 
TLC599A3005 
Criteria for Injection 2 (Week 24}: 
Confidential 
Patients will not continue with Injection 2 if any of the following criteria are met: 
2. 
Occurrence of adrenal insufficiency through Week 24. 
3. 
If female and of childbearing potential, have a positive urine pregnancy test result at Week 24. 
4. 
Positive urine drug or alcohol test result at Week 24. (Drug use allowed with prescription.) 
STUDY DRUGS 
Study drug will be administered in a bli nded manner via IA injection into the index knee. 
• 
Study Drug (TLC599): 
• 
Dexamethasone sodium phosphate (DSP) 12 mg with I 00 mM phospholipid (PL) (I mL) 
• 
Reference Drug (DSP): 
• 
DSP 4 mg ( I mL) 
• 
Placebo: 
• 
Normal saline ( I mL) 
Patients will be randomly assigned lo one of the following treatment groups in a 2: I: I ratio. 
Group 
Injection 1 (Day I) 
Injection 2 (Week 24) 
A 
TLC599 
TLC599 
B 
DSP 
TLC599 
c 
Placebo 
Placebo 
Rescue Medication: 
• 
Total acetaminophen use up to 3 g/day (not allowed within 24 hours before study visits) 
Final Version 5.0, 09-Mar-2022 
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Taiwan Liposome Company, Ltd. 
TLC599A3005 
ASSESSMENTS 
Efficacy Assessments: 
Confidential 
• 
Western Ontario & McMaster Universities Osteoarthritis Index (WOMAC, Version 3. 1) 
o 
WOMAC comprises 24 questions, each on a 0-4 Likert scale (total score on a 0-96 scale) with 
assessment based on the previous 24 hours 
o 
Sub-scale scores of Pain (5 items, total sub-scale score on a 0-20 scale), Stiffness (2 items, total 
sub-scale score on a 0-8 scale), and Physical Function ( 17 items, total sub-scale score on a 0-68 scale) 
arc added together to determine the WOMAC Composite score 
o 
Composite and sub-scale scores of WOMAC will be normalized to a scale of 0-4 for analysis. 
• 
Patient Global Impression of Change (PGIC) 
• 
o 
PGIC is a single-item question that measures change in patients' overall improvement rated on a 
7-point scale including "very much improved," "much improved," "minimally improved," "no 
change," "minimally worse," "much worse," or "very much worse" 
• 
Numeric rating scale (NRS) for average pain, as recorded on a daily patient diary 
o 
0-1 0 scale, with 0 representing "no pain" and I 0 as "the worst possible pain" 
o 
Every evening patients will assess their average pain intensity for the previous 24 hours 
• 
Use of rescue medication for index knee pain: acetaminophen as recorded in a dai ly patient diary 
Safety Assessments: 
-
• 
Patient safely wi ll be evaluated by physical examination, vital signs assessments (heart rate, respiratory rate, 
sitting blood pressure, and temperature). clinical laboratory assessments (hematology, chemistry, 
urinalysis). HbA le, morning serum cortisol. 
12-lead electrocardiogram (ECG). knee 
radiographs, concomitant medications/therapies, adverse events (A Es). and signs and symptoms of adrenal 
insufficiency. 
ENDPOINTS 
The primary efficacy endpoint is: 
I. 
Change from Baseline in WOMAC Pain at Weck 12 (Group A vs. Group C) 
The secondary efficacy endpoints are: 
I. 
Change from Baseline in WOMAC Pain al Week 16 (Group A vs. Group C) 
2. 
Change from Baseline in WOMAC Pain al Week 20 (Group A vs. Group C) 
3. 
Change from Baseline in WOMAC Pain at Week 24 (Group A vs. Group C) 
4. 
Change from Baseline in WOMAC Pai n al Weck 36 (Group A vs. Group C) 
5. 
Change from Baseline in WOMAC Function al Weck 12 (Group A vs. Group C) 
6. 
Patient Global Impression of Change (PGIC) at Week 12 (Group A vs. Group C) 
7. Total rescue acetaminophen consumption through Week 12 (Group A vs. Group C) 
8. 
Durable responder with '.:'.30% decrease in WOMJ\C Pain from Baseline for Weeks 4 through 12 (Group/\ 
vs. Group C) 
9. 
Change from Baseline in WOMAC Function at Week 36 (Group A vs. Group C) 
I 0. PGIC at Week 36 (Group A vs. Group C) 
11. Change from Baseline in WOMAC Pain at Week 12 (Group A vs. Group B) 
12. Change from Baseline in WOMAC Pain at Week 52 (Group A vs. Group C) 
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Taiwan Liposome Company. Ltd. 
TLC599A3005 
STATISTICAL METHODS 
General Statistical Considerations: 
Confidential 
All efficacy and safety data will be listed and descriptively summarized by injection (Injection 1 or Injection 2) 
and treatment group (Group A, B, or C). Continuous variable summaries will include the number of patients, 
mean, standard deviation (SD), first quartile, median, third quartile, minimum, and maximum. Categorical 
variables will include the frequency and percentage of patients in each category. All statistical assessments w ill 
be 2-sided 0.05 sign ificance level. 
Database lock and unblinding will occur after the last patient in the study has completed the study. 
Analysis Populations: 
• 
Safety Population (SAF): The Safety Population includes all patients who receive any dose of study drug; 
the population will be determined for each study period. The SAF population wi ll be the primary 
population for safety evaluation. 
• 
Fu ll Analysis Set (FAS): The FAS includes all randomized patients who receive Injection I. The 
FAS population will be the primary population for efficacy analysis. as well as for descriptive summaries 
other than safety (demographic and baseline. disposition, protocol deviations. medical history, etc.). 
• 
Per Protocol Population (PP): The PP Population includes all patients who receive 2 doses of study drug, 
have primary efficacy evaluation at Weeks 12. 24. and 36. and do not have important protocol deviations 
affecting primary efficacy evaluation. 
• 
Modified Per Protocol (mPP): The mPP Population includes all patients who receive the first dose of 
study drug. have primary efficacy evaluation at Weeks 12 and 24, and do not have important protocol 
deviations affecting primary efficacy evaluation. 
Efficacy Analysis: 
Analysis of Primmy and Key Seconda1y Endpoints: 
Efficacy variables will be descriptively summarized by treatment group and by injection period within each 
group, based on the FAS population. unless otherwise specified. For all the continuous variables. the normalized 
numbers will be used for analysis, where applicable, unless otherwise specified. 
The overall type I en-or rate will be controlled for primary and key secondary endpoints using hierarchical testing 
based on a fixed-sequence procedure. If statistical significance is declared for the primary analysis. formal 
statistical inference wi ll continue at the 0.05 level for the secondary endpoints in the defined sequence until a 
non-significant result is reached. All other P values from key secondary endpoints, after a non-significant P value 
is reached, as well as other additional endpoints. will be considered exploratory. 
An analysis of covariance (AN COVA) model with treatment group as fixed effect and baseline value of the 
endpoint (when applicable) as covariates will be perforrned for the primary and key secondary continuous 
endpoints. 
Sensitivity analyses will be conducted to estimate sensitivity estimators and to assess the robustness of efficacy 
results. 
Additional Endpoints: 
Additional endpoints and subgroup analyses will also be tested at a 2-sided 0.05 significance level. 
The analysis of all continuous and categorical additional endpoints will be performed using an A NCO YA model 
Final Version 5.0, 09-Mar-2022 
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Taiwan Liposome Company, Ltd. 
TLC599A3005 
Safety Analvsis: 
Confidential 
Safety variables include physical examination, vital signs assessments (heart rate, respiratory rate, sitting blood 
pressure, and temperature), clinical laboratory assessments (hematology, chemistry. urinalysis), HbA I c, 
morning serum cortisol, 
12-lead electrocardiogram (ECG). knee radiographs, 
concomitant medications/therapies, AEs, and signs and symptoms of adrenal insufficiency. Medical history and 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), and concomitant 
medication will be coded using the World Health Organization Drug (WHO Drug) Global Dictionary . 
Conti nuous safety data will be summarized by visit and include changes from baseline. Continuous data will 
also be converted to categorical values where possible (i.e., below, within, and above normal ranges) and 
summarized in shi ft from baseline tables. Categorical safety data collected by visit will be summarized showing 
the counts and percentages in each category at each visit, as well as shifts from baseline as appropriate. 
Interim Analysis: 
An interim analysis will not be performed. 
SAMPLE SIZE DETERMINATION 
This is a 3-arm parallel-group randomized controlled study. Approximately 500 patients will be randomized in 
According to these assumptions. 500 patients will be randomly assigned in a 2: I: I ratio to ensure that the study 
is well powered for primary and key secondary endpoints to be tested via the fixed-sequence testing method. 
Final Version 5.0, 09-Mar-2022 
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Taiwan Liposome Company, Ltd. 
TLC599A3005 
1.1. Schedule of Events 
Period 
Visit 
Day (D)/W eek (W) 
Window (days)d 
Informed consent 
Inclusion/ 
exclusion criteria 
Demographics and medical 
history 
Vital signs• 
Height and weight 
Physical examination 
Knee radiographr 
12-lead ECGg 
Clinical chemistry/ hematology 
and HbA I c (fasted state) 
Coagulation Panel 
Serology (HlV/1-IBV/HCY) 
Urinalysis 
Pregnancy testi 
Drug screen and alcohol breath 
tests (onsite) 
Morning serum cortisolk 
-
Trainingm 
Daily knee pain diary (NRS)" 
WOMAC 
PGIC 
Randomization 
Synovial fluid aspiration/ Study 
drug administration 
Rescue medicationP 
Concomitant medications 
Adverse events 
Final Version 5.0, 09-Mar-2022 
scR• 
2/ 
I 
BL 
NIA 
Dl 
$ -28 
N/A 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Xh 
x· 
xh 
Xh 
x 
x 
x 
x 
x 
x 
x 
x I x 
I x 
x 
x 
Confidential 
Injection I Period 
JO I 
3 
4 
5 
6 
7 
8 
9 
BL 
11 
12 
Wl 
W2 
W4 
W8 
Wt 2 
'vV16 
W20 
w24• 
W25' 
W26' 
±3 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
±3 
±3 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 2 
x 
x 
x 
x 
x 
x 
x 
x 
I 
I 
I 
I 
I x I 
I 
I x I 
I 
~ Record throughout the study 
I x I x I x I x I x I x I x I x I x I x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
xo 
~ Review throughout the study 
~ Record throughout the study 
~ Record throughout the study 
Injection 2 Period 
19 
l3 
14 
15 
16 
17 
18 
EOS/ 
ET 
W28 
W32 
W36 
W40 
W44 
W48 
W52 
±7 
±7 
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7 
7 
7 
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Abbreviations: 
BL = Baseline; D =Day: ECG= electrocardiogram; EOS =End of Study Visit; ET= Early Termination Visit; 
HbAlc = hemoglobin A le; HBY = hepatitis B virus; I-ICY= hepatitis C virus; Hl Y =human immunodeficiency virus; 
·· 
NRS = numeric rating scale: PGIC =Patient Global Impression of Change; W =Week; WOMAC= Western Ontario & McMaster Universities Osteoarthritis Index. 
a 
Screening procedures may occur at any time during the Screening period unless otherwise specified. Patients who fail screening because of a mild infectious illness present 
at the Baseline or Screening, may be rescreened after the infection has resolved with approval of the medical monitor. Documented diagnosis ofOA in the index knee can 
be completed as part of study screening. 
b 
Patients who cannot attend the Week 24 visit within the visit window because of restrictions resulting from COYID-19, will be encouraged to return to the site before 
Week 28 to complete the Week 24 visit assessments, if feasible. However, Injection 2 may only be administered within the allowed visit window. 
c 
These procedures and visits (Week 25 and Week 26) are only required for patients who receive Injection 2 and will take place at 1 and 2 weeks after Injection 2, 
respectively. 
d 
Visit 3 (Week I) to Visit 19 (Week 52) should occur at the specified time point relative to Visit 2 (Day I/Baseline), except Visit 11(Week25) and Visit 12 (Weck 26). 
e 
Heart rate, respiratory rate, sitting blood pressure, and temperature will be measured after the patient has been in a sitting position for 5 minutes. 
f 
A posterior-anterior X-ray radiograph will be performed for both knees in standing fixed-flexion (approximately 20 degrees), as applicable. For the Week 24 and Week 52 
visits, the posterior-anterior X-ray radiograph may be performed within 14 days before the visit. 
g 
The 12-lead ECG will be performed after the patient has been supine for at least 5 minutes. 
h 
If the patient is potentially eligible based on currently available data except laboratory abnormalities, the assessments may be repeated once only to reassess eligibility. 
Only glucose (fasted state) will be tested in the Visit 2 (Baseline) visit before 9 AM and before study drug administration (Injection I). 
Pregnancy tests perfonned only for women of childbearing potential. Serum pregnancy tests will be performed at Screening; urine pregnancy tests will be perfonned before 
dosing at Visit 2 (Baseline/Day I) and Visit I 0 (Week 24, only required for patients receiving Injection 2); and performed at EOS (Week 52) or ET. 
k 
Serum samples for measurement of cortisol should be collected before 9 AM (and before study drug administration for !Jtjection 1 and lnjection 2 at Visit 2 [Day I] and 
Visit I Q_[Week 24 l, respectively). A ~erum cortisol_yalue <l_µg/dL ~Screening cannot be retested. 
m 
Training and assessment of knowledge on pain ratings, allowable rescue medication, and entering data into the diary will be conducted at Screening, Baseline, Week 12, 
Week 24, and Week 36; and as needed throughout the study. 
n 
A diary will be used daily to collect responses from patients on index knee pain over the previous 24 hours. Training regarding entering data into the diary will be given. 
Patients will first be asked to score their average pain in each knee by NRS over the previous 24 hours at the initial Screening visit. After the first Screening visit (Visit I), 
the diary must be completed for each knee in the evening daily for at least 5 of the last 7 days of the screening period before returning to the study site for Visit 2 
(Day I/Baseline). After randomization, the patient will record their response on index knee pain in the diary every evening throughout the study until the last day prior to the 
EOS/ET visit. Sites should monitor patient compliance of diary entries regularly throughout the 52 weeks. If a patient is not compliant, the site should contact the patient as 
soon as non-compliance is observed. 
o 
Procedures for those receiving Injection 2. The patient should be checked for the criteria listed in Section 6.6.3 before study drug administration. 
p 
Initial rescue medication bottle will be dispensed at Screening and as needed. Between Screening and EOS/ET, patients will record the previous 24-hour use of 
acetaminophen rescue medication daily into the diary. Rescue medication will be reviewed at every study visit. 
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2. TABLE OF CONTENTS 
Confidential 
I. 
PROTOCOL SUMMARY ....................................................................................................... 3 
1.1. Schedule of Events ....................................................................................................... 11 
2. 
TABLE OF CONTENTS ...................................................................................................... 13 
2. 1. 
List of In-text Figures ................................................................................................... 17 
AMENDMENT 04 - SUMMARY OF CHANGES AND RATIONALE ................................... 18 
3. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................... 29 
4. 
INTRODUCTION ................................................................................................................. 31 
4.1. Background and Rationale ........................................................................................... 3 1 
4.2. Clinical Experience ...................................................................................................... 31 
4.3. Non-clinical Experience ............................................................................................... 32 
4.4. Summary of Potential Risks and Benefits .................................................................... 33 
5. 
OBJECTIVES ........................................................................................................................ 34 
5.1. 
Pri1nary Objective ......................................................................................................... 34 
5.2. Secondary Objectives ................................................................................................... 34 
6. 
STUDY DESIGN .................................................................................................................. 35 
6.1 . Overall Study Design and Plan .................................................................................... 35 
6.2. Rationale and Discussion of Study Design .................................................................. 36 
6.3. Selection of Doses in the Study .................................................................................... 36 
6.4. Study Sites .................................................................................................................... 37 
6.5. Study Completion Definition ....................................................................................... 37 
6.6. Study Population .......................................................................................................... 37 
6.6. 1. Inclusion Criteria .............................................................................................. 37 
6.6.2. Exclusion Criteria ............................................................................................. 38 
6.6.3. Criteria for Injection 2 (Week 24) .................................................................... 40 
6.7. Patient Withdrawal from the Study .............................................................................. 40 
6.8. Patient Replacement Criteria ........................................................................................ 41 
7. 
