A Phase IIa, Randomized, Double Blinded, Placebo Controlled, Dose Finding Study for Single Dose Administration of TLC599 in Patients With Osteoarthritis (OA) of Knee
Phase: PHASE2
Conditions: Osteoarthritis of the Knee
Sponsor: Taiwan Liposome Company

Taiwan Liposome Company, Ltd 
Version: 7.0
Protocol Number TLC599A2003
Date: 03 Aug 2018
Clinical Study Protocol
Protocol Title:
A 
Phase 
IIa, 
Randomized, 
Double-blinded, 
Placebo-controlled, Dose-finding Study for Single-dose 
Administration 
of 
TLC599 
in 
Patients 
with 
Osteoarthritis (OA) of Knee
Protocol Number:
TLC599A2003
Date of Protocol/Version No.:
03 Aug 2018 / Version 7.0
Product:
TLC599
Study Phase:
IIa
Sponsor:
Taiwan Liposome Company, Ltd.
11F-1, No. 3, Yuanqu St., Nangang District,
Taipei City, Taiwan 115
Tel: +886 2 2655 7377
Fax: +886 2 2655 7366
Study Representative:
Sheue-Fang Shih, PhD
Taiwan Liposome Company, Ltd.
11F-1, No. 3, Yuanqu St., Nangang District,
Taipei City, Taiwan 115
Tel: +886 2 2655 7377 ext. 302
Fax: +886 2 2655 7366
Medical Monitor:
Dr. Rashna Cama, M.D. 
Senior Medical Director
Head - Immunology and Internal Medicine
TSSU – Medical Sciences, Asia
Quintiles 
Mobile: + 91 9619168365
Office: +91 22 61544240
Confidentiality Statement
This confidential information in this document is provided to you as an Investigator or 
consultant for review by you, your staff, and the applicable Institutional Review 
Board/Independent Ethics Committee.
Your acceptance of this document constitutes 
agreement that you will not disclose the information contained herein to others without 
written authorization from the Sponsor.
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Taiwan Liposome Company, Ltd 
Version: 7.0
Protocol Number TLC599A2003
Date: 03 Aug 2018
SYNOPSIS
Name of Sponsor/Company:
Taiwan Liposome Company, Ltd. (TLC)
Name of Finished Product:
TLC599
Name of Active Ingredient:
Dexamethasone sodium phosphate (DSP)
Title of Study:
A Phase IIa, Randomized, Double-blinded, Placebo-controlled, Dose-finding Study for 
Single-dose Administration of TLC599 in Patients with Osteoarthritis (OA) of Knee
Protocol No:
TLC599A2003 
Study Sites:
Global study, around 8 to 13 sites
Study duration: The study will be conducted for approximately
27 weeks including a 21-day screening period and a 24-week follow-up 
period.
Phase: IIa
Objectives:
Primary:
The primary objective is to evaluate the treatment efficacy of different test doses of TLC599 in patients with 
OA pain of knee.
Secondary:
The secondary objective is to evaluate the safety of different test doses of TLC599 in patients with OA of 
knee.
Pharmacokinetics:
The concentrations of dexamethasone and dexamethasone 21-phosphate in the synovial fluid at the end of 
study (EOS) or early termination (ET).
Methodology: This is a Phase IIa, multi-center, double-blind, prospective, randomized, placebo (normal 
saline)-controlled study, intending to explore the treatment efficacy of 2 different dose levels of TLC599 
compared to the placebo in patients with OA of the knee.
Planned number of patients:
Approximately 24 patients in each of 3 different study groups (a total of 
approximately 72 patients) will participate in the study.
Diagnosis and
main criteria for inclusion:
Main Criteria for inclusion
Before the start of any screening procedure, all patients must have signed 
an informed consent form and be willing to follow the procedures as 
described in the protocol.
(1)
Male or female patients, at least 50 years of age.