TREATMENTS ..................................................................................................................... 42 
7. 1. 
Identification of Study Drugs ....................................................................................... 42 
7.2. Treatment Administration ............................................................................................ 42 
7.3. Selection of Timing of Dose for Each Patient .............................................................. 43 
7.4. Dose Adjustment Criteria ............................................................................................. 43 
7.5. Treatment Compliance ................................................................................................. 43 
7.6. Method of Assigning Patients to Treatment Groups .................................................... 43 
7.7. Blinding and Unblinding Treatment Assignment ........................................................ 43 
7.8. Rescue Medication ....................................................................................................... 44 
7.9. Concomitant Medications ............................................................................................. 44 
7. 10. Prohibited Therapies ..................................................................................................... 44 
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7.11. Dispensing and Storage ................................................................................................ 45 
7.12. Drug Accountability ..................................................................................................... 45 
8. 
STUDY PROCEDURES AND ASSESSMENTS ................................................................. 46 
8. 1. Study Visits .................................................................................................................. 46 
8.1.1. Phone Visits ...................................................................................................... 46 
8.2. Study Duration ............................................................................................................. 47 
8.3. Study Periods and Visits ............................................................................................... 47 
8.3.1. Screening (Visit I) ............................................................................................ 47 
8.3.2. Visit 2 (Baseline, Day I, and Injection I) ........................................................ 48 
8.3.3. Follow-up Assessments .................................................................................... 49 
8.3.3.1. 
Visit 3 (Week I) and Visit 4 (Week 2) .................................................. 49 
8.3.3.2. 
Visits 5 Through 9 (Every 4 Weeks from Week 4 Through Week 20).49 
8.3.3.3. 
Visit I 0 (Week 24 and Injection 2) ....................................................... 50 
8.3.3.4. 
Visits 11 and 12 (Weeks 25 and 26)- Injection 2 Follow-up 
Assess1nents ........................................................................................... 5 I 
8.3.3.5. 
Visits 13 Through 18 (Every 4 Weeks from Week 28 Through 
Week 48) ............................................................................................... 51 
8.3.4. End of Study (Week 52) or Early Termination Visit ....................................... 52 
8.4. Assessments .................................................................................................................. 53 
8.4.1. Efficacy ............................................................................................................ 53 
8.4.1.1. 
Western Ontario & McMaster Universities Osteoarthritis Index (V3. I) 
53 
8.4.1.2. 
Patient Global Impression of Change .................................................... 53 
8.4.1.4. 
Numeric Rating Scale ............................................................................ 54 
8.4.1.5. 
Rescue Medication Use ......................................................................... 54 
8.4.2. Safety ................................................................................................................ 54 
8.4.2.1. 
Clinical Laboratory Safety Assessments ............................................... 54 
8.4.2.2. 
Clinical Examinations ........................................................................... 56 
9. 
ADVERSE EVENTS ............................................................................................................. 57 
9.1. Definitions .................................................................................................................... 57 
9.1.1. Adverse Events ................................................................................................. 57 
9.1.2. Serious Adverse Events .................................................................................... 57 
9.1.3. Treatment-emergent Adverse Events ............................................................... 57 
9.2. Event Assessment and Follow-up of Adverse Events .................................................. 58 
9.2.1. Collection ......................................................................................................... 58 
9.2.2. Evaluation ......................................................................................................... 58 
9.2.2.1. 
Severity of Adverse Events ................................................................... 58 
9.2.2.2. 
Seriousness ............................................................................................ 58 
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9.2.2.3. 
Action(s) Taken ..................................................................................... 59 
9.2.2.4. 
Outcome at the Time of Last Observation ............................................ 59 
9.2.2.5. 
Adverse Event Relationship to Study Drug .......................................... 59 
9.2.3. Documentation ................................................................................................. 60 
9.2.4. Treatment of Adverse Events ........................................................................... 60 
9.2.5. Reporting .......................................................................................................... 61 
9.2.5.1. 
Serious Adverse Events ......................................................................... 61 
9.3. Special Considerations ................................................................................................. 62 
9.3. l. Adverse Events of Special Interest.. ................................................................. 62 
9.3. 1. 1. 
Potential for Adrenal Suppression ......................................................... 62 
9.3.2. Pregnancy ......................................................................................................... 63 
I 0. DATA SAFETY MONITORING BOARD .......................................................................... 64 
11. ST A TISTICS ......................................................................................................................... 65 
11 .1. Study Endpoints ........................................................................................................... 65 
11.1 .1. Efficacy Endpoints ........................................................................................... 65 
11.1.1.1. Primary Efficacy Endpoint.. .................................................................. 65 
11.1.1.2. Secondary Efficacy Endpoints .............................................................. 65 
11.1.2. Additional Endpoints ........................................................................................ 66 
11.1.3. Safety and Tolerability Endpoints .................................................................... 67 
11.2. Analysis Populations .................................................................................................... 67 
I 1.3. Statistical Analyses ....................................................................................................... 68 
11.3 .1. Study Patients and Demographics .................................................................... 68 
11.3. I. I. Disposition and Withdrawals ................................................................ 68 
11.3 .1.2. Protocol Deviations ............................................................................... 69 
11.3.1.3. Demographics and Other Baseline Characteristics ............................... 69 
11.3.2. Exposure and Compliance ................................................................................ 69 
l l .3.3. Efficacy Analysis ............................................................................................. 69 
l 1.3 .3 .1. Primary Analysis ................................................................................... 69 
11.3.3.2. Secondary Analyses .............................................................................. 71 
l 1.3 .3 .3. Exploratory Analyses ............................................................................ 71 
11.3.4. Safety and Tolerability Analyses ..................................................................... 72 
11.3.4.1. Adverse Events ...................................................................................... 72 
11.3.4.2. Clinical Laboratory Evaluations ............................................................ 72 
11.3.4.3. Vital Signs ............................................................................................. 73 
11.3.4.4. Twelve-lead Electrocardiograms ........................................................... 73 
l l.3.4.5. Physical Examination Findings ............................................................. 73 
11.3 .4.6. Knee Radiographs ................................................................................. 73 
11.3.4.7. Concomitant Medications ...................................................................... 73 
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11 .3.5. Interim Analysis ............................................................................................... 73 
11.4. Sample Size Determination .......................................................................................... 73 
12. STUDY CONDUCT .............................................................................................................. 75 
12.1. Sponsor and Investigator Responsibilities ................................................................... 75 
12.1 .1. Sponsor Responsibilities .................................................................................. 75 
12.1.2. Investigator Responsibilities ............................................................................ 75 
12.1.3. Confidentiality and Privacy .............................................................................. 75 
12.2. Site Initiation ................................................................................................................ 76 
12.3. Screen Failures ............................................................................................................. 76 
12.4. Study Documents ......................................................................................................... 77 
12.4.1. Informed Consent ............................................................................................. 77 
12.4.2. Case Report Forms ........................................................................................... 77 
12.4.3. Source Docurnents ............................................................................................ 77 
12.5. Data Quality Control .................................................................................................... 78 
12.5. I. Monitoring Procedures ..................................................................................... 78 
12.5 .2. Data Managernent. ............................................................................................ 78 
12.5.3.Quality Assurance/Audit .................................................................................. 79 
12.6. Study Termination ........................................................................................................ 79 
12.6.1. Premature Study Termination .......................................................................... 79 
12.7. Study Site Closure ........................................................................................................ 80 
12. 7. I . Record Retention .............................................................................................. 80 
12.8. Changes to the Protocol.. .............................................................................................. 80 
12.9. Use of Information and Publication ............................................................................. 80 
13. FINAL CLINICAL STUDY REPORT ................................................................................. 82 
14. ETHICAL AND LEGAL CONSIDERATIONS ................................................................... 83 
14.1. Declaration of Helsinki and Good Clinical Practice .................................................... 83 
14.2. Patient Information and Informed Consent and/or Assent.. ......................................... 83 
14.3. Approval by Institutional Review Board and Independent Ethics Committee ............ 83 
14.4. Finance and Insurance .................................................................................................. 83 
15. REFERENCES ...................................................................................................................... 84 
16. ATTACHMENTS .................................................................................................................. 85 
16.1. lnyestigator"s Agreement ............................................................................................. 85 
APPENDICES .............................................................................................................................. 87 
A. 
American College of Rheumatology Classification Criteria for Osteoarthritis of the 
Knee .............................................................................................................................. 88 
B. 
Kellgren and Lawrence System for Classification of Osteoarthritis of the Knee ........ 89 
C. 
WOMAC Osteoarthritis Index Version V3. l ............................................................... 90 
D. 
Patient Global Impression of Change (PGIC) Assessment .......................................... 96 
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2.1. List ofln-text Figures 
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Figure I: 
Study Design ..................................................................................................... 36 
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AMENDMENT 04 - SUMMARY OF CHANGES AND RATIONALE 
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SUMMARY OF AMENDED SECTIONS 
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Section 
11.2 Analysis Populations 
11 .3.1.2. Protocol Deviations 
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Protocol Amendment 3 (v4) 
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I Protocol Amendment 4 (vS) 
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AMENDED PROTOCOL 
Confidential 
The following are the amended protocol and appendices, including all revisions specified above. 
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3. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ABBREVIATION 
EXPLANATION 
ACR 
American College of Rheumatology 
I 
ADL 
Activities of Daily Living 
AE 
adverse event 
AEAI 
AE which is a potential symptom or sign of adrenal insufficiency 
AESI 
AE of special interest 
ANCOVA 
analysis of covariance 
AUC 
area under the time-concentration curve 
~-hCG 
human chorionic gonadotropin, beta subunit 
BOCF 
base! ine-observation-carried-forward 
CFR 
Code of Federal Regulations 
CIA 
collagen-induced arthritis 
CRA 
clinical research associate 
CSR 
clinical study report 
DSP 
dexamethasone sodium phosphate 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOS 
End of Study 
ET 
Early Termination 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HbAlc 
hemoglobin A I c 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
IA 
intra-articular 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
independent ethics committee 
IND 
investigational new drug 
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ABBREVIATION 
EXPLANATION 
IRB 
institutional review board 
JWRS 
interactive web response system 
JSN 
Joint space narrowing 
LOCF 
last-observation-carried-forward 
MAR 
missing at random 
MCMC 
Monte Carlo Markov Chain 
MedDRA 
Medical Dictionary for Regulatory Activities 
MNAR 
missing not at random 
mPP 
Modified Per Protocol 
NSAID 
Non-steroidal anti-inflammatory drug 
NRS 
numeric rating scale 
OA 
osteoarthritis 
PGIC 
Patient Global Impression of Change 
PL 
phospholipid 
pp 
Per Protocol 
PT 
preferred term 
QOL 
Quality of life 
QTc 
QT interval corrected for heart rate 
RBC 
red blood cell count 
SAE 
serious adverse event 
SAF 
Safety population 
SAP 
statistical analysis plan 
SD 
standard deviation 
soc 
system organ class 
TEAE 
treatment-emergent adverse event 
TLC 
Taiwan Liposome Company, Ltd. 
ULN 
upper limit of normal 
us 
United States 
I 
WOMAC 
Western Ontario & McMaster Universities Osteoarthritis Index 
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4. 
INTRODUCTION 
4.1. Background and Rationale 
Confidential 
Osteoarthritis (OA) is a common degenerative joint disorder of the articular cartilage associated 
with hypertrophic bone changes. Treatment for OA primarily involves a non-pharmacological 
combination of exercise and lifestyle modification, pharmacological treatment, supplementation 
with glucosamine or chondroitin sulphate, and surgical joint replacement. Among pharmacological 
treatments, corticosteroids have both anti-inflammatory and anti-angiogenic properties, and they 
are routinely given via inject intra-ait icular (IA) injection for the treatment of chronic knee joint 
diseases to relieve pain, reduce inflammation, and improve mobility. There are several Food and 
Drug Administration (FDA)-approved corticosteroids for IA use, including dexamethasone, 
methylprednisolone, betamethasone, and triamcinolone. However, when effective, the mean 
duration of benefit may be relatively short, often lasting for only 2 to 4 weeks. 1 Furthermore, 
repeated injections of corticosteroids may increase the risk of local and systemic side effects, 
including pericapsular calcification, tendon rupture, skin atrophy/depigmentation, steroid 
arthropathy, joint infection, facial flushing, hypersensitivity, and hyperglycemia. Common 
practice is to use IA corticosteroids no more than once every 3 months. 
Dexamethasone is a highly potent glucocorticoid whose action is mediated by the binding of the 
corticosteroid molecule to receptors located within sensitive cells. The physiological function of 
glucocorticoid is complex and may include a number of mechanisms such as modification of 
movement and function of leukocytes, reduction of vascular permeability, and reduced 
prostaglandin synthesis.2 TLC599 is a drug product designed to improve the stability of 
dexamethasone sodium phosphate (DSP) through formulation with the BioSeizer platform 
technology. DSP is the pro-drug of dexamethasone and has been approved for indications of 
endocrine disorders, rheumatic diseases, and dermatologic, allergic, or ophthalmic diseases 
through intravenous or intramuscular administration route. Also, DSP is used to treat the synovitis 
of osteoa1thritis, rheumatoid arthritis or gouty arthritis through lA or soft tissue administration 
route and keloid, localized inflammation of lichen planus, psoriatic plaques, granuloma annulare 
or discoid lupus erythematosus may be treated through intralesional administration route. 
BioSeizer is a proprietary, lipid-based drug delivery system developed by Taiwan Liposome 
Company (TLC), which can entrap both small molecules and large molecules and then slowly 
release these therapeutic agents. The release profile of compounds or proteins can be adjusted by 
modulating the concentration of phospholipids (PLs). By prolonging the local residence time of 
therapeutic agents, TLC599 in turn reduces treatment frequency and risk to maximize the clinical 
benefit. Therefore, TLC599 provides an ideal, safe, and long-acting DSP delivery for the treatment 
inOA. 
4.2. Clinical Experience 
Two clinical studies for treating knee osteoarthritis with TLC599 via IA route at different dose 
levels (Study TLC599A 1001 in Taiwan and Study TLCA599A2003 in Taiwan/Australia) were 
completed. TLC599A IOOI was completed and TLCA599A2003 was completed, and the clinical 
study report was prepared for submission. Another pharmacokinetic study of TLC599 
(TLC599A2004) filed under the US Investigational New Drug (IND) is currently in the patient 
recruitment phase. 
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Study TLC599A I 00 I (Clinicaltrials.gov No: NCT02803307) was the first study to administer 
TLC599 by IA injection in patients with OA of the knee and there were no significant safety signals 
detected. It was a randomized, open-label study to evaluate the preliminary efficacy and safety of 
TLC599 dose levels of 6 mg and 12 mg DSP, with 20 patients per dose group. 
TLC599A2003 (ClinicalTrials.gov Identifier: NCT03005873) was a randomized Phase 2a study 
with single IA injection of either TLC599 at 2 dose levels or Placebo (normal saline) on Day 0, 
with a follow-up period of24 weeks. A total of 75 patients were administered with I of the 3 study 
treatments. 
4.3. Non-clinical Experience 
Local treatment of TLC599 by IA administration showed markedly sustained inhibitory activity 
in 
animal models of in flammatory diseases. The TLC599-induced amelioration of 
collagen-induced arthritis (CIA) was evaluated in 2 rat studies. Following a single intra-plantar 
dose administration of DSP solution ofTLC599 in rats with CIA, the hind-paw swelling decreased 
in animals treated with either unformulated DSP treatment or TLC599. However, swelling 
recurred earlier for unformulated DSP treatment (Day 22) compared to TLC599 (Day 26). A 
similar outcome was obtained following repeat-dose administration, though the duration of 
anti-arthritic effects associated with T LC599 persisted for a longer period following repeat vs. 
single doses. 
Also, TLC599 did not cause significant toxic effect locally and systemically after IA 
administration in single- and repeat-dose studies in rabbits and dogs. 
The toxic findings of 
T LC599 after IV administration to rats are comparable to those of DSP without significant 
additional toxic findings and delayed toxicities. 
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4.4. Summary of Potential Risks and Benefits 
The potential benefits of study participation are that patients with OA of the knee may experience 
sustained pain relief as a result of treatment with TLC599. 
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5. 
OBJECTIVES 
5.1. Primary Objective 
Confidential 
The primary objective is to evaluate the efficacy of a single IA dose of TLC599 in patients with 
OA of the knee. 
5.2. Secondary Objectives 
Secondary objectives include the following: 
• 
To evaluate the efficacy of repeat doses of TLC599 in patients with OA of the knee 
• 
To evaluate the safety of single and repeat IA doses ofTLC599 in patients with OA of the 
knee 
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6. 
STUDY DESIGN 
6.1. Overall Study Design and Plan 
Confidential 
This is a Phase 3 randomized, double-blind, placebo- and active comparator-controlled pivotal 
study. Approximately 500 adult patients with moderate to severe pain due to OA of the knee who 
meet all entry criteria will be enrolled and randomized into in a 2:1:1 ratio to receive TLC599 
12 mg (Group A), DSP 4 mg (Group B), or Placebo (normal saline) (Group C) via IA injection 
into the designated index knee at Baseline (Injection I). At Week 24, patients will receive 
Injection 2 per their randomly assigned dosing regimen (Group A, B, or C) via IA injection into 
the index knee (see Section 6.6.3 for Criteria for Injection 2). Patients who received TLC599 
12 mg (Group A) or DSP (Group B) for Injection I will receive blinded TLC599 12 mg for 
Injection 2 and those who received Placebo for Injection 1 (Group C) will receive Placebo for 
Injection 2. 
All patients will be followed for a total of 52 weeks, regardless of whether or not they receive 
Injection 2. Patients who do not receive Injection 2 will be encouraged to continue in the study 
through 52 weeks of follow-up. Efficacy and safety of 2 doses of TLC599 will be evaluated in 
comparison with Placebo and DSP through Week 52. 
To enter the study, patients must be at least 40 years of age and have documented diagnosis ofOA 
in the index knee based on American College of Rheumatology (ACR) Criteria for Classification 
of Idiopathic OA of the knee (the ACR diagnostic criteria is provided in Appendix A). Patients 
will not be eligible if they have unstable index knee joint as determined by the investigator based 
on physical examination (with or without buckling or giving way) because of an acute injury 
(defined as injury within 6 months, e.g., anterior cruciate ligament injury or tear). 
The study duration is expected to be up to 56 weeks for each patient, including a Screening period 
of up to 4 weeks before randomization, Injection 1 Period of 24 weeks and Injection 2 Period of 
28 weeks. 
Patients will return to the study site at Week 1, Week 2, and every 4 weeks through Week 52 
post-dose to complete efficacy and safety assessments as applicable. Patients who receive 
Injection 2 will return to the clinic for 2 additional follow-up visits (Week 25 and Week 26). 
Efficacy will be assessed by WOMAC, numeric rating scale (NRS), 
and Patient Global Impression of Change (PGIC) at the time points 
indicated in the schedule of events (Section 1.1 ). 
Safety will be assessed by physical examination, vital signs measurements (heart rate, respiratory 
rate, sitting blood pressure and temperature), clinical laboratory assessments (hematology, 
chemistry, urinalysis), HbA le, morning serum cortisol, 
12-lead 
electrocardiogram (ECG), knee radiographs, concomitant medications/therapies, adverse events 
(AEs), and signs and symptoms of adrenal insufficiency. 
All AEs observed by the study personnel or reported by the patient during the study (after the 
patient has signed the informed consent form [ICF] through the End of Study [EOS]/Early 
Termination [ET] visit) will be documented. 
Patients who do not complete the study through Week 52 will make every effort to complete 
ET procedures. 
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The diagram of the study design is provided in Figure I. 
Figure 1: 
Study Design 
Group 
·~ : 
1 
c 
! TLC599 
: : i OSP 
! Placebo 
111 I 
SCR 
BLTW4 
' 
Wl/ 2 
Blinded Injection 1 
WS 
W12 
W16 
! TLC599 
: i TLC599 
i Placebo 
111 I 
W20 
W2~W28 
' 
W25/ 26 
Blinded Injection 2 
W32 
W36 
W40 
W44 
W48 
W52 
Abbreviations: BL = Baseline (Day I); DSP 
dexamcthasone sodium phosphate; Rand 
Randomization; 
SCR = Screening; W = Week. 
6.2. Rationale and Discussion of Study Design 
IA corticosteroid injection is a commonly used treatment with an excellent safety profile. A 
limitation of IA injection with corticosteroids is the modest duration of treatment effect, which 
often lasts for only 2 to 4 weeks. Repeat injections are possible in the same joint, but there are 
limited data on the safety and duration of the effectiveness of this procedure. Thus, there is a 
pressing need for a more sustained duration of an IA corticosteroid injection. 
This is a Phase 3, randomized, double-blind, placebo- and active-controlled study to evaluate the 
efficacy and safety ofTLC599 in patients with OA of the knee. The duration of follow-up after an 
IA injection for this study (up to 52 weeks) is somewhat longer than typical OA studies ( 12 to 
16 weeks) as the duration of effect from the study drug is expected to be longer. Additionally, a 
second injection in the same index knee will be administered where appropriate at Week 24 to 
assess the safety and effectiveness of repeat dosing. The planned efficacy, safety, and tolerability 
endpoints for single and repeated dosing of TLC599 are appropriate for evaluating its sustained 
pain relief through an extended period of up to 52 weeks follow-up monitoring. 
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6.4. Study Sites 
Confidential 
The study will take place at approximately 45 to 50 sites in the US and Australia. 
6.5. Study Completion Definition 
The clinical trial is considered completed when the last participant's last study visit has occurred. 
6.6. Study Population 
Approximately 500 patients are planned for randomization. 
6.6.1. Inclusion Criteria 
A patient will be eligible for study participation if he or she meets all of the following criteria: 
1. Male or female ~40 years of age, inclusive. 
2. Body mass index ~O kg/m2. 
3. Has symptoms associated with OA of the index knee for at least 6 months before Screening. 
4. Documented diagnosis of OA in the index knee based on ACR Criteria for Classification of 
Idiopathic OA of the knee (clinical and radiological including standing fixed-flexion 
posterior-anterior X-ray of the knee). 
5. OA with Kellgren-Lawrence Grade 2 to 3 severity in the index knee based on the grade per 
X-ray assessed by a central radiologist reader at Screening. 
6. Initial patient-reported pain with NRS score ~4 (on a 0-10 scale) in at least 1 knee (index 
knee) at Screening (rating of average pain over previous 24 hours). 
7. Patient-reported pain with average daily NRS score of 5.0 to 9.0 (inclusive) in the index 
knee, AND with non-index knee pain score of ::;4.0, based on diaries completed daily for at 
least 5 of the last 7 days of the screening period before randomization. 
8. Patient-reported WOMAC Pain sub-scale (hereafter referred to as WOMAC Pain) score ~6 
(combined score on a 0-20 scale) in the index knee before dosing at Baseline. 
9. a. IF FEMALE, must meet all of the following: 
• 
Not breast feeding; 
• 
Not planning to become pregnant during the study; 
• If of childbearing potential (defined as non-post-hysterectomy or non-post-menopausal 
[amenorrheic for at least 2 years]), must have a negative pregnancy test result (human 
chorionic gonadotropin, beta subunit W-hCG]) at Screening and Baseline, and must 
commit to the use of an acceptable and effective form of birth control for the duration 
of the study and unti I at least 6 months after the last dose of study drug. 
b. IF MALE, must be surgically sterile (biologically or surgically) or commit to the use of 
a reliable method of birth control (must agree to use double-barrier contraception in the 
event of sexual activity), or be practicing abstinence for the duration of the study and 
until at least 6 months after the last dose of study drug. 
l 0. Is able to read, understand, and sign the lCF, communicate with the investigator, and 
understand and comply with protocol requirements. 
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6.6.2. Exclusion Criteria 
Confidential 
A patient will be excluded from the study if he or she meets any of the following criteria: 
1. Use of any of the following medications within the specified period: 
a. IA corticosteroid in any joint within 3 months before Screening, or triamcinolone acetate 
extended-release injectable suspension (Zilretta®) within 6 months before Screening 
b. IA hyaluronic acid in any knee joint within 6 months before Screening 
c. Systemic corticosteroids within 4 months before Screening or chronic use within I year 
before Screening 
d. NSAIDs (except topical use on regions other than the index knee) within 14 days before 
the Baseline visit 
e. Platelet-rich plasma or other prolotherapy within 6 months before Screening 
f. 
Chronic opioid use (use exceeding 4 days per week) within the last 30 days before 
Screening 
g. Any chemotherapeutic or systemic immunosuppressant agents for inflammatory diseases 
within 6 months before Screening 
h. Anti-coagulants, including warfarin, heparin, low molecular weight heparin, or 
dabigatran within I week of Screening and the Baseline visit. Low-dose acetylsalicylic 
acid or other anti-platelet medications are allowed 
1. 
Live attenuated vaccine within 3 months before Screening 
j. Any investigational therapy within 4 weeks or within 5 half-lives before Screening, 
whichever is longer 
2. Patient who is not ambulatory. 
3. Any surgery or arthroscopy in the index knee within 12 months before Screening. 
4. Unstable index knee joint as determined by the investigator based on physical examination 
(with or without buckling or giving way) because of an acute injury (defined as injury within 
6 months of Screening, e.g., anterior cruciate ligament injury or tear). 
5. History of infective arthritis in the index knee. 
6. Suspected/concurrent infection in either knee at Screening or Baseline before study drug 
administration. 
7. Any skin lesion/breakdown at the anticipated injection site or any condition that impairs 
penetration of the index knee joint space. 
8. Documented gout attack in index knee within 6 months before Screening or presence of 
tophus in index knee. 
9. Patient with any amputation in any lower limb. 
I 0. Documented history and confirmed autoimmune disease including but not limited, reactive 
arthritis, 
systemic lupus erythematosus, Sjogren' s syndrome, systemic sclerosis, 
inflammatory myositis, mixed connective tissue disease, palindromic rheumatism, reactive 
arthritis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Behcet's disease, 
arthritis 
associated 
with 
inflammatory 
bowel 
disease, 
sarcoidosis, 
vasculitis, 
cryoglobulinemia, or amyloidosis. 
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11 . Any condition that could possibly confound the patient's assessment of index knee pain per 
the investigator's judgment (i.e., ipsilateral hip OA, radicular low back pain, and hip pain 
referred to the index knee). 
12. Substance abuse disorder, or positive urine drug test for illegal drug substances or 
non-prescribed 
controlled 
substances 
including 
amphetamines, 
barbiturates, 
benzodiazepines, cocaine, opiates, phencyclidine, and tetrahydrocannabinol; or positive 
alcohol breath test. 
13. History of primary or secondary adrenal insufficiency. 
16. History of bleeding disorders. 
17. History of acquired or congenital immunodeficiency diseases, or positive test results for 
human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virns (HCV) 
current infection at Screening. 
18. Any active infection requiring treatment with antibiotics. 
19. History of treated malignancy which is disease free for :SS years before Screening, except 
basal cell carcinoma of skin or carcinoma in situ of the uterine cervix. 
20. Stroke or myocardial infarction within 12 months before Screening. 
2 1. Uncontrolled and unstable concurrent medical or psychiatric illness, including but not 
limited to, poorly controlled diabetes, poorly controlled hypertension, dementia, 
schizophrenia, or bipolar disorder that will jeopardize the safety of the patient, interfere with 
the objectives of the protocol, or affect the patient compliance with study requirements, as 
determined by the investigator. 
22. Abnormalities of the following laboratory parameters at Screening: 
a. hemoglobin A le (HbA lc) >9.0% 
b. platelet count <80,000/µL 
c. hemoglobin <8.0 g/dL 
d. total white blood cell count <4000/µL 
e. serum bilirubin/alanine aminotransferase/ aspartate aminotransferase >2 times upper 
limit of normal (ULN) for the laboratory reference ranges 
f. 
serum creatinine level > I .5X ULN 
g. prothrombin time/International Normalized Ratio > ULN for the laboratory reference 
range 
23. Known allergy or hypersensitivity to the study drugs or their components. 
24. ls an immediate family member (spouse, parent, child, or sibling; biological or legally 
adopted) of personnel directly affiliated with the study at the clinical study site. 
25. Employed by sponsor (i.e., is an employee, temporary contract worker, or designee 
responsible for the conduct of the study). 
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6.6.3. Criteria for Injection 2 (Week 24) 
Patients will not continue with Injection 2 if any of the following criteria are met: 
2. Occurrence of adrenal insufficiency through Week 24. 
3. If female and of childbearing potential, have a positive urine pregnancy test result at 
Week 24. 
4. Positive urine drug or alcohol test result at Week 24. (Drug use allowed with prescription.) 
6.7. Patient Withdrawal from the Study 
All patients will be advised that they are free to withdraw from participation in this study at any 
time, for any reason, and without prejudice. The investigator should make every reasonable 
attempt to keep patients in the study; however, patients must be withdrawn from the study if they 
withdraw consent to participate. Patients who do not receive Injection 2 do not need to be 
withdrawn and will be encouraged to continue in the study through 52 weeks of follow-up. If a 
patient does not receive Injection 2, it will not be considered a protocol deviation. Investigators 
must attempt to contact patients who fail to attend scheduled visits by telephone or other means to 
assess the possibility of an AE being the cause of withdrawal. Should this be the cause, the AE 
must be documented, reported, and fo llowed as described in Section 9.2. 
A pa1t icipant should be withdrawn from the study if any of the following occurs: 
• 
Pregnancy 
• 
Significant study non-compliance 
• 
Lost to follow-up 
• 
A surgical procedure or IA drug administration in the index knee 
• 
Lack of therapeutic effect that is intolerable or otherwise unacceptable to the patient 
• 
If any clinical AE, laboratory abnormality, or other medical condition or situation occurs such 
that continued participation in the study would not be in the best interest of the participant 
• 
The investigator or the Sponsor stops the study for any reason 
If important restricted medication deviations occur, they should be discussed with the medical 
monitor before withdrawing the patient from the study. 
The investigator should contact the medical monitor to discuss any non-compliance or safety 
concerns before withdrawing a patient from the study. 
The reason for participant withdrawal from the study will be recorded on the eCRF. Patients w ho 
sign the ICF, are randomized, and receive study drug, and subsequently withdraw, or are 
withdrawn from the study, will not be replaced. 
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6.8. Patient Replacement Criteria 
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Withdrawn patients will not be replaced. Randomized and treated patients withdrawn from the 
study may not re-enter. The patient number for a withdrawn patient will not be reassigned to 
another patient. 
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7. 
TREATMENTS 
7.1. Identification of Study Drugs 
Confidential 
Packaging, labeling, and dispensing information for TLC599 are provided in the pharmacy 
manual, available as a separate document. 
The active comparator, DSP, will be supplied to study centers. The vial of DSP for injection 
contains DSP solution at the concentration of 4.0 mg/mL. DSP should be stored at 20°C to 25°C 
(68°F to 77°F) (see USP Controlled Room Temperature) in accordance with the package insert. 
Protect from freezing, sensitive to head. Do not autoclave. 
Placebo will be supplied to study centers. The vial of Placebo contains 0.9% normal saline. Normal 
saline should be stored below 25°C (77°F) or in accordance with the package insert. 
7.2. Treatment Administration 
Study drug will be administered in a blinded manner via IA injection into the index knee: 
Study Drug (TLC599): 
• 
Dexamethasone sodium phosphate (DSP) 12 mg with l 00 mM phospholipid (PL) ( 1 mL) 
Reference Drug (DSP): 
• 
DSP 4 mg ( I mL) 
Placebo: 
• 
Normal saline (1 mL) 
Patients will be randomly assigned in a 2: I: I ratio to one of the following treatment groups 
(Group A, B, or C). 
Treatment Assignment for Injection 1 and Injection 2 
Group 
Injection I (Day I) 
Injection 2 (Week 24) 
A 
TLC599 
TLC599 
B 
DSP 
TLC599 
c 
Placebo 
Placebo 
Guidance and recommendations for the study drug injection procedure are provided in the 
pharmacy manual. 