(2)
Has any symptoms associated with OA of the knee for at least 
6 months prior to the screening visit and confirmation of OA based
on the clinical and radiological criteria of American College of 
Rheumatology Criteria for Classification of Idiopathic OA of the 
knee (standing fixed-flexion posteroanterior X-ray of the knee of 
approximately 20 degrees) within 6 months prior to the screening 
visit or during the screening period.
(3)
The study knee has OA with Grade 2 to 3 severity based on the 
Kellgren-Lawrence grades according to confirmatory X-ray result 
in inclusion criterion 2.
(4)
Patients with patient related visual analogue scale (VAS) score of 
5.0 to 9.0 of study knee prior to the study drug administration at 
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Taiwan Liposome Company, Ltd 
Version: 7.0
Protocol Number TLC599A2003
Date: 03 Aug 2018
baseline. The VAS score of study knee should be equal or higher 
than non-study knee. 
Note: If the patient has been confirmed to have OA for one knee but the 
VAS score of this knee is lower than the other knee which was not 
diagnosed with OA, the patient should be excluded and screened failure.
(5)
Willing and able to comply with study procedures and provide 
written informed consent.
Main Criteria for exclusion
(1)
Patients who received systemic corticosteroids within the last 
30 days prior to study drug administration.
(2)
Patients who start new rehabilitation or exercise program during 
screening period.
(3)
Patients using glucosamine or chondroitin or dietary supplement
with unstable dose or frequency within 4 weeks before screening 
visit.
(4)
Patients who use prohibited medications within 7 days prior to 
study drug administration or any pain control medication including 
acetaminophen within 48 hours prior to study drug administration.
(5)
Patients who use prohibited medications other than acetaminophen 
and oral NSAIDs from screening visit to 7 days prior to study drug 
administration.
(6)
Documented history and confirmed autoimmune disease including 
but not limited to secondary OA, Reiter’s syndrome, systemic 
lupus erythematosus, Sjögren’s syndrome, systemic sclerosis, 
inflammatory 
myositis, 
mixed 
connective 
tissue 
disease, 
palindromic rheumatism, reactive arthritis, rheumatoid arthritis, 
psoriatic arthritis, ankylosing spondylitis, Bechet’s disease, arthritis 
associated 
with 
inflammatory 
bowel 
disease, 
sarcoidosis, 
vasculitis, cryoglobulinemia, or amyloidosis.
(7)
Evidence of intra-articular bleeding of the study knee at baseline
prior to study drug administration.
(8)
History of infective arthritis in the study knee, or suspected /
concurrent infection in the study knee at baseline prior to study 
drug administration.
(9)
Documented gout attack in study knee within 6 months, evidence 
of tophi formulation, or active gouty arthritis attack prior to the 
baseline.
(10) Patient with any amputation in any lower limb.
(11) Any condition that could possibly confound the patient's 
assessment of study knee pain in judgement of the investigator 
(i.e., ipsilateral hip OA, radicular low back pain, and hip pain refer 
to the study knee).
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Taiwan Liposome Company, Ltd 
Version: 7.0
Protocol Number TLC599A2003
Date: 03 Aug 2018
(12) Unstable study knee joint as determined by the investigator based 
on physical examination (with or without buckling or giving way) 
due to an acute injury (defined as injury within 6 months, eg. 
anterior cruciate ligament injury or tear); OR any surgery or 
arthroscopy in the study knee within the 12 months prior to the 
screening visit.
(13) Clinical symptoms and signs of acute infection or infection-related 
inflammation in the other knee before study drug administration.
(14) Use of IA corticosteroid, hyaluronic acid, or other IA injection in 
the study knee within 3 months prior to the screening visit.
(15) Any skin lesion / breakdown at the anticipated injection site or any 
condition that impairs penetration of the study knee joint space.
(16) Patient with body mass index > 40 kg/m2 at the screening visit.
(17) Platelet count < 80,000/μL, or blood coagulation disorders, 
including patients with hemophilia, decompensated liver cirrhosis 
or uremia at the screening visit.
(18) History of acquired or congenital immunodeficiency diseases.
(19) Concurrent systemic active or uncontrolled infectious disease.
(20) A history of treated malignancy which is dLVHDVHIUHHIRU 5 years 
prior to the screening visit, except basal-cell carcinoma of skin or 
carcinoma-in-situ of the uterine cervix.
(21) Stroke or myocardial infarction within 3 months prior to the 
screening visit.
(22) Uncontrolled and unstable concurrent medical or psychiatric 
illness, including but not limited to, poorly controlled diabetes 
(defined as HbA1c > 9.0%), poorly controlled hypertension (mean 
arterial pressure [2/3 diastolic blood pressure + 1/3 systolic blood 
pressure] > 110mmHg), severe 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.
(23) Patients with a condition or in a situation which, in the assessment 
of the investigators, will interfere with the patient’s ability to 
comply or cooperate with the dosing and visit schedules and the 
protocol evaluations or may not be suitable for this study (e.g. 
illiterate).
(24)
Use of any chemotherapeutic or systemic immunosuppressant 
agents for inflammatory diseases within 6 months prior to the 
screening visit.
(25) Current use of anticoagulants, including warfarin, heparin, 
low-molecular weight heparin, or dabigatran.
(26) Use of any investigational agent within 4 weeks prior to study drug 
administration or within 5 half-lives of the product, whichever is 
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Taiwan Liposome Company, Ltd 
Version: 7.0
Protocol Number TLC599A2003
Date: 03 Aug 2018
longer.
(27) Known allergy or hypersensitivity to the study drug or its 
components.
(28) Female patients who are pregnant, nursing, planning to become 
pregnant, or who are of childbearing potential (defined as all the 
female 
patients
after 
puberty, 
unless 
they 
have 
been 
post-menopausal for at least 2 years, are sterile based on a 
documented ovarian failure, or are surgically sterile, such as after 
hysterectomy, bilateral oophorectomy, or bilateral tubal ligation)
and not using reliable means of contraception (e.g. established use 
of oral, transdermal, injected or implanted hormonal methods of 
contraception, placement of an intrauterine device or intrauterine
system, barrier methods of contraception, male sterilization, total 
abstinence, etc.).
(29) Abnormalities of laboratory parameters as described below will 
qualify for exclusion at the screening visit:
x hemoglobin < 8 g/dL;
x total white blood cell count < 4000/ μL;
x serum 
bilirubin/
alanine 
aminotransferase/
aspartate 
aminotransferase > 2 times upper limit of normal (ULN) for the 
laboratory reference ranges;
x eGFR <30 ml/min;
x prothrombin time / International Normalized Ratio > ULN for 
the laboratory reference range.
(30) Contraindication to undergoing magnetic resonance imaging (MRI)
for both knees including but not limited to pacemaker, metal 
sutures, presence of shrapnel or iron filings.
Test product, dose and mode 
of administration:
Test product: TLC599
(1)
low-dose group: 12 mg DSP with 100 μmol PL (1.0 mL) via intra-
articular injection;
(2)
high-dose group: 18 mg DSP with 150 μmol PL (1.5 mL) via 
intra-articular injection.
Reference therapy, dose, and 
mode of administration:
Placebo group: Normal saline 1.5 mL via intra-articular injection
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Taiwan Liposome Company, Ltd 
Version: 7.0
Protocol Number TLC599A2003
Date: 03 Aug 2018
Criteria for evaluation:
Primary Endpoint:
The primary endpoint is to evaluate the change from baseline by Western Ontario and McMaster Universities 
Osteoarthritis Index (WOMAC) pain subscale through Week 12.
Secondary Endpoints:
(1)
Change from baseline to Weeks 1, 4, 8, 12, 16, 20, and 24 in the patient rated visual analogue scale 
(VAS), and pain / function subscales of WOMAC.
(2)
Change from baseline through Weeks 12, 16, 20 and 24 in VAS, and pain / function subscales of 
WOMAC
(3)
Area under the effect curve (AUEC) of the VAS from baseline to Week 12, 16, 20 and 24.