The index knee for study drug administration will be determined before randomization at Visit 2 
(Baseline). The index knee is selected primarily based on the documented diagnosis of OA, 
Kellgren-Lawrence grade, NRS score at the initial Screening visit, and average daily NRS score 
before randomization. Therefore, the index knee can only be identified at the Baseline visit. The 
study drug injection may be administered using ultrasound-guided needle placement, depending 
on the facility available at each study site. If imaging-guided injection is not used, then 
confirmation of location of the needle within the index knee joint may be verified by aspirating 
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joint fluid. If there is a substantial effusion within the knee joint, the effusion should be aspirated, 
when possible, such that the estimated remaining joint fluid in the knee is approximately 
5 to I 0 mL. The amount of joint fluid aspirated should be recorded. If it is part of the site's standard 
practice, pre-injection analgesics may be administered. However, nothing other than the study drug 
may be administered into the IA space. All medications used should be recorded in the concomitant 
medication record. 
Post-procedure observation for patient safety can be per the investigator' s discretion. Patients 
should not take a hot bath or shower, or expose the injected knee to external heat, within 12 hours 
after the injection. 
7.3. Selection of Timing of Dose for Each Patient 
The study drug injection will only be given on Day I (Injection I) and Week 24 (Injection 2) if 
the patient meets the eligibility criteria (Sections 6.6. l through 6.6.3). 
7.4. Dose Adjustment Criteria 
Not appl icable. 
7.5. Treatment Compliance 
All injections at the study site should be under the surveillance of appropriate study personnel. 
Injection procedure details will be recorded in the patient's eCRF. 
7.6. Method of Assigning Patients to Treatment Groups 
In this parallel-group randomized study, patients who meet study eligibility criteria will be 
randomly assigned in a 2: I: I ratio to 12 mg T LC599, 4 mg DSP, or Placebo (normal saline). The 
randomization schedule will be computer generated using a permuted block algorithm and will 
randomly allocate study drug to randomization numbers. The randomization numbers will be 
assigned sequentially through a central interactive web response system (I WRS) as patients meet 
the eligibility criteria. Study center will not be a blocking factor in the randomization schedule. 
The randomization schedule will be prepared by 
before the start of the study. 
No one involved in the study performance will have access to the randomization schedule before 
official unblinding of treatment assignment. No patient will be randomized into this study more 
than once. 
7.7. Blinding and Unblinding Treatment Assignment 
All patients, investigators, and study personnel involved in the conduct of the study, including data 
management, will be blinded to treatment assignment, with the exception of a specified unblinded 
statistician and programmer from 
who will have access to the randomization 
code, the unblinded medical monitor, and the unblinded pharmacist or designee and unblinded 
injector at each study site. The unblinded study personnel will not participate in study procedures 
or data analysis before unblinding of the study data to all study-related personnel. The patient 
treatment assignment for Injection I will remain blinded until the last patient has completed the 
study. The procedure for treatment blinding is presented in the pharmacy manual. 
Study personnel will make every effort to safeguard the integrity of the study blind to minimize 
bias in the conduct of the study. Treatment unblinding is discouraged if knowledge of the treatment 
assignment will not materially change the planned management of a medical emergency. 
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Unblinding will be permitted in a medical emergency that requires immediate knowledge of the 
patient's treatment assignment. 
Unblinding should be discussed in advance with the medical monitor, if possible. For emergency 
unblinding, study personnel will use the IWRS to obtain unblinding information. If the investigator 
is not able to discuss treatment unblinding in advance, then he/she must notify the medical monitor 
as soon as possible about the unblinding incident without revealing the patient's treatment 
assignment. 
The investigator or designee must record the date and reason for treatment unblinding on the 
appropriate eCRF for that patient. In all cases that are not emergencies, the investigator must 
discuss the event with the medical monitor before unblinding the patient's treatment assignment. 
If treatment assignment is unblinded for an individual patient, study personnel will be notified of 
that patient's treatment assignment without unblinding the treatment assignments for the remaining 
patients in the study. The overall study blind will not be compromised. [fa patient's treatment 
assignment is unblinded, he/she may or may not be asked to withdraw from the study. The 
investigator will make this decision after consultation with the medical monitor and the sponsor. 
Overall unblinding will take place only after database lock has been achieved. 
7.8. Rescue Medication 
Acetaminophen rescue medication may be used and will be provided to and managed by the study 
sites. The daily allowed acetaminophen dosage is up to 3 g/day. No acetaminophen is allowed 
within 24 hours before study visits. 
will provide the appropriate package insert for the acetaminophen rescue 
medication to be used during the study to each investigator. 
The name and dosage regimen of the rescue medication must be recorded daily in the diary with 
the indication recorded as " rescue medication." 
7.9. Concomitant Medications 
Patients may continue to receive any ongoing prescription medications, dietary supplement, or 
exercise program of the knee that they were receiving at the time of Screening, unless otherwise 
prohibited (See Prohibited Therapies, Section 7.10), and which are recorded in the source 
document and appropriate eCRF. These medications, or their doses, should not be changed during 
the course of the study unless under the direction of the prescribing physician. 
7.10. Prohibited Therapies 
All concomitant medications used (including over-the-counter medications and herbal 
supplements) will be recorded in the source document and on the appropriate eCRF. 
The following therapies are prohibited after the informed consent is signed, and throughout the 
study, unless otherwise specified: 
• 
IA corticosteroid in any joint 
• 
IA hyaluronic acid in any knee joint 
• 
Systemic corticosteroids (topical use allowed except on the index knee) 
• 
Acetaminophen within 24 hours prior to Baseline and subsequent study visits 
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• 
Non-steroidal anti-inflammatory drugs within 14 days before the Baseline visit and throughout 
the study (topical use allowed except on the index knee) 
• 
New initiation of duloxetine, pregabalin and gabapentin (a patient may continue the prior use 
of these drugs during the study) 
• 
Platelet-rich plasma or other prolotherapy 
• 
Opioid use is not permitted, with the exception ofhydrocodone, oxycodone, or tramadol, which 
may be used with the following limitations: 
o 
Any combination analgesic containing an opioid is prohibited 
o 
However, episodic use ( <4 days per week) of hydrocodone, oxycodone, or tramadol is 
permitted 
o The use of any opioid (including hydrocodone, oxycodone, or tramadol) within 24 hours 
before the Baseline visit and subsequent study visits is prohibited 
• 
Any chemotherapeutic or systemic immunosuppressant agents for inflammatory diseases 
• 
Anti-coagulants, including warfarin, heparin, low molecular weight heparin, or dabigatran 
(low-dose acetylsalicylic acid and other anti-platelet medications allowed) 
• 
Live attenuated vaccine 
• 
Any investigational therapy 
• 
Physical and occupational therapy or new rehabilitation program in index knee 
• 
Acupuncture or any surgical or invasive procedure on either knee (including study knee joint 
synovial fluid aspiration except prior to study drug administration) 
• 
Oral cannabidiol (CBD) in any form; inhalation is allowed and topical use is allowed except 
on the index knee 
Patients receiving excluded therapies during the screening period will be treated as screen failures 
and ineligible for randomization. If a patient uses any prohibited medication or treatments 
mentioned as above after study drug administration during the study period, it will be defined as a 
protocol deviation. Whether such protocol deviation is considered as significant study non-
compliance leading to withdrawal will be based on the investigator's judgment after consulting the 
sponsor and the blinded medical monitor. 
7.11. Dispensing and Storage 
Details regarding dispensing and storage of study drug are provided in the pharmacy manual. 
7.12. Drug Accountability 
The investigator or designee must maintain adequate records showing the receipt, dispensing, 
return, or other disposition of the study drugs, including the date, quantity, batch or code number, 
and identification of patients (patient number) who received the study drugs. The investigator wi II 
not supply the study drug to any person except those named as sub-investigators on the Form 
FDA 1572, designated study personnel, and patients in this study. The accountability will be 
performed by separate unblinded monitors during the time that blinding is required. 
Upon completion of the study, the study drugs (partly used, unused, and empty packaging) must 
be left in the original packaging and returned to the sponsor or designee for destruction, unless the 
sponsor makes other arrangements for local destruction. 
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8. 
STUDY PROCEDURES AND ASSESSMENTS 
Patients must provide written informed consent before any study-related procedures are initiated, 
including the cessation of prohibited concomitant therapy. 
For the timing of assessments and procedures throughout the study, refer to the schedule of events 
(Section I. I). Throughout the study, every reasonable effort should be made by study personnel to 
follow the timing of assessments and procedures in the schedule of events for each patient. If a 
patient misses a study visit for any reason, the visit should be rescheduled as soon as possible. 
8.1. Study Visits 
Study assessments throughout the study should occur in-person at the study site. If a patient cannot 
attend a study site visit because of restrictions resulting from the novel coronavirus (COVID-19), 
phone visits may replace in-person site visits and should occur per protocol schedule and within 
the regular visit window when possible (see Section 8.1.1). Patients who cannot attend the 
Week 24 visit within the visit window because of restrictions resulting from COVID-19, will be 
encouraged to return to the site before Week 28 to complete the Week 24 visit assessments, if 
feasible. However, Injection 2 may only be administered within the allowed visit window. 
8.1.1. Phone Visits 
On the scheduled day of the phone visit, site staff shall contact the patient by phone and conduct 
all study procedures that do not require direct physical contact (e.g., laboratory tests, physical 
examinations, radiographs, etc.). Adverse event and concomitant medication review should occur 
as per usual procedure. 
Patients with symptoms of potential adrenal insufficiency should be encouraged to visit the study 
site for a laboratory test. If the study site is closed for patient's visiting, the patient should be 
referred to a local laboratory, urgent care, primary care physician, or emergency room for testing 
and/or follow-up as appropriate. 
Prior to the phone call, the site staff wi ll activate visit date in the electronic data capture (EDC) 
system. Site staff should enable the Patient Diary Activation for the site visit in interactive response 
technology. Site staff will confirm with the patient that assessments have populated. If the dai ly 
diary is not functioning during the call, the site will need to manually document the patient's 
responses on paper assessments. Then contact their assigned CRA for instructions on how to enter 
responses into the EDC manually. 
If the study site is closed, site staff will work from home calling patients and use the EDC website 
provided - https://login.imedidata.com/login. There is no change in username/password. The 
process for entering the date of visit is the same whether or not the user is working from the office. 
Site staff should remain in contact with the Principal Investigator and keep them aware of the 
patients' condition to ensure patient safety. The authorized investigator should be responsible for 
any medical judgment (when needed) and/or monitoring of potential symptom of adrenal 
insufficiency (local laboratory test for cortisol can be taken if it is medically urgent). 
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8.2. Study Duration 
Confidential 
The planned sequence and maximum duration of the study periods for each patient will be as 
follows: 
I. Screening period: up to 4 weeks 
2. Injection l period: up to 24 weeks following the administration oflnjection I 
3. Injection 2 period: up to 28 weeks following the administration of Injection 2 
Patients who do not receive Injection 2 will be followed for up to 52 weeks following the 
administration of Injection I. 
The maximum study duration for each patient is approximately up to 56 weeks. 
8.3. Study Periods and Visits 
8.3.1. Screening (Visit 1) 
The patient must be screened within 28 days before enrollment in the study. The following 
procedures will be performed at Screening: 
I. Obtain written informed consent. 
2. Assess inclusion/exclusion criteria. Documented diagnosis of OA in the index knee can be 
completed as part of study screening. 
3. Training and assessment of knowledge on pain ratings, allowable rescue medication, and 
entering data into the diary. 
4. Ask patients to score their average pain in each knee over the previous 24 hours by NRS 
(diary) onsite. 
5. Collect demographic information and medical history. 
6. Measure vital signs (heart rate, respiratory rate, sitting blood pressure, and temperature) 
after the patient has been in a sitting position for 5 minutes. 
7. Measure height and weight. 
8. Perform a physical examination. 
9. Perform a posterior-anterior X-ray radiograph for both knees in standing fixed-flexion 
(approximately 20 degrees), if applicable. 
10. Perform 12-lead ECG after the patient has been supine for at least 5 minutes. 
11. Collect blood samples (fasted state) for clinical chemistry, hematology, HbA 1 c, serology, 
and coagulation tests. If the patient is potentially eligible based on currently available data, 
except laboratory abnormalities, the assessments may be repeated once only to reassess 
eligibility. 
13. Collect urine sample for urinalysis. 
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14. For women of childbearing potential, perform serum pregnancy test (~-hCG). 
15. Perform drug screen and alcohol breath tests (onsite). 
16. Dispense initial rescue medication. Rescue medication will be dispensed as needed at the 
subsequent visits. 
17. Ask patients to score their average pain in each knee over the previous 24 hours by NRS 
every evening (diary) for at least 5 of the last 7 days of the screening period before returning 
to the study site for Visit 2 (Baseline, Day 1 ). 
18. Ask patients to record their rescue medication use daily in the diary. 
19. Record concomitant medications use. 
8.3.2. Visit 2 (Baseline, Day 1, and Injection 1) 
The following procedures will be performed at Visit 2 (Baseline Day 1 ): 
I. Confirm inclusion/exclusion criteria, 
2. Review demographics and medical history. 
3. Measure vital signs (heart rate, respiratory rate, sitting blood pressure, and temperature) 
after the patient has been in a sitting position for 5 minutes. 
4. For women of childbearing potential, perform urine pregnancy test before dosing. 
5. Perform drug screen and alcohol breath tests (onsite). 
6. Collect serum samples for measurement of cortisol and fasting glucose, before 9 AM and 
before study drug administration (Injection 1 ). 
7. Review rescue medication use and the diary records. Rescue medication will be dispensed 
as needed. 
8. Record concomitant medications use. 
9. Record AEs. 
10. Review training and assessment of knowledge on pain ratings, allowable rescue 
medication, and entering data into the diary. 
l l . Complete WOMAC. 
13. After Steps 1 through 11 are completed, perform randomization for eligible patients. 
14. Perform synovial fluid aspiration and administer study drug (Injection 1 ). 
15. Investigator to assess patient for AEs after the injection. 
16. Ask patients to score their average pain in the index knee for the previous 24 hours by NRS 
every evening. 
17. Ask patients to record rescue medication use daily in the diary. 
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8.3.3. Follow-up Assessments 
Confidential 
8.3.3.1. Visit 3(Week1) and Visit 4 (Week 2) 
Patients will return to the study site at Week l (±3 days) and Week 2 (±3 days) after Injection I 
and have the following procedures performed. 
I. Measure vital signs (heart rate, respiratory rate, sitting blood pressure, and temperature) 
after the patient has been in a sitting position for 5 minutes. 
2. Collect serum sample for measurement of cortisol before 9 AM. 
3. Review rescue medication use and the diary records. Rescue medication will be dispensed 
as needed. 
4. Complete WOMAC. 
5. Complete PGIC. 
6. Record concomitant medications use. 
7. Record AEs. 
8. Ask patients to score their average pain in the index knee for the previous 24 hours by NRS 
every evening. 
9. Ask patients to record their rescue medication use daily in the diary. 
8.3.3.2. Visits 5 Through 9 (Every 4 Weeks from Week 4 Through Week 20) 
Patients will return to the study site at Week 4 (±7 days) and every 4 weeks (±7 days) through 
Week 20 to have the following procedures performed: 
I. Measure vital signs (heart rate, respiratory rate, sitting blood pressure, and temperature) 
after the patient has been in a sitting position for 5 minutes. 
2. Collect blood samples for clinical chemistry, hematology, and HbA I c in a fasted state 
(Visit 7 only). 
3. Collect serum sample for measurement of cortisol before 9 AM. 
4. Review training and assessment of knowledge on pain ratings, allowable rescue 
medication, and entering data into the diary (Visit 7 or as needed). 
5. Complete WOMAC. 
6. 
7. Complete PGIC. 
8. Record concomitant medication use. 
9. Record AEs. 
I 0. Review rescue medication use and the diary records. Rescue medication will be dispensed 
as needed. 
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11 . Ask patients to score their average pain in the index knee for the previous 24 hours by NRS 
every evening. 
12. Ask patients to record their rescue medication use daily in the diary. 
8.3.3.3. Visit 10 (Week 24 and Injection 2) 
Patients who have completed through Week 24 and meet the Injection 2 criteria (Section 6.6.3) 
will receive a second injection of blinded study drug (see Section 7.2) at Week 24 (± 7 days). 
Patients who do not receive Injection 2 may remain in the study unless they choose to withdraw 
or are withdrawn from the study for other reasons. 
The following procedures will be performed (Steps I through 17 should be completed before study 
drug administration): 
1. Measure vital signs (heart rate, respiratory rate, sitting blood pressure, and temperature) 
after the patient has been in a sitting position for 5 minutes. 
2. Perform physical examination. 
3. Collect serum sample for measurement of cortisol before 9 AM. 
4. Collect blood samples for clinical chemistry, hematology, and HbA I c in a fasted state. 
5. Perform a posterior-anterior X-ray radiograph for both knees in standing fi xed-flexion 
(approximately 20 degrees), as applicable. This may be performed within 14 days before 
this visit. 
6. Perform 12-lead ECG after the patient has been supine for at least 5 minutes. 
7. Collect urine sample for urinalysis. 
8. For women of childbearing potential, perform urine pregnancy test W-hCG) before dosing. 
9. Perform drug screen and al coho I breath tests ( onsite). 
10. Review training and assessment knowledge on pain ratings, allowable rescue medication, 
and entering data into the diary. 
11. Review rescue medication use and the diary records. Rescue medication will be dispensed 
as needed. 
12. Record concomitant medications. 
13. Record AEs. 
14. Complete WOMAC. 
15. 
16. Complete PGIC. 
17. Confirm if the patient is disqualified from receiving Injection 2 (see Section 6.6.3). 
18. Perform synovial fluid aspiration and administer study drug (Injection 2). 
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19. Investigator to assess patient for AEs after the injection. 
20. Ask patients to score their average pain in the index knee for the previous 24 hours by 
NRS. 
21. Ask patients to record their rescue medication use daily in the diary. 
8.3.3.4. Visits 11 and 12 (Weeks 25 and 26) - Injection 2 Follow-up Assessments 
Patients who receive Injection 2 will return to the clinic for Injection 2 follow-up assessments 
1 week (±3 days) and 2 weeks (±3 days) after Injection 2. Patients who do not receive Injection 2 
will continue with their fo llow-up assessments as described in Section 8.3.3.5. 
1. Measure vital signs (hea11 rate, respiratory rate, sitting blood pressure, and temperature) 
after the patient has been in a sitting position for 5 minutes. 
2. Collect serum sample for measurement of cortisol before 9 AM. 
3. Review rescue medication use and the diary records. Rescue medication will be dispensed 
as needed. 
4. Complete WOMAC. 
5. Complete PGIC. 
6. Record concomitant medications use. 
7. Record AEs. 
8. Ask patients to score their average pain in the index knee for the previous 24 hours by NRS 
every evening. 
9. Ask patients to record their rescue medication use daily in the diary. 
8.3.3.5. Visits 13 Through 18 (Every 4 Weeks from Week 28 Through Week 48) 
Patients will return to the study site at Week 28 (±7 days) and every 4 weeks (±7 days) through 
Week 48 to have the fo llowing procedures performed: 
I. Measure vital signs (hea11 rate, respiratory rate, sitting blood pressure, and temperature) 
after the patient has been in a sitting position for 5 minutes. 
2. Perform 12-lead ECG after the patient has been supine for at least 5 minutes (Visit 18 only). 
3. Collect serum sample for measurement of cortisol before 9 AM. 
4. Collect blood samples for clinical chemistry, hematology, and HbAlc (Visits 15 and 
18 only) in a fasted state. 
5. Perform urinalysis (Visit 18 only). 
6. Review rescue medication use and the diary records. Rescue medication will be dispensed 
as needed. 
7. Review training and assessment of knowledge on pain ratings, allowable rescue 
medication, and entering data into the diary (Visit 15 or as needed). 
8. Complete WOMAC. 
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9. 
I 0. Complete PGIC. 
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11 . Record concomitant medications use. 
12. Record AEs. 
13. Ask patients to score their average pain in the index knee for the previous 24 hours by NRS 
every evening. 
14. Ask patients to record their rescue medication use daily in the diary. 
8.3.4. End of Study (Week 52) or Early Termination Visit 
At Week 52 (EOS) or upon early termination of the study, the following procedures will be 
performed for all patients, if applicable: 
I. Measure vital signs (heart rate, respiratory rate, sitting blood pressure, and temperature) 
after the patient has been in a sitting position for 5 minutes. 
2. Perform physical examination. 
3. Perform a posterior-anterior X-ray radiograph for both knees in standing fi xed-flexion 
(approximately 20 degrees), as applicable. This may be performed within 14 days before 
this visit. 
4. Perform 12-lead ECG after the patient has been supine for at least 5 minutes. 
5. Collect blood samples for clinical chemistry, hematology, and HbA I c in fasted state. 
6. For women of childbearing potential, perform urine pregnancy test (B-hCG). 
7. Perform drug screen and alcohol breath tests (onsite). 
8. Collect serum sample for measurement of cortisol before 9 AM. 
9. Complete WOMAC. 
10. 
11. Complete PGIC. 
12. Review rescue medication use and the diary records. 
13. Record concomitant medications. 
14. Record AEs. 
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8.4. Assessments 
8.4.1. Efficacy 
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8.4.1.1. Western Ontario & McMaster Universities Osteoarthritis Index (V3.1) 
The WOMAC is a widely used, self-administered assessment used to measure pain, stiffness, and 
physical function in patients with OA. Jt is considered to be a reliable and valid instrument.3•4•5 It 
comprises 24 questions, each on a 0-4 Likert scale (total score on a 0-96 scale) with assessment 
based on the previous 24 hours. The 3 sub-scale scores of Pain (5 items, total sub-scale score on a 
0-20 scale), Stiffness (2 items, total sub-scale score on a 0-8 scale), and Difficulty Performing 
Daily Activities (Physical Function) ( 17 items, total sub-scale score on a 0-68 scale) are added 
together to determine the WOMAC Composite score. Composite and sub-scale scores of WOMAC 
will be normalized to a scale of 0-4 for analysis. Higher scores on the WOMAC indicate worse 
pain, stiffness, and functional limitations. 
T he WOMAC is provided in Appendix C. 
8.4.1.2. Patient Global Impression of Change 
The PGIC is a self-administered instrument that measures patients' rating of overall improvement 
with treatment on a 7-point scale including "veiy much improved," "much improved," "minimally 
improved," "no change," "minimally worse," "much worse," or "veiy much worse." 
The PGIC assessment is provided in Appendix D. 
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8.4.1.4. Numeric Rating Scale 
The NRS is an I I -point scale from 0 to I 0. On this scale, 0 = no pain and 10 = the worst possible 
pain. The NRS will be assessed as the average pain over the last 24 hours. 
Every evening, the patient will rate his or her knee pain intensity using the following question on 
a daily patient diary for the previous 24 hours: "On a scale from 0 to 10, where "zero" represents 
"no pain" and "1 O" represents "the worst possible pain," how would you rate the average pain that 
you have been feeling in your knee over the last 24 hours?" 
8.4.1.5. Rescue Medication Use 
Patients may take the rescue medication provided by the study site for pain of the index knee as 
needed, except within 24 hours before a planned study visit. Acetaminophen is provided as the 
only allowed rescue medication. The name and dosage regimen must be recorded in the patient 
diary with the indication of"rescue use" specified. The daily allowed acetaminophen dosage is up 
to 3 g/day. 
8.4.2. Safety 
Patient safety will be evaluated by physical examination, vital signs assessments (heart rate, 
respiratory rate, sitting blood pressure, and temperature), clinical laboratory assessments 
(hematology, chemistry, urinalysis), HbA le, morning serum cortisol, 
12-lead ECG, knee radiographs, concomitant medications/therapies, AEs, and signs and symptoms 
of adrenal insufficiency. 
8.4.2.1. Clinical Laboratory Safety Assessments 
8.4.2.1.1. Clinical Laboratory Tests to be Performed 
Samples for the following laboratory tests will be collected at the time points specified in the 
schedule of events (Section I.I). Hematology, clinical chemistry, and HbA lc will be collected in 
a fasted state. 
Hematology: 
Clinical 
Chemistry: 
Coagulation Panel 
Serum Cortisol 
Urinalysis: 
hemoglobin, hematocrit, red blood cell (RBC) count, mean corpuscular 
hemoglobin, mean corpuscular hemoglobin 
concentration, mean 
corpuscular volume, platelet count (or estimate), white blood cell count 
including differential 
albumin, total bilirubin, total protein, calcium, alkaline phosphatase, 
alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, 
creatinine, glucose, sodium, potassium, chloride, bicarbonate, lactate 
dehydrogenase, uric acid 
prothrombin time (PT), international normalized ratio (INR) 
morning cortisol should be before 9 AM 
pH, specific gravity, blood, glucose, protein, ketones, nitrite, leukocyte 
esterase 
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Serology: 
human immunodeficiency virus (HIV) anti-body, hepatitis B surface 
antigen, HCV anti-body 
Urine Drug Screen: amphetamines, 
barbiturates, 
benzodiazepines, 
cocaine, 
opiates, 
phencyclidine, and tetrahydrocannabinol. The panel also includes 
methadone, oxycodone, methamphetamine, and ecstasy per the standard 
kit 
Pregnancy Test 
for women of childbearing potential only 
Urine/serum 
(B-hCG) 
HbA le 
hemoglobin Ale 
Alcohol breath test 
Estimated measurement of blood alcohol content 
Blood and urine samples for hematology, clinical chemistry, urinalysis, and serum pregnancy tests 
(B-hCG), serum cortisol, and coagulation panel will be sent to a central laboratory for analysis. 
Urine pregnancy test, urine drug screen, and breath test will be performed at the study site. 
Serology will also include a confirmation test for all positive HlV, HBV, and HCV test results. 
Central laboratory morning serum cortisol results will be blinded to the patient, site staff, and 
blinded study team members (except Screening, Day I [pre-dose], and Week 20); results will be 
available to a separate unblinded medical monitor. Monitoring of cortisol values and management 
of potential signs and symptoms of adrenal insufficiency are discussed in greater detail in 
Section 9.3.1.1. 
8.4.2.1.2. Specimen Handling Requirements 
Standard operating procedures at the study sites will be followed for sample handling. 
8.4.2.1.3. Evaluation of Clinical Laboratory Values 
The normal ranges of values for the clinical laboratory assessments in this study will be provided 
by the responsible laboratory and submitted to TLC before the beginning of the study. They will 
be regarded as the reference ranges on which decisions will be made. 
If a laboratory value is out of the reference range, it is not necessarily clinically significant. The 
investigator must evaluate the out-of-range values. 
All clinical laboratory values that in the investigator's opinion show clinically significant or 
pathological changes during or after termination of treatment must be reported as AEs and 
followed, as described in Section 9.2. 
All measurements described in this section are recognized standard methods. 
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8.4.2.2. Clinical Examinations 
8.4.2.2.1. Vital Signs 
Confidential 
Vital signs (heart rate, respiratory rate, sitting blood pressure, and temperature) will be measured 
after the patient has been in a sitting position for 5 minutes. 
Height and weight will be measured at Screening only. 
8.4.2.2.2. Twelve-lead Electrocardiogram 
A standard 12-lead ECG will be performed after the patient has been supine for at least 5 minutes. 
All ECG recordings will be identified with the patient number, date, and time of the recording and 
recorded in the patient's eCRF. 
8.4.2.2.3. Physical Examination 
The fo llowing physical examination will be performed at the time points indicated in the schedule 
of events (Section I. I): 
• General Appearance 
• Abdomen 
• Head/Face 
• Skin, Hair, and Nails 
• Eyes/Fundoscopy 
• Musculoskeletal: Extremities, Spine 
• Ears/Hearing 
• Vascular/Circulatory 
• Nose 
• Lymphatic 
• Mouth, Teeth, and Throat 
• Psychiatric/Behavior 
• Neck and Thyroid 
• Brief neurologic 
• Chest/Lungs 
8.4.2.2.4. Knee Radiographs 
A posterior-anterior X-ray radiograph will be performed for both knees (as applicable) in standing 
fixed-flexion (approximately 20 degrees) at the time points indicated in the schedule of events 
(Section 1.1). Minimum joint space width (in unit of millimeter) in the standing fixed-flexion 
anteroposterior view will be measured and recorded for analysis. Presence or absence of 
subchondral bone changes, osteonecrosis, and insufficiency fracture will be assessed. 
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9. 
ADVERSE EVENTS 
9.1. Definitions 
9.1.1. Adverse Events 
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An AE is defined as any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product that does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
use of a medicinal product, whether or not related to the medicinal product. 
Pre-existing diseases or conditions will not be considered AEs unless there is an increase in the 
frequency or severity, or a change in the quality of the disease or condition. (Worsening of a 
pre-existing condition is considered an AE.) 
9.1.2. Serious Adverse Events 
An SAE is any untoward medical occurrence that at any dose: 
• 
Results in death 
• 
Is life-threatening 
NOTE: The term "life-threatening" in the definition of "serious" refers to an event in which 
the patient was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it were more severe. 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
An elective hospital admission to treat a condition present before exposure to the study drug, 
or a hospital admission for a diagnostic evaluation of an AE, does not qualify the condition or 
event as an SAE. 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly 
NOTE: A congenital anomaly in an infant born to a mother who was exposed to the study drug 
during pregnancy ~ an SAE. However, a newly diagnosed pregnancy in a patient that has 
received a study drug is not considered an SAE unless it is suspected that the study drug(s) 
interacted with a contraceptive method and led to the pregnancy. 
• 
Is an important medical event 
NOTE: Medical and scientific judgment should be exercised in deciding whether it is 
appropriate to consider other situations serious, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require intervention to prevent one of the other outcomes listed in the definition 
above. Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias, or convulsions that do not result in hospitalization, 
development of drug dependency, or drug abuse. 
9.1.3. Treatment-emergent Adverse Events 
An AE is defined as treatment emergent if the first onset or worsening at the time of or following 
the sta1t of treatment with study drug through the Fol low-up Visit or ET, whichever occurs first. 
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9.2. Event Assessment and Follow-up of Adverse Events 
Any AE will be followed to a satisfactory resolution, until it becomes stable, or until it can be 
explained by a known cause (i.e., concurrent condition or medication) and clinical judgment 
indicates that further evaluation is not warranted. All findings relevant to the final outcome of an 
AE must be reported in the patient's medical record and recorded on the eCRF page. 
9.2.1. Collection 
The investigator is responsible for the detection and documentation of events meeting the criteria 
and definition of an AE or SAE described previously. At each visit, the patient will be allowed 
time to spontaneously report any issues since the last visit or evaluation. The investigator will then 
monitor and/or ask about or evaluate AEs using non-leading questions, such as the following: 
• 
"How are you feeling?" 
• 
"Have you experienced any issues since your last visit?" 
• 
"Have you taken any new medications since your last visit?" 
Any clinically relevant observations (including laboratory abnormalities) made during the visit 
wi ll also be considered AEs. All AEs observed by the study personnel or reported by the patient 
during the study (after the patient has signed the ICF through the EOS/ET visit) will be 
documented. 
9.2.2. Evaluation 
9.2.2.1. Severity of Adverse Events 
The clinical severity of an AE will be classified as: 
Mild 
Moderate 
Severe 
Usually transient and may require only minimal treatment or therapeutic 
intervention. The event does not generally interfere with usual activities of 
daily living. 
Usually alleviated with additional specific therapeutic intervention. The event 
interferes with usual activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the patient. 
Interrupts usual activities of daily living, or significantly affects clinical status, 
or may require intensive therapeutic intervention. 
It is important to distinguish between severe AEs and SAEs. Severity is a classification of intensity 
whereas an SAE is an AE that meets serious criteria. 
9.2.2.2. Seriousness 
The investigator is to evaluate whether the AE meets serious criteria. 
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9.2.2.3. Action(s) Taken 
Action taken may consist of the following: 
Not applicable 
Determination of a value is not relevant in the current context. 
Unknown 
Not known, not observed, not recorded, or refused. 
Other action taken 
Specify other action taken. 
9.2.2.4. Outcome at the Time of Last Observation 
The outcome at the time of last observation wi 11 be classified as: 
• Recovered/reso I ved 
• Recovered/resolved with sequelae 
• Recovering/resolving 
• Not recovered/not resolved 
• Fatal* 
• Unknown 
*Only select fatal as an outcome when the AE results in death. If more than I AE is judged to be 
possibly related to the patient's death, the outcome of death should be indicated for each such AE. 
Although "fatal" is usually an event outcome, events such as sudden death or unexplained death 
should be reported as SAEs. 
9.2.2.5. Adverse Event Relationship to Study Drug 
The investigator must make an assessment of each AE's relationship to the study drug. The 
categories for classifying the investigator's opinion of the relationship are as follows: 
Not related 
An AE with sufficient evidence to accept that there is no causal relationship 
to study drug administration (e.g., no temporal relationship to drug 
administration, because the drug was administered after onset of event; 
investigation shows that the drug was not administered; another cause was 
proven.) 