(4)
Area under the effect curve of the WOMAC pain subscale from baseline to Week 12, 16, 20 and 24.
(5)
Proportion of responders by a decrease of > 30% or > 50% in patient-rated VAS from baseline to 
Weeks 1, 4, 8, 12, 16, 20, and 24.
(6)
Proportion of responders by a decrease of > 30% or > 50% in WOMAC pain subscale from baseline to 
Weeks 1, 4, 8, 12, 16, 20, and 24.
(7)
Proportions of durable responders with persistent response since Week 1till Weeks 12, 16, 20, and 24, 
respectively, by pain relief > 30% in VAS.
(8)
Proportions of durable responders with persistent response since Week 1 till Weeks 12, 16, 20, and 24, 
respectively, by pain relief > 30% in WOMAC pain subscales.
(9)
Proportions of durable responders with persistent response since Week 1 till Weeks 12, 16, 20, and 24, 
respectively, by outcome measured in rheumatology- Osteoarthritis Research Society International set 
of responder criteria.
(10) Change from baseline to Weeks 1, 4, 8, 12, 16, 20, and 24 in EuroQol-5 Dimension questionnaire.
(11) Total consumption of acetaminophen at Weeks 1, 4, 8, 12, 16, 20, and 24.
(12) Safety and tolerability.
Pharmacokinetic Endpoints:
The concentrations of dexamethasone and dexamethasone 21-phosphate in synovial fluid of the study knee 
joint at end of study or early termination.
Statistical methods:
Sample size calculation:
This is an exploratory study and there is no formal sample size evaluation. 
It is expected to have 
approximately 20 patients in each study groups completing 24-week follow-up period after study drug 
administration. Given a drop-out rate of 15%, approximately 24 patients in each study group will be enrolled 
and a total of approximately 72 patients will be randomly assigned.
General statistical considerations:
All efficacy and safety variables will be summarized using descriptive statistics. Continuous variables will 
be presented as number of observations, mean, standard deviation, median and range; while categorical 
variables will be presented as number of observations, count, and percentage in frequency table.
In this study, safety population is used for any safety analysis. The intent-to-treat (ITT), modified Intent-to-
treat (mITT) and per-protocol (PP) populations will be used in analysis of efficacy variables, but the major 
efficacy conclusion will be based on the results obtained from mITT population. The analysis of
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Taiwan Liposome Company, Ltd 
Version: 7.0
Protocol Number TLC599A2003
Date: 03 Aug 2018
dexamethasone and dexamethasone 21-phosphate concentrations in the synovial fluid will be conducted 
based on the pharmacokinetic (PK) population.
Unless otherwise specified, all statistical assessments will be 1-sided and evaluated at the 5% level of 
significance. 
All analyses, summaries, and listings will be performed using statistical analysis software (Version 9.2 or 
higher).
Further details regarding the definition of analysis variables and analysis methodology will be specified in a 
statistical analysis plan (SAP) to address all study objectives. The SAP will be developed and approved 
before database lock.
Analysis population:
The populations for analysis applied into this study are defined as follows: 
(1)
Intent-to-treat population:  all enrolled and randomized patients.
(2)
Safety population: All patients who receive any dose of study drug administration will be included in 
the safety population. 
(3)
Modified Intent-to-treat population: The mITT population indicates all enrolled patients who receive 
one complete dose of study drug administration and have at least one complete efficacy evaluation after 
study drug dosing. 
(4)
Per-protocol population: The PP population is a subset of mITT population fulfilling evaluable criteria 
without any major protocol deviation and has evaluation at baseline, Week 12 and at least 2 other 
evaluation within 12 weeks.
(5)
Pharmacokinetics population: All ITT patients who receive any dose of study drug, and those who 
consented for synovial fluid collection from the study knee at the end of study (EOS)/early termination 
(ET) visit. 