Unlikely 
related 
Possibly related 
An AE, including laboratory test abnormality, with a temporal relationship to 
study drug administration that makes a causal relationship improbable, and in 
which other drugs, events, or underlying disease provide plausible 
explanations. 
An AE with a reasonable time sequence to administration of the study drug, 
but that could also be explained by concurrent disease or other drugs or events. 
Information on drug withdrawal may be lacking or unclear. 
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Probably 
related 
An AE with evidence to suggest a causal relationship, and the influence of 
other factors is unlikely. The clinical event, including an abnormal laboratory 
test result, occurs within a reasonable time after administration of the study 
intervention, is unlikely to be attributed to concurrent disease or other drugs 
or chemicals, and follows a clinically reasonable response on withdrawal 
(de-challenge). Re-challenge information is not required to fulfill this 
definition. 
Definitely 
related 
An AE occurring in a plausible time relationship to study drug administration 
and that cannot be explained by a concurrent disease or other drugs or events. 
The response to withdrawal of the drug (de-challenge) is clinically reasonable. 
9.2.3. Documentation 
All AEs that occur within the period of AE follow-up for the study must be documented in the 
eCRF with the fol lowing information, where appropriate. (The AE follow-up period for the study 
is described in Section 9.2.) 
• 
AE name or term 
• 
When the AE first occurred (start date and time) 
• 
When the AE stopped (stop date and time or an indication of "ongoing'") 
• 
Severity of the AE 
• 
Seriousness (hospitalization, death, etc.) 
• 
Actions taken 
• 
Outcome 
• 
Investigator opinion regarding the AE relationship to the study drug(s) 
• 
Whether it is an AE of special interest (AES!) and whether it is an AE which is a potential 
symptom or sign of adrenal insufficiency (AEAI) (see Section 9.3.1) 
9.2.4. Treatment of Adverse Events 
Adverse events that occur during the study will be treated, if necessary, by established standards 
of care. The decision about whether the patient may continue in the study will be made by the 
sponsor after consultation with the investigator and/or medical monitor. 
If AEs occur in a patient that are not tolerable, the investigator must decide whether to stop the 
patient's involvement in the study and/or treat the patient. Special procedures may be 
recommended for the specific study drug, such as the collection of a serum sample for determining 
blood concentrations of study drug, specific tapering procedures, or treatment regimens, as 
appropriate. 
For double- or triple-blinded studies, it is not necessary to unblind a patient's treatment assignment 
in most circumstances, even if an SAE has occurred. If unblinding is necessary, see Section 7.7 
for a description of the unblinding procedures. 
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9.2.5. Reporting 
9.2.5.1. Serious Adverse Events 
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Any SAE must be reported by the investigator if it occurs during the clinical study or within 
30 days of receiving the study drug, whether or not the SAE is considered to be related to the 
investigational product. A copy of SAE forms and supporting documents must be emailed within 
24 hours to the attention of the safety officer at: 
At the time of first notification, the investigator or designee should provide the following 
information, if available: 
• 
Protocol number 
• 
Repo1ter (study site and investigator) 
• 
Patient's study number 
• 
Patient' s year of birth 
• 
Patient' s gender 
• 
Date of first dose of study drug( s) 
• 
Date of last dose of study drug(s), if applicable 
• 
Adverse event term 
• 
Date of occurrence of the event 
• 
A brief description of the event, outcome to date, and any actions taken 
• 
The seriousness criteria( on) that were met 
• 
Concomitant medication at onset of the event 
• 
Relevant medical history information 
• 
Relevant laboratory test findings 
• 
Investigator's opinion of the relationship to study drug(s) ("Is there a reasonable possibility 
that the study drug caused the SAE? Yes or No?") 
• 
Whether and when the investigator was unblinded as to the patient's treatment assignment 
Any missing or additional relevant follow-up information concerning the SAE should be sent to 
the sponsor/sponsor representative via the same contact details above as soon as possible on a 
follow-up SAE Report Form, together with the following minimal information (initial report, AE, 
date of occurrence, patient identification, study identification, study drug, and site number); this 
will allow the follow-up information to be linked to the initial SAE report. 
Specific information may be requested by 
via email communication. 
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The investigator is required to comply with applicable regulations (including local laws and 
guidance) regarding the notification of his or her health authorities, institutional review board 
(IRB)/independent ethics committee (IEC), principal and coordinating investigators, study 
investigators, and institutions. Each investigator is obligated to learn about the reporting 
requirements for investigators in his or her country. The study monitor may be able to assist with 
this. 
9.3. Special Considerations 
9.3.1. Adverse Events of Special Interest 
and patients should be 
closely monitored should these AEs occur. 
These events will be followed closely during the study and considered AESis. 
9.3.1.1. Potential for Adrenal Suppression 
Transient cortisol reduction is a well described physiologic response in patients who receive IA 
cortisol injections and should not necessarily be considered an AE. Laboratory evidence of adrenal 
insufficiency should be assessed in conjunction with clinical signs and symptoms. 
Patients and investigators will be educated about symptoms of adrenal insufficiency, and an 
assessment of clinical signs and symptoms indicating potential adrenal insufficiency will be 
performed as part of AE evaluation at every visit or contact. 
Patients will be provided a wallet card identifying the potential risk for adrenal insufficiency and 
asked to carry it at all times. This card should include the patient's identifying information, contact 
information for the investigator, and should note the potential need for emergency glucocorticoid 
therapy in the setting of shock, surgery, etc. 
Morning serum cortisol as measured by the central laboratory will be blinded to the patient, site 
staff, and blinded study team members (except Screening, Day I [pre-dose], and Week 20); results 
will be reviewed by a separate unblinded medical monitor. 
If there is clinical evidence of adrenal insufficiency that may compromise the patient's safety , the 
investigator should use a local laboratory to obtain a cortisol level or 
and/or refer the patient to his or her primary care physician or to an endocrinologist. The 
investigator may also contact the blinded medical monitor to discuss the patient's case and request 
review of prior cortisol values. 
The unblinded medical monitor will monitor all serum cortisol values. If sustained cortisol 
suppression is observed beyond 4 weeks following an injection, or any other cortisol values are 
seen that might appear to compromise patient safety, the unblinded medical monitor may contact 
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the investigator to review the patient's condition including any potential signs or symptoms of 
adrenal insufficiency and discuss potential follow-up laboratory testing. 
9.3.2. Pregnancy 
All women of childbearing potential who participate in the study should be counseled on the need 
to practice adequate birth control and on the importance of avoiding pregnancy during study 
participation. 
Women of childbearing potential must use a highly effective method of birth control unti I at least 
6 months after the last dose of study drug. Acceptable and effective methods of birth control for 
this study include: 
• 
Absolute sexual abstinence (no sexual intercourse or genital contact with a male partner) 
• 
Monogamous partner who is vasectomized 
• 
Use of double-barrier contraception 
• 
Use of an approved insertable, injectable, transdermal, or combination oral contraceptive for 
greater than 2 months prior to Screening. 
Pregnancy testing will be conducted before administration of the study drug on every woman of 
childbearing potential. A woman who is found to be pregnant at Screening will be excluded from 
the study and considered to be a screening failure. 
After participation in the study, women should be asked to contact the investigator or study staff 
immediately if pregnancy occurs or is suspected. The investigator is responsible for following the 
pregnancy until delivery or termination. 
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10. DATA SAFETY MONITORING BOARD 
A data safety monitoring board will not be used in this study. 
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11. STA TIS TI CS 
11.1. Study Endpoints 
11.1.1. Efficacy Endpoints 
11.1.1.1.Primary Efficacy Endpoint 
The primary efficacy endpoint is: 
Confidential 
• 
Change from Baseline in WOMAC Pain at Week 12 (Group A vs. Group C) 
11.1.1.2. Secondary Efficacy Endpoints 
The following key secondary efficacy endpoints will be evaluated in a hierarchical sequence: 
I. Change from Baseline in WOMAC Pain at Week 16 (Group A vs. Group C) 
2. Change from Baseline in WOMAC Pain at Week 20 (Group A vs. Group C) 
3. Change from Baseline in WOMAC Pain at Week 24 (Group A vs. Group C) 
4. Change from Baseline in WOMAC Pain at Week 36 (Group A vs. Group C) 
5. Change from Baseline in WOMAC Function at Week 12 (Group A vs. Group C) 
6. PGIC at Week 12 (Group A vs. Group C) 
7. Total rescue acetaminophen consumption through Week 12 (Group A vs. Group C) 
8. Durable responder with ::::30% decrease in WOMAC Pain from Baseline for Weeks 4 
through 12 (Group A vs. Group C) 
9. Change from Baseline in WOMAC Function at Week 36 (Group A vs. Group C) 
10. PGIC at Week 36 (Group A vs. Group C) 
11 . Change from Baseline in WOMAC Pain at Week 12 (Group A vs. Group B) 
12. Change from Baseline in WOMAC Pain at Week 52 (Group A vs. Group C) 
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11.1.2. Additional Endpoints 
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• 
Absolute value, change, and percent change from Injection 1 Baseline at each week in average 
daily pain in the index knee 
• 
Total and average daily consumption of rescue acetaminophen by week 
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11.2. Analysis Populations 
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The following analysis populations are planned for this study: 
Safety Population (SAF): The Safety Population includes all patients who receive any dose of 
study drug; the population will be determined for each study period. Injection 1 Period reporting 
will require that Injection 1 has been received; Injection 2 Period reporting will require that 
Injection 2 has been received. The SAF population will be the primary population for safety 
evaluation. 
Full Analysis Set (FAS): The FAS includes al I randomized patients who receive Injection 1. The 
FAS population will be the primary population for efficacy analysis, as well as for descriptive 
summaries other than safety (demographic and baseline, disposition, protocol deviation, medical 
history, etc.). 
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Per Protocol Population (PP): The PP Population includes all patients who receive 2 doses of 
study drug, have primary efficacy evaluation at Weeks 12, 24, and 36, and do not have important 
protocol deviations affecting primary efficacy evaluation. 
Modified Per Protocol (mPP): The mPP Population includes all patients who receive the first 
dose of study drug, have primary efficacy evaluation at Weeks 12 and 24, and do not have 
important protocol deviations affecting primary efficacy evaluation. 
The PP and mPP populations will be used for supportive analysis of selected efficacy endpoints. 
For the PP population, patients must have a valid WOMAC Pain assessment at Baseline, Week 12, 
Week 24, and Week 36; for the mPP population, patients must have a valid WOMAC Pain 
assessment at Baseline, Week 12, and Week 24. (A valid assessment is within the analysis visit 
window and not excluded due to an intercurrent event as described in Section I I .3 .3. I). 
Important protocol deviations are determined in accordance with the protocol deviation guidance 
plan. Membership in the PP and mPP analysis populations will be determined after blinded data 
review of important protocol deviations affecting primary efficacy evaluation before database lock 
and study unblinding. 
If a patient is randomized incorrectly or is administered the incorrect study drug, analyses of the 
FAS population will be based on the assigned treatment, whereas analyses of all other populations 
will be based on the actual treatment received. 
11.3. Statistical Analyses 
This section presents a summary of the planned statistical analyses. A statistical analysis plan 
(SAP) that describes the details of the analyses to be conducted will be written before database 
lock. 
Unless otherwise indicated, all testing of statistical significance will be 2-sided, and a difference 
resulting in a P value of :S 0.05 will be considered statistically significant. All other P values from 
key secondary endpoints, after a non-significant P value is reached as well as other additional 
endpoints, will be considered exploratory. 
Summary statistics will be provided for the variables described in the following subsections. 
Continuous variable summaries will include the number of patients, mean, standard deviation 
(SD), first quartile, median, third quartile, minimum, and maximum. Categorical variables will 
include the frequency and percentage of patients in each category. 
11.3.1. Study Patients and Demographics 
11.3.1.1.Disposition and Withdrawals 
The numbers of patients screened, failed screening, randomized, receiving Injection I or 2, 
completing, and withdrawing, along with reasons for withdrawal and timing of withdrawal, will 
be tabulated overall and by treatment group. Reasons for not receiving Injection 2 will also be 
tabulated. The number of patients in each analysis population will be reported. 
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11.3.1.2.Protocol Deviations 
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Protocol deviations will be identified and important deviations will be classified before unblinding 
and will be summarized or listed as appropriate. Important protocol deviations affecting primary 
efficacy evaluation will be used to assess patient inclusion into PP and mPP populations. 
11.3.1.3.Demographics and Other Baseline Characteristics 
These analyses will be conducted for all analysis populations. 
Demographic variables will include age, sex, race, weight, BMI, and region. Baseline patient 
characteristics will include medical history, including confirmation of OA diagnosis and time since 
diagnosis, Kellgren-Lawrence Grade, normalized WOMAC scores, and average daily pain. 
11.3.2. Exposure and Compliance 
All patients will receive up to 2 study drug injections at the study site under the surveillance of 
appropriate study personnel and, therefore, no compliance will be calculated. Injection procedure 
details and study drug batch or lot number(s) will be recorded in the patient's EDC system and 
summarized or I isted as appropriate. 
11.3.3. Efficacy Analysis 
Efficacy variables will be summarized by treatment group and by injection period within each 
group using the FAS population, unless otherwise specified. For all the continuous variables, the 
normalized numbers will be used for analysis, where applicable, unless otherwise specified. 
The overall type J error rate will be controlled for primary and key secondary endpoints using 
hierarchical testing, based on a fixed-sequence procedure. 
lf statistical significance is declared for the primary analysis, formal statistical inference w ill 
continue at the 0.05 level for the secondary endpoints in the defined sequence until a non-
significant result is reached. All other P values from key secondary endpoints, after a non-
significant P value is reached, as well as other additional endpoints, will be considered exploratory. 
11.3.3.1.Primary Analysis 
The primary efficacy analysis and estimation of the primary estimand will be based on the FAS 
population, the mPP population, and the PP population. 
The primary estimand is the difference in mean change from Baseline in WOMAC Pain score at 
Week 12 between TLC599 vs. Placebo (as defined in the Treatment Assignment Table in 
Section 7.2). T he endpoint and intercurrent events for the primary estimand are defined as fo llows: 
• Endpoint: Change from Baseline in WOMAC Pain score at Week 12 
• Intercurrent Events: 
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An ANCOV A will be performed with treatment group as a fixed effect and Baseline WOMAC 
Pain score as a covariate. Multiple imputation will be used to impute missing intermittent and 
post-withdrawal WOMAC Pain scores considered to be missing at random. Post-withdrawal 
missing data due to lack of efficacy, AE, or surgical procedure/IA drug administration in the index 
knee will be assumed to be MNAR; all other missing and post-withdrawal data will be assumed to 
be MAR. 
The ANCOVA model will be 
conducted on each imputation and the results will be combined using Rubin's rules in SAS PROC 
MIANALYZE. 
The least-squares mean comparing TLC599 to Placebo along with the corresponding 95% 
confidence interval, will be used to estimate the treatment difference. 
Sensitivity analyses will be conducted to estimate sensitivity estimators and to assess the 
robustness of efficacy results, including: 
• 
A sensitivity analysis using a tipping point procedure to assess the robustness of the multiple 
imputation results. 
• 
A mixed-effects model repeated measures (MMRM) approach will be used as a sensitivity 
analysis for the primary endpoint. Treatment group, study visit (as a categorical variable) and 
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site will be modeled as fixed effects, with a treatment-by-visit interaction and baseline 
WOMAC Pain score as a covariate. Patient will be included as a random effect. Prior to 
implementing the model, MNAR data due to intercurrent events will be imputed using BOCF 
and non-missing data affected by the use of intercurrent medications and procedures will be 
replaced using BOCF, as described for the primary analysis method. The MMRM will 
include both observed and BOCF imputed data. 
If further sensitivity analysis on the primary endpoint is performed, it will be described in the SAP. 
Descriptive summaries (such as mean, standard error, first quartile, median, third quartile, 
minimum, and maximum) will also be provided for the primary endpoint. 
11.3.3.2. Secondary Analyses 
Continuous secondary endpoints will be analyzed using the same methodology as for the primary 
endpoint, unless otherwise indicated. 
For analysis of categorical secondary endpoints, the difference in the predictive marginal proportions 
will be the basis of comparison between treatment groups. 
The corresponding 95~Cf and P value will also be 
presented. 
11.3.3.3.Exploratory Analyses 
For additional endpoints derived using the baseline prior to Injection 1, descriptive statistics for 
each variable will be presented for each visit until the end of study and summarized by treatment 
group and by injection period within each group. For additional endpoints derived using the 
baseline prior to Injection 2, descriptive statistics for each variable will be presented by treatment 
group. Efficacy endpoints relative to Injection 2 baseline will only be analyzed for patients who 
receive Injection 2. 
The analysis of all continuous additional endpoints will be performed using an AN COY A model 
as described for the single-dose primary endpoint. 
Categorical exploratory endpoints will be analyzed using the same methodology as the categorical 
secondary endpoints. 
P values from additional endpoints will be considered nominal and no adjustments for 
multiplicity will be made. 
Subgroup analyses of the primary and secondary endpoints will be performed by age (<65 or 2:65 
years), sex, race (Caucasian or non-Caucasian), and Kellgren-Lawrence grade (2 or 3). Further 
details will be provided in the SAP. 
Mean value, mean change, and percent change from baseline in WOMAC Pain and weekly 
average daily pain will be plotted over time. 
A cumulative distribution plot of percent change in WOMAC Pain by treatment group will be 
produced for each time point from Injection I Baseline through Week 52 Patients who 
discontinue treatment are defined as non-responders with 0% improvement (no change from 
Baseline). 
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11.3.4. Safety and Tolerability Analyses 
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Safety analyses will be conducted using data from the SAF population (as defined in Section 11.2). 
Safety variables include physical examination, vital signs assessments (heart rate, respiratory rate, 
sitting blood pressure, and temperature), clinical laboratory assessments (hematology, chemistry, 
urinalysis), HbA le, morning serum cortisol, 
12-lead electrocardiogram 
(ECG), knee radiographs, concomitant medications/therapies, AEs, and signs and symptoms of 
adrenal insufficiency. Medical history and AEs will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA), and concomitant medication will be coded using the World 
Health Organization Drug (WHODrug) Global Dictionary. 
The safety data will be descriptively summarized by treatment group within each injection period. 
The safety profile following the first and second injections will be evaluated through the 
examination of the following comparisons: 
I. Group A versus Group B for safety data collected fo llowing Injection 2. 
2. Safety data in Group A, collected following Injection I versus Injection 2. 
Continuous safety data will be summarized by visit and include changes from baseline (Injection 
I and/or Injection 2 Baseline). Continuous data will also be converted to categorical values where 
possible (i.e., below, within, and above normal ranges) and summarized in shift from baseline 
tables. Categorical safety data collected by visit will be summarized showing the counts and 
percentages in each category at each visit, as well as shifts from baseline as appropriate. 
11.3.4.1.Adverse Events 
The Medical Dictionary for Regulatory Activities terminology will be used to classify all AEs with 
respect to system organ class (SOC) and PT. 
Treatment-emergent AEs are defined as AEs with onset at the time of or following the start of 
treatment with study drug through EOS or ET, whichever occurs first. 
The number and percentage of patients with A Es wi ll be displayed for each treatment group by 
SOC and PT. Summaries of AEs by severity and relationship to study drug will also be provided. 
Serious AEs and AEs resulting in discontinuation of study drug will be summarized separately in 
a similar manner. Patient listings of AEs, SAEs and AEs causing discontinuation of study drug 
will be produced. 
11.3.4.2. Clinical Laboratory Evaluations 
Descriptive summaries (mean, SD, first quartile, median, third quartile, minimum, and maximum) 
of actual (absolute) values and changes from Baseline values and GeoMean percentage change (if 
appropriate) will be presented for clinical laboratory values by treatment group and time point. 
The number of patients with clinical laboratory values categorized as below, within, or above 
normal ranges will be tabulated showing change from Baseline (shift tables) for each clinical 
laboratory analyte by treatment group and by time point. Pre- and post-treatment values will also 
be presented with analysis summary of mean changes from Baseline. 
Laboratory values that are outside the normal range will also be flagged in the data listings, along 
with the corresponding normal ranges. 
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11.3.4.3. Vital Signs 
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Vital sign parameters will be summarized using descriptive statistics at Baseline and at each 
post-Baseline time point. Vital signs will be tabulated showing change from Baseline (shift tables) 
for each parameter by treatment group and by time point. Pre- and post-treatment values may also 
be presented with a summary of mean changes from Baseline. 
11.3.4.4. Twelve-lead Electrocardiograms 
The number and percentage of patients with normal and abnormal ECG findings will be 
summarized by treatment group and time point. Summary statistics will be displayed by treatment 
group for QT and QT interval corrected for heart rate (QTc) calculated using Bazett's and 
Fridericia · s QT correction methods. 
Descriptive summaries (mean, SD, first quartile, median, third quartile, minimum, and maximum) 
will be presented for ECG measures of PR interval, QRS interval, QT interval, QTc interval (both 
correction methods), and heart rate by treatment group and time point. 
11.3.4.5. Physical Examination Findings 
The number and percentage of patients with normal and abnormal findings in the complete 
physical examination will be displayed by each treatment group. 
11.3.4.6.Knee Radiographs 
The change in joint space width from baseline will be summarized descriptively. The number of 
patients with presence of subchondral bone changes or osteonecrosis/insufficiency fracture wi II be 
summarized. 
11.3.4.7. Concomitant Medications 
The number and percentage of patients with incidence of concomitant medications (other than 
acetaminophen) used as a rescue medication as determined by an indication for index knee pain 
will be summarized by treatment group. 
11.3.5. Interim Analysis 
An interim analysis will not be performed. 
11.4. Sample Size Determination 
This is a 3-arm parallel-group randomized controlled study. Approximately 500 patients will be 
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According to these assumptions, 500 patients will be randomly assigned in a 2: I: I ratio to ensure 
that the study is well powered for primary and key secondary endpoints to be tested via the 
fixed-sequence testing method. 
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12. STUDY CONDUCT 
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Steps to ensure the accuracy and reliability of data include the selection of qualified investigators 
and appropriate study sites, review of protocol procedures with the investigator and associated 
personnel before the study, periodic monitoring visits, and meticulous data management. 
12.1. Sponsor and Investigator Responsibilities 
12.1.1. Sponsor Responsibilities 
The sponsor is obligated to conduct the study in accordance with strict ethical principles 
(Section 14). 
Taiwan Liposome Company, Ltd. agrees to provide the investigator with sufficient material and 
support to permit the investigator to conduct the study according to the study protocol. 
12.1.2. Investigator Responsibilities 
By signing the Investigator's Agreement (Section 16.1 ), the investigator indicates that he or she 
has read the protocol carefully, fully understands the requirements, and agrees to conduct the study 
in accordance with the procedures and requirements described in this protocol. 
The trial will be conducted in accordance with International Council for Harmonisation of 
Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Good Clinical 
Practice (GCP) and applicable US Code of Federal Regulations (CFR). The Principal Investigator 
will assure that no deviation from, or changes to, the protocol will take place without prior 
agreement from the IND sponsor, and funding agency; and documented approval from the 
IRB/IEC, except where necessary to eliminate an immediate hazard(s) to trial participants. All 
personnel involved in the conduct of this study have completed Human Subjects Protection and 
JCH GCP training. 
Investigators should ensure that all persons who are delegated study-related responsibilities are 
adequately qualified and info1med about the protocol, the study drug(s), and their specific duties 
within the context of the study. Investigators are responsible for providing TLC with 
documentation of the qualifications, GCP training, and research experience for themselves and 
their staff as required by the sponsor and the relevant governing authorities. 
To ensure compliance with the guidelines, the study may be audited by an independent person. 
The investigator agrees, by written consent to this protocol, to cooperate fully with compliance 
checks by allowing access to all study documentation by authorized individuals. 
12.1.3. Confidentiality and Privacy 
Participant confidentiality and privacy is strictly held in trust by participating investigators, their 
staff, and the sponsor. This confidentiality is extended to cover testing of biological samples, in 
addition to clinical information relating to participants. Therefore, the study protocol, 
documentation, data, and all other information generated will be held in strict confidence. No 
information concerning the study or the data will be released to any unauthorized third party 
without prior written approval of the sponsor. 
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the sponsor, representatives of the I RB/I EC, 
regulatory agencies, or pharmaceutical company supplying study drug may inspect all documents 
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and records required to be maintained by the investigator, including, but not limited to, medical 
records (office, clinic, or hospital) and pharmacy records for participants in this study. The clinical 
study site will permit access to such records. 
The study participant's contact information will be stored securely at each clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure location 
for as long a period as dictated by the reviewing IRB/IEC, institutional policies, or sponsor 
requirements. 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, 
will be transmitted to and stored a-
. This will not include the participant's contact 
or identifying information. Rather, individual participants and their research data will be identified 
by a unique study identification number. The study data entry and study management systems used 
by clinical sites and by 
staff will be secured and password-protected. At the end 
of the study, all study databases will be de-identified and archived at 
12.2. Site Initiation 
Study personnel may not screen or enroll patients into the study until receiving notification from 
the sponsor or designee that the study can be initiated at the study site. The study site will not be 
authorized for study initiation until: 
I. The study site has received the appropriate IRB/IEC approval for the protocol and the 
appropriate ICF. 
2. All regulatory/GCP documents have been submitted to and approved by the sponsor or its 
designee. 
3. The study site has a Clinical Trial Agreement in place. 
4. Study site personnel, including the investigator, have participated in a study initiation 
meeting or received proper training for the study. 
12.3. Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to the study intervention. 
Patients who fail inclusion and/or exclusion criteria may be rescreened for the study with approval 
of the medical monitor. Also, patients may only be rescreened once. Individuals who do not meet 
the criteria for participation in this study (screen failure) because of a laboratory test finding or 
insufficient washout of previously adm inistered prohibited medications or mild infectious illness 
present at Screening or Baseline may be rescreened following confirmation with the medical 
monitor. 
Patients who initially do not meet any of the fo llowing inclusion/exclusion criteria may not be 
rescreened: 
• 
Patients who fail to meet screening morning serum cortisol (cortisol value <5 µg/dL) 
• 
• 
Patients who do not meet X-ray Kellgren-Lawrence grade criteria 
• 
Patients who do not meet criteria related to knee pain 
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For rescreening, a repeat X-ray is not needed if one was completed within 6 months of the rescreen 
date through the Central Imaging Vendor for this study, and as long as the X-ray met eligibility 
requirements and site has received approval from the medical monitor to rescreen. Documented 
diagnosis of OA in the index knee can be completed as part of the initial study screening and does 
not need to be repeated. 
If a patient is eligible to enter the study after having previously failed Screening, the patient will 
be assigned a new patient identification number. 
12.4. Study Documents 
All documentation and material provided by TLC for this study are to be retained in a secure 
location and treated as confidential material. 
12.4.1. Informed Consent 
Consent forms describing in detail the study intervention, study procedures, and risks are given to 
the participant. Written documentation of informed consent is required before sta1ting 
intervention/administering study intervention. 
Consent forms will be IRB/IEC-approved and the participant will be asked to read and review the 
document. The investigator will explain the research study to the participant and answer any 
questions that may arise. A verbal explanation will be provided in terms suited to the participant's 
comprehension of the purposes, procedures, and potential risks of the study and of their rights as 
research participants. Participants will have the opportunity to carefully review the written consent 
form and ask questions before signing. The participant will sign the informed consent document 
before any procedures being done specifically for the study. 
12.4.2. Case Report Forms 
By signing the Investigator's Agreement (Section 16.1 ), the investigator agrees to maintain 
accurate eCRFs and source documentation as part of the case histories for all patients who sign an 
!CF. 
Case report forms are considered confidential documents and should be handled and stored 
accordingly. The sponsor or its designee will provide the necessary training on the use of the 
specific eCRF system used during the study to ensure that the study information is captured 
accurately and appropriately. 
To ensure data accuracy, eCRF data for individual patient visits should be completed as soon as 
possible after the visit. All requested information must be entered in the eCRF/EDC system 
according to the completion guidelines provided by the sponsor or its designee. 
The eCRFs must be signed by the investigator or a sub-investigator. These signatures serve to 
attest that the information contained in the eCRF is accurate and true. 
12.4.3. Source Documents 
Information recorded in the eCRF/EDC system should be supported by corresponding source 
documentation. Examples of acceptable source documentation include, but are not limited to, 
hospital records, clinic and office charts, laboratory notes, and recorded data from automated 
instruments, memoranda, and pharmacy dispensing records. 
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Clinical laboratory data required by the protocol will be transferred electronically from the central 
laboratory to the sponsor or designee. A paper copy of laboratory results will be provided to the 
study site and should be retained with each patient's source data. 
12.5. Data Quality Control 
TLC and its designees will perform quality control checks on this clinical study. 
12.5.1. Monitoring Procedures 
TLC and/or its designee will conduct site visits to monitor the study and ensure compliance with 
the protocol, GCP, and applicable regulations and guidelines. The assigned clinical research 
associate(s) (CRA[s]) will visit the investigator and study site at periodic intervals and maintain 
periodic communication. The investigator agrees to allow the CRA(s) and other authorized TLC 
personnel access. The CRA(s) will maintain current personal knowledge of the study through 
observation, review of study records and source documentation, and discussion of the conduct of 
the study with the investigator and staff. While on site, the CRA(s) will review the following: 
• 
Regulatory documents, directly comparing entries in the eCRF/EDC system with the source 
documents 
• 
Consenting procedures 
• 
AE procedures 
• 
Storage and unblinded monitoring for accountability of study drug and study materials 
T he CRA will ask for clarification and/or correction of any noted inconsistencies. Procedures for 
correcting eCRF are described in the study manual. As representatives of the sponsor, CRAs are 
responsible for notifying project management of any noted protocol deviations. 
By signing the Investigator' s Agreement (Section 16.1 ), the investigator agrees to meet with the 
CRA(s) during study site visits; to ensure that study staff is available to the CRA(s) as needed; to 
provide the CRA(s) access to all study documentation, to the clinical supplies dispensing and 
storage area; and to assist the monitors in their activities, if requested. Further, the investigator 
agrees to allow TLC or designee auditors or inspectors from regulatory agencies to review records 
and to assist the inspectors in their duties, if requested. 
12.5.2. Data Management 
TLC or designee will be responsible for activities associated with the data management of this 
study. The standard procedures for handling and processing records will be followed per GCP and 
standard operating procedures. A comprehensive data management plan w ill 
be developed, including a data management overview, description of database contents, annotated 
eCRF, pre-entry review list, self-ev ident correction conventions, query contacts, and consistency 
checks. 
Study site personnel will be responsible for providing resolutions to all data queries. The 
investigator will be required to document electronic data review to ensure the accuracy of the 
corrected and/or clarified data. Procedures for soliciting and documenting resolution to data 
queries are described in the study manual. 
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12.5.3. Quality Assurance/Audit 
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This study will be subject to audit by TLC or its designee. Audits may be performed to check 
compliance with GCP guidelines and can include: 
• 
Site audits 
• 
Trial Master File audits 
• 
Database audits 
• 
Document audits (e.g., protocol and/or clinical study report [CSR]) 
TLC or its designee may conduct additional audits on a selection of study sites, requiring access 
to patient notes, study documentation, and facilities or laboratories used for the study. 
The study site, facilities, all data (including source data), and documentation will be made available 
for audit by quality assurance auditors and for IRB/IEC or regulatory authorities according to GCP 
guidelines. The investigator agrees to cooperate with the auditor during the visit and will be 
available to supply the auditor with eCRFs or other files necessary to conduct that audit. Any 
findings will be strictly confidential. 
If a regulatory authority informs the investigator that it intends to conduct an inspection, the 
investigator shall notify TLC immediately. 
12.6. Study Termination 
The study may be terminated at the discretion of TLC at any time and for any reason. 
The end of this study is defined as the date of the last visit of the last patient (last patient out or 
last patient last visit) participating in the study. Within 90 days of the end of the clinical study, 
TLC or designee will notify the IRBs/IECs and regulatory authorities about the regular term ination 
of the study as required according to national laws and regulations. 
12.6.1. Premature Study Termination 
The study may be suspended temporarily or terminated prematurely is there is sufficient reasonable 
cause at any time by TLC, IRBs/IECs, regulatory authorities, respective steering committees, or 
the coordinating investigator. A decision to prematurely terminate the study is binding to all 
investigators of all study sites. 