Efficacy analysis:
All efficacy analyses will be conducted for the mITT and PP populations as well as ITT population.
For the primary efficacy analysis, the overall change from baseline in WOMAC pain subscale over 12 weeks 
will be analyzed using a mixed-effects model for repeated measures (MMRM) with restricted maximum 
likelihood estimation.  The model will include factors of treatment, visit (as a categorical variable), baseline 
value of the WOMAC pain subscale score as fixed factors, site as random factor, and treatment-by-visit as 
interaction terms.  This methodology will be used to compare treatment groups for change from baseline 
through Week 12.  The model estimates by treatment group, contrast estimates for between-group (pairwise) 
comparisons, standard errors, 90% CIs, and p-values will be presented.
An MMRM model as described for primary efficacy analysis will be used to analyze the overall change from 
baseline in WOMAC pain / function subscale and VAS over 12, 16, 20 and 24 weeks as well as the change 
from baseline in WOMAC pain / function subscale and VAS at each scheduled visit.
Analysis of covariance (ANCOVA) is to be used for secondary efficacy endpoints measured in continuous 
scale, including treatment group, and the baseline value of that endpoint and the study sites as covariate if 
appropriate. Within each treatment group, the total consumption of acetaminophen, changes from baseline in
patient-rated VAS, WOMAC pain subscale, WOMAC function subscale, and EQ-5D at scheduled time 
points, and AUEC of VAS/WOMAC pain subscale will be summarized using descriptive statistic and 
estimated using the least squares mean. The 2-sided 90% confidence interval for LSM will be reported for 
each treatment arm.
The frequency and percentage will be used to summarize patients achieving the response criteria at scheduled 
time points and patients achieving the durable response criteria and will be presented by treatment group.  
Treatment comparisons of each TLC599 dose treatment with placebo will be made using a logistic regression 
analysis with treatment group, study site, and the baseline value of that endpoint as covariate in the model.
Explorative univariate models will be used to identify the possible prognostic factors associated with 
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Taiwan Liposome Company, Ltd 
Version: 7.0
Protocol Number TLC599A2003
Date: 03 Aug 2018
WOMAC pain subscale and VAS, e.g. age, gender, race, unilateral or bilateral knee pain, and baseline 
severity by VAS or pain score and Kellgren-Lawrence grades.  The subgroup analysis will be performed 
according to the results of regression model.
Safety analysis:
The assessment of safety will be based mainly on the frequency of adverse events (AEs), which includes all 
serious AEs (SAEs) and AEs, clinical laboratory data, vital signs, physical examination, electrocardiogram 
(ECG) result, articular cartilage assessment by MRI, and other safety findings.
All safety variables will be summarized using descriptive statistic based on the safety population. No 
inferential statistics are planned.
Pharmacokinetics analysis: 
The concentrations of dexamethasone and dexamethasone 21-phosphate in the synovial fluid of the study 
knee at EOS will be summarized by treatment group using descriptive statistics. 
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Taiwan Liposome Company, Ltd 
Version: 7.0
Protocol Number TLC599A2003
Date: 03 Aug 2018
Schedule of Events
Visit
Screening
1(Baseline)
2
3
4
5
6
7
8
EOS/E
T
Week/Day 
Day -21 ~ -
1
Day -1 ~ 0
Day 
3
Week 
1
Week
4
Week 
8
Week 
12
Week 
16
Week 
20
Week 
24
Window (day)
± 1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
Informed consent
X
Inclusion/exclusion criteria
X
X
Demographics and medical history
X
Physical 
examination 
and 
vital 
signs1
X
X
X
X
X
X
X
X
X
X
X-ray examination2
X
Clinical chemistry and hematology3
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
12-lead ECG
X
X
HbA1c
X
X
X
Blood cortisol4
X
X
X
X
X
X
X
X
X
Urine pregnancy test5
X
X
X
VAS Score6
X
X
X
X
X
X
X
X
X
WOMAC score6
X
X
X
X
X
X
X
X
X
EQ-5D6
X
X
X
X
X
X
X
X
X
Randomization6,
X
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Taiwan Liposome Company, Ltd 
Version: 7.0
Protocol Number TLC599A2003
Date: 03 Aug 2018
Visit
Screening
1(Baseline)
2
3
4
5
6
7
8
EOS/E
T
Week/Day 
Day -21 ~ -
1
Day -1 ~ 0
Day 
3
Week 
1
Week
4
Week 
8
Week 
12
Week 
16
Week 
20
Week 
24
Window (day)
± 1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
Excessive synovial fluid aspiration /
analysis & Study drug 
administration 6,7,
X
MRI examination8
X
X9
Concomitant medication
AE/SAE
Diary card10
Pharmacokinetics samples 
collection (synovial fluid)
(optional)11
X
1.
Height is measured only at screening. Weight is measured at screening, Visit 1, 4, 5, 6, 7, 8 and EOS/ET. Vital signs including BP, HR, RR, tympanic temperature will be 
assessed at each follow-up visit.
2.
The X-ray examination will include a chest PA view and examination for both knees. Standing fixed-flexion PA X-ray of the knees of approximately 20 degrees and lateral 
view of X-ray examination will be performed for both knees, if it has not been performed during the 6 months prior to screening.
3.
INR of PT and aPTT should be performed at the screening visit only. HbA1c should be performed at screening visit, Visit 6 and the EOS/ET visit. Other laboratory tests 
(clinical chemistry and hematology) at Visit 1 will be performed before study drug administration. Fasting glucose examination is not required for the screening visit, but will 
be required for all subsequent visits, from Visit 1 to EOS/ET visit.
4.
A blood sample to measure the plasma or serum cortisol level should be collected before 10:00 am or based on local lab requirement at the scheduled visits and before study 
drug administration at Visit 1.
5.
Urine pregnancy tests will be performed only for women with childbearing potential.
6.
At Visit 1, some local sites may have facility constraint for study drug preparation. Randomization, VAS, WOMAC, and EQ-5D questionnaires should be performed at the 
same day. Study drug administration is allowed to be performed at the same day as randomization or one day after randomization. The day of study drug administration is 
defined as Day 0.
7.
For patient with excessive synovial effusion, it is accepted to aspirate the excessive synovial fluid during study drug administration procedure. However, the characteristic 
and amount of the aspirated fluid should be recorded. The aspirated fluid can be sent for laboratory examination if there is any concern of infection, intra-articular bleeding or 
the OA diagnosis is questionable.
8.
For the articular cartilage evaluation of the knees, all subjects should have MRI examination conducted for MOAKS grading during the screening period or prior to 
randomization, and at the end of study/early termination. MRI images will be performed for both knees.
9.
MRI examination can be performed within 21 days prior to EOS/ET visit.
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Taiwan Liposome Company, Ltd 
Version: 7.0
Protocol Number TLC599A2003
Date: 03 Aug 2018
10.
Use of acetaminophen will be recorded on diary card.
11.
Synovial fluid from the study knee will be collected after completion of efficacy evaluation (VAS, WOMAC and EQ-5D) at EOS or within 3 days after ET visit, only if the 
subject has provided written informed consent for this procedure. In addition, it will only be aspired if appropriate synovial fluid volume in the study knee is ensured by local 
ultrasound examination and/or at the investigator’s discretion prior to the aspiration.
Abbreviations: AE=adverse event; BP=blood pressure; ECG=electrocardiogram; EOS=end of study; EQ-5D=EuroQol-5 Dimension; ET=early termination; HbA1c=glycosylated 
hemoglobin; HR=heart rate; INR= international normalized ratio; MOAKS=MRI Osteoarthritis Knee Score; MRI=magnetic resonance imaging; PA=posterior-anterior; PT= 
prothrombin time; aPTT=partial thromboplastin time; RR=respiratory rate; SAE=serious adverse event; VAS=visual analogue score; WOMAC=Western Ontario McMaster 
Universities.
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