Within 15 days of premature termination of a clinical study, TLC or its designee will notify the 
lRBs/IECs and regulatory authorities about the premature termination as required according to 
national laws and regulations. TLC or its designee must clearly explain the reasons for premature 
termination. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping 
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met 
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If the study is terminated prematurely, all investigators must inform their patients and take 
appropriate follow-up measures to ensure protection of the patients' interests. Study sites may be 
asked to have all patients currently participating in the study complete all of the assessments for 
the ET visit. 
12.7. Study Site Closure 
At the end of the study, all study sites will be closed. TLC may terminate participation of a study 
site at any time. Examples of conditions that may require premature termination of a study site 
include, but are not limited to, the following: 
• 
Non-compliance with the protocol and/or applicable regulations and guidelines 
• 
Inadequate patient enrollment 
12.7.1. Record Retention 
After completing the study, TLC will receive the original eCRFs or at least a legible copy and 
retain the documents for at least 5 years after the completion of the study. 
One copy will remain with the investigator. The investigator shall arrange for the retention of the 
patient identification codes, patient files and other source data unti I at least 5 years after the last 
approval of a marketing application in an lCH region and until there are no pending or 
contemplated marketing applications in an ICH region, or until at least 2 years have elapsed since 
the formal discontinuation of the clinical development of the product. These documents need to be 
retained for a longer period of time ifrequired by applicable regulatory authorities or by agreement 
with the sponsor. 
At the end of such period, the investigator shall notify the sponsor in writing of his or her intent to 
destroy all such material. The sponsor shall have 30 days to respond to the investigator' s notice, 
and the sponsor shall have a further opportunity to retain such materials at the sponsor's expense. 
Copies of these study records (and all study-related documents, including source data) shall be 
kept by the investigator for the maximum period of time permitted by the hospital, institution, or 
private practice. 
12.8. Changes to the Protocol 
This protocol cannot be altered or changed except through a formal protocol amendment, which 
requires the written approval of TLC. The protocol amendment must be signed by the investigator 
and approved by the IRB or !EC before it may be implemented. Protocol amendments will be filed 
with the appropriate regulatory agency(s) having jurisdiction over the conduct of the study. 
12.9. Use oflnformation and Publication 
All 
information concerning TLC599, TLC's operations, 
patent applications, formula, 
manufacturing processes, basic scientific data, and formulation information supplied by T LC or 
designee to the investigator, and not previously published, is considered confidential and remains 
the sole property of TLC. Case report forms also remain the property of TLC. The investigator 
agrees to use this information for purposes of study execution through finalization and will not use 
it for other purposes without the written consent of the sponsor. 
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The information developed in this study will be used by TLC in connection with the continued 
development of TLC599 and thus may be disclosed as required to other clinical investigators or 
government regulatory agencies. 
The information generated by this study is the property of TLC. Publication or other public 
presentation of TLC599 data resulting from this study requires prior review and written approval 
of TLC. Abstracts, manuscripts, and presentation materials should be provided to TLC for review 
and approval at least 30 days before the relevant submission deadline. Data from individual study 
sites must not be published separately. 
It is agreed that the results of the study will not be submitted for presentation, abstract, poster 
exhibition, or publication by the investigator until TLC has reviewed and commented on such a 
presentation or manuscript for publication. lf applicable, this study will be registered at 
ClinicalTrials.gov, and results information from this study will be submitted to ClinicalTrials.gov. 
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13. FINAL CLINICAL STUDY REPORT 
TLC will retain ownership of the data. 
The final CSR may be submitted to the regulatory authorities. 
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14. ETHICAL AND LEGAL CONSIDERATIONS 
14.1. Declaration of Helsinki and Good Clinical Practice 
This study will be conducted in compliance with the April 1996 ICH Guidance for Industry GCP 
E6 (including archiving of essential study documents), the Integrated Addendum to !CH E6 (R2) 
of November 2016, the Declaration of Helsinki, the applicable regulations of the countries in 
which the study is conducted, and with the Commission Directives 2001 /20/Ethics Committee 
(EC) and 2005/28/EC. 
14.2. Patient Information and Informed Consent and/or Assent 
A properly constituted, valid IRB/IEC must review and approve the protocol, the investigator's 
!CF, and related patient information and recruitment materials before the start of the study. 
It is the responsibility of the investigator to ensure that written informed consent is obtained from 
the patient before any activity or procedure is undertaken that is not part of routine care. 
14.3. Approval by Institutional Review Board and Independent Ethics Committee 
A valid IRB/IEC must review and approve this protocol before study initiation. Written 
notification of approval is to be provided by the investigator to the sponsor's monitor before 
shipment of study drug supplies and will include the date of the committee's approval and the 
chairperson's signature. This written approval must consist of a completed I RB/I EC approval form 
containing the same information. 
Until the investigator has received written approval by the IRB/IEC, no patient may undergo any 
procedure not part of routine care for the patient's condition. 
Protocol amendments must also be reviewed and approved by the IRB/IEC. Written approval from 
the IRB/IEC, or a designee, must be received by TLC before implementation. This written 
approval will consist of a completed I RB/IEC approval form containing the same information. 
14.4. Finance and Insurance 
Details on finance and insurance will be provided in a separate agreement between the investigator 
and the sponsor. 
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15. REFERENCES 
Confidential 
1. JUni P, Hari R, Rutjes AW, Fischer R, Silletta MG, Reichenbach S, et al. Intra-articular 
corticosteroid for knee osteoarthritis. Cochrane Database Syst Rev. 2015 
Oct 22;(10):CD005328. 
2. Pekarek B, Osher L, Buck S, Bowen M. Intra-articular corticosteroid injections: a critical 
literature review with up-to-date findings. Foot (Edinb). 2011 Jun;21 (2):66-70. 
3. Bellamy N. Pain assessment in osteoarthritis: experience with the WOMAC osteoarthritis 
index. Semin Arthritis Rheum. 1989; 18: 14 17. 
4. Chan AT, Manson JE, Albert CM, et al. Nonsteroidal antiintlammatory drugs, 
acetaminophen, and the risk of cardiovascular events. Circulation. 2006; 113(1 2): 1578 1587. 
5. Bellamy N, Buchanan WW, Goldsmith CH, Campbell J, Stitt L W. Validation study of 
WOMAC: a health status instrument for measuring clinically important patient relevant 
outcomes to anti rheumatic drug therapy in patients with osteoarthritis of the hip or knee. J 
Rheumatol. 1988; 15:1833 1840. 
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16. ATTACHMENTS 
16.1. Investigator's Agreement 
PROTOCOL NUMBER: 
TLC599A3005 
Confidential 
PROTOCOL TITLE: 
A 
Phase 
3, 
Randomized, 
Double-blind, 
Placebo-
and 
Active-controlled Study to Evaluate the Efficacy and Safety of 
TLC599 in Patients with Osteoarthritis of the Knee 
PROTOCOL VERSION: 
Amendment 4, Version 5.0 (09-Mar-2022) 
The undersigned acknowledges possession of and has read the investigator's brochure on the study 
drug and has discussed these data with the study monitor. Having considered fully all the available 
information, the undersigned considers that it is ethically justifiable to give the study drug to 
selected patients in his or her care, according to the study protocol. 
He or she agrees to use the study material, including the study drug, only as specified in the 
protocol. He or she understands that changes cannot be made to the protocol without prior written 
approval of Taiwan Liposome Company, Ltd. 
He or she understands that any deviation from the protocol may lead to early termination of the 
study. 
He or she agrees to report to Taiwan Liposome Company, Ltd. within time any clinical AE or 
abnormal laboratory value that is serious, whether or not considered related to the administration 
of the study drug. 
He or she agrees to comply with Taiwan Liposome Company, Ltd. and regulatory requirements 
for the monitoring and auditing of this study. 
In addition, he or she agrees that the study will be carried out in accordance ICH, the Declaration 
of Helsinki, and the local laws and regulations relevant to the use of new therapeutic agents. 
I, the undersigned, have carefully read this protocol and agree that it contains all the necessary 
information required to conduct the study. 
Principal Investigator: 
Printed Name: 
Signature: 
Date: 
Investigator's name and address (stamp) 
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APPENDICES 
Confidential 
A. American College of Rheumatology (ACR) Classification Criteria for Osteoarthritis of the 
Knee 
8. Kellgren and Lawrence System for Classification of Osteoarthritis of Knee 
C. WOMAC Osteoatthritis Index Version YA3. I 
D. Patient Global Impression of Change (PGIC) Assessment 
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A. American College of Rheumatology Classification Criteria for Osteoarthritis of the Knee 
Adapted from R. Altman, E. Asch, D. Bloch, G. Bole, D. Borenstein, K. Brandt, el al. The American 
College of Rheumatology criteria for the classification and reporting of osteoarthritis of the knee. 
Arthritis Rheum 1986;29:1039-1049. 
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B. Kellgren and Lawrence System for Classification of Osteoarthritis of the Knee 
The Kellgren and Lawrence system is a method of classifying the severity of knee osteoarthritis 
(OA) using 5 grades: 
Grade 0: No radiographic features of OA are present 
Grade I: Doubtful joint space narrowing (JSN) and possible osteophytic lipping 
Grade 2: Definite osteophytes and possible JSN on posteroanterior weight-bearing radiograph 
Grade 3: Multiple osteophytes, definite JSN, sclerosis, possible bony deformity 
Grade 4: Large osteophytes, marked JSN, severe sclerosis and definite bony deformity 
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C. WOMAC Osteoarthritis Index Version V3.1 
INSTR'UCTIONS TO PATIENTS 
In Sections A, B, and C questions are asked in the following format. Please mark 
your answers by putting an " X " in one of the boxes. 
EXAMPLES: 
·1. If you put your " X " in the box on the far left as shown below, 
none 
~ 
mild 
0 
moderate 
0 
severe 
D 
then you are indicating that you feel no pain_ 
extreme 
D 
2_ If you put your " X " in the box on the far right as shown below, 
none 
D 
mild 
0 
moderate 
0 
severe 
D 
then you are indicating that you feel extreme pain_ 
3_ Please note: 
extreme 
~ 
a) tt1at the further to the right you place your" X ", the more pain 
you feel. 
b) that the further to the left you place your " X ", the less pain 
you feel. 
c) please do not place your " X " outside any of the boxes_ 
You w ill be asked to indicate on this type of scale the amount of pain, stiffness 
or disability you have felt during the last 24 hours. 
Think about your 
(study joint) when answering the 
questions_ Indicate the severity of your pain and stiffness and the difficulty you 
have in doing daily activities that you feel are caused by the arthritis in 
your 
{study joint)_ 
Your study joint has been identified for you by your health care professional. 
If you are unsure which joint is your study joint, please ask before completing 
the questionnaire_ 
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Section A 
PAIN 
Think about the pain you felt in your ____ 
(study joint) caused 
by your arthritis during the last 24 hours. 
(Please mark your answers with an " X ".) 
QUESTION: How much pain have you had 
1. when walking on a flat surface? 
none 
mild 
moderate 
0 
0 
0 
2. when going up or down stairs? 
none 
0 
mild 
0 
moderate 
0 
severe 
0 
severe 
0 
extreme 
0 
extreme 
0 
3. at night while in bed? (that is - pain that disturbs your sleep) 
Study Coordinator 
Use Only 
PAIN1 
PAIN2 
none 
mild 
moderate 
severe 
extreme 
PAIN3 
0 
0 
0 
0 
0 
4. while sitting or lying down? 
none 
mild 
0 
0 
5. while standing? 
none 
0 
mild 
0 
Final Version 5.0, 09-Mar-2022 
moderate 
0 
moderate 
0 
severe 
0 
severe 
0 
extreme 
0 
extreme 
0 
PAIN4 
PAIN5 
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Section B 
STIFFNESS 
Think about the stiffness (not pain) you felt in your _____ (study 
joint) caused by the arthritis during the last 24 hours. 
Stiffness is a sensation of decreased ease in moving your joint. 
(Please mark your answers with an • X "_) 
6. 
How severe has your stiffness been after you first woke up 
in the morning? 
none 
D 
mild 
D 
moderate 
D 
severe 
D 
extreme 
D 
7. 
How severe has your stiffness been after sitting or lying down or 
while resting later in the day? 
none 
D 
mild 
D 
Final Vers ion 5.0, 09-Mar-2022 
moderate 
D 
severe 
D 
extreme 
D 
Study Coordinator 
Use Only 
STIFF6 
STIFF? 
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Section C 
DIFFICULTY PERFORMING DAILY ACTIVITIES 
Think about the difficulty you had in doing the following daily physical 
activities caused by the arthritis in your 
(study joint) during 
the last 24 hours. 
By this we mean your abiJity to move around and 
take care of yourself. {Please mark your answers with an · x ".) 
QUESTION: How much difficulty have you had 
8. 
when going down the stairs? 
none 
mild 
moderate 
0 
0 
0 
9. 
when going up the stairs? 
none 
mild 
moderate 
0 
0 
0 
10. when getting up from a sitting position? 
none 
mild 
moderate 
0 
0 
0 
11. while standing? 
none 
mild 
moderate 
0 
0 
0 
12. when bending to the floor? 
none 
mild 
moderate 
0 
0 
0 
13. when walking on a nat surface? 
none 
mild 
moderate 
0 
0 
0 
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severe 
0 
severe 
0 
severe 
0 
severe 
0 
severe 
0 
severe 
0 
extreme 
0 
extreme 
0 
extreme 
0 
extreme 
0 
extreme 
0 
extreme 
0 
Study Coordinator 
Use Only 
PFTN8 
PFTN9 
PFTN10 
PFTN11 
PFTN1 2 
PFTN13 
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DIFFICULTY PERFORMING DAILY ACTIVITIES 
Think about the difficulty you had in doing the following daily physical 
activities caused by the arthritis in your 
(study joint) during 
the last 24 hours. 
By this we mean your ability to move around and 
take care of yourself. (Please mark your answers with an " x ".) 
QUESTION: How much difficulty have you had 
Study Coordinator 
Use Only 
14. getting in or out of a car, or getting on or off a bus? 
none 
mild 
moderate 
severe 
extreme 
PFTN14 
0 
0 
0 
0 
0 
15. while going shopping? 
none 
mild 
moderate 
severe 
extreme 
PFTN15 
0 
0 
0 
0 
0 
16. when putting on your socks or panty hose or stockings? 
none 
mild 
moderate 
severe 
extreme 
PFTN16 
0 
0 
0 
0 
0 
17. when getting out of bed? 
none 
mild 
moderate 
severe 
extreme 
PFTN17 
0 
0 
0 
0 
0 
18. when taking off your socks or panty hose or stockings? 
mild 
moderate 
extreme 
PFTN18 
none 
severe 
0 
0 
0 
0 
0 
19. while lying in bed? 
none 
mild 
moderate 
severe 
extreme 
PFTN19 
0 
0 
0 
0 
0 
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DIFFICULTY PERFORMING DAILY ACTIVITIES 
Think about the difficulty you had in doing the following daily physical 
activities caused by the arthritis in your 
(study joint) during 
the last 24 hours. 
By this we mean your ability to move around and 
take care of yourself. (Please mark your answers with an " x ".) 
QUESTION: How much difficulty have you had 
20. when getting in or out of the bathtub? 
none 
mild 
moderate 
0 
0 
0 
21 . while sitting? 
none 
0 
mild 
0 
moderate 
0 
22. when getting on or off the toilet? 
none 
mild 
moderate 
0 
0 
0 
23. while doing heavy household chores? 
none 
mild 
moderate 
0 
0 
0 
24. while doing light household chores? 
none 
mild 
moderate 
0 
0 
0 
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severe 
0 
severe 
0 
severe 
0 
severe 
0 
severe 
0 
extreme 
0 
extreme 
0 
extreme 
0 
extreme 
0 
extreme 
0 
Study Coordinator 
Use Only 
PFTN20 
PFTN21 
PFTN22 
PFTN23 
PFTN24 
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D. Patient Global Impression of Change (PGIC) Assessment 
Compared to before study treatment, the overall pain from my knee osteoarthritis is: 
(Tick only one response) 
D 1. very much improved 
D 2. much improved 
D 3. minimally improved 
D 4. no change 
D 5. minimally worse 
D 6. much worse 
D 7. very much worse 
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