Clinical trial NCT03093701
Conditions: Retinal Vein Occlusion Macula Edema
Sponsor: Taiwan Liposome Company
Start date: 2017-04-01; Completion date: 2019-02-04
Enrollment: 31 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Randomized, double-masked trial designed to investigate the use of TLC399 (ProDex) in subjects with macular edema due to CRVO or BRVO.

Detailed description:
Part 1 is a randomized, double-maskedtrial trial designed to investigate the use of TLC399 in subjects with macular edema due to CRVO or BRVO. Three different dose strengths will be evaluated.

Part 2 is a randomized, double-masked study designed to evaluate 2 doses of TLC399 in subjects with macular edema due to CRVO or BRVO. Subjects will be randomized 1:1 to receive two different dose strenghs of investigational product.

Arms: arm 1: TLC399 (ProDex) 0.36mg DSP with 100 mM PL arm 2: TLC399 (ProDex) 0.6 mg DSP with 100 mM PL arm 3: TLC399 (ProDex) 0.6 mg DSP with 50 mM PL arm 4: TLC399 (ProDex) 0.84 mg DSP with 50 mM PL
Interventions: intervention 1: TLC399 (ProDex)
Intervention descriptions: intervention 1: 2-vial system: TLC399-DSP and TLC399-Lipid

Protocol documents:
Prot_SAP_000.pdf: 
TLC399 (ProDex)
Taiwan Liposome Company, Ltd.
Clinical Trial Protocol: TLC399A2002
12 October 2018, v5.0
CLINICAL TRIAL PROTOCOL: TLC399A2002
Protocol Title:
A Phase IIa Trial of TLC399 (ProDex) in Subjects
with Macular Edema due to Retinal Vein Occlusion 
(RVO)
Protocol Number:
TLC399A2002
FDA IND Number:
109804
Study Phase:
IIa
Product Name:
TLC399 (ProDex)
Indication:
Macular edema due to central retinal vein occlusion 
(CRVO) or branch retinal vein occlusion (BRVO)
Study Centers:
Multicenter
Sponsor:
Taiwan Liposome Company, Ltd. (TLC)
11F-1, No. 3, Yuanqu St., Nangang District,
Taipei, Taiwan 115
Contract Research 
Organization:
Ora, Inc.
300 Brickstone Square
Andover, MA 01810
Date and Version
Original Protocol:
15 November 2016
Version 1.0
Amendment 1
24 May 2017
Version 2.0
Amendment 2
20 December 2017
Version 3.0
Amendment 3
21 September 2018
Version 4.0
Amendment 4
12 October 2018
Version 5.0
Statement of Compliance with Good Clinical Practice
This study will be performed in compliance with the ethical principles of the Declaration of Helsinki and
the International Conference on Harmonisation (ICH) Harmonised Tripartite Guideline for Good Clinical 
Practice (GCP).
Confidentiality Statement
This protocol is confidential and the information available within it may not be reproduced or otherwise 
disseminated.
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TLC399 (ProDex)
Taiwan Liposome Company, Ltd.
Clinical Trial Protocol: TLC399A2002
12 October 2018, v5.0
SPONSOR PERSONNEL
Clinical Project Manager:
Jenny Chen, Clinical Project Manager, Clinical 
Development
Office: +886-2-2655-7377  ext. 212
Mobile/Alternative Tel: +886-935-798-802
Fax: +886-2-2655-9188
Sponsor’s Medical 
Representative:
Terry Tien-Tzu Tai, MD
Office: +886-2-2655-7377  ext. 801
Mobile/Alternative Tel: +886-963-621-919
Fax: +886-2-2655-9188
Representative of Sponsor:
Sheue-Fang Shih, PhD
Office: +886-2-2655-7377  ext. 302
Mobile/Alternative Tel: +886-983-480-952
Fax: +886-2-2655-9188
ORA PERSONNEL
Department Vice President:
Aron Shapiro
Office: +1-978-685-8900 ext. 9443
Mobile/Alternative Tel: +1-978-886-2925
Fax: +1-978-689-0020
Project Lead:
Bhakti Patel
Office: +1-978-685-8900
Mobile/Alternative Tel: +1-213-219-9325
Fax: +1-978-689-0020
Medical Monitor
David Hollander, MD
Office: +1-978-685-8900
Mobile/Alternative Tel: +1-949-231-0004
Fax: +1-877-919-7491
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TLC399 (ProDex)
Taiwan Liposome Company, Ltd.
Clinical Trial Protocol: TLC399A2002
12 October 2018, v5.0
SYNOPSIS
Protocol Title:
A Phase IIa Trial of TLC399 (ProDex) in Subjects with 
Macular Edema due to Retinal Vein Occlusion (RVO)
Protocol Number:
TLC399A2002
Investigational Product:
TLC399 (ProDex)
Study Phase:
IIa
Primary Objective:
To evaluate the efficacy of different strengths of TLC399 
(ProDex) administered as a single intravitreal (IVT) 
injection in the improvement of visual acuity in subjects
with macular edema due to RVO
Secondary Objectives:
x
To evaluate the safety and tolerability of different 
strengths of TLC399 (ProDex) in subjects with 
macular edema due to RVO
x
To evaluate the efficacy of different strengths of 
TLC399 (ProDex) for reducing retinal thickness in 
subjects with macular edema due to RVO
Overall Study Design:
Structure:
Part 1: Multi-center, randomized, double-masked
Part 2: Multi-center, randomized, double-masked
Duration:
Subjects will be evaluated for safety and efficacy for 12 
months after the single IVT injection of TLC399 
(ProDex).
Treatment Period: Single day (Day 1)
Follow-up Period: Up to 12 months
Controls:
Not applicable
Dosage/Dose Regimen/ 
Instillation/Application/
Use:
TLC399 (ProDex):
x
Group 1: 0.36 mg dexamethasone sodium 
phosphate (DSP) with 100 mM phospholipid (PL)
(30 μL)
x
Group 2: 0.6 mg DSP with 100 mM PL (50 μL)
x
Group 3: 0.6 mg DSP with 50 mM PL (50 μL)
x
Group 4: 0.84 mg DSP with 50 mM PL (70 μL)
In Part 1, subjects will be assigned to Group 1, 2, or 3 
(randomized 1:1:1).
In Part 2, subjects will be assigned to Group 3 or 4 
(randomized 1:1).
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TLC399 (ProDex)
Taiwan Liposome Company, Ltd.
Clinical Trial Protocol: TLC399A2002
12 October 2018, v5.0
Summary of Visit 
Schedule:
Visit 1 (Day -14 to Day -1): Screening
Visit 2 (Day 1): Eligibility Confirmation and 
Randomization/Treatment
Visits 3-5 (Days 2 [+2 days], 14 [±2 days], 30 [±3 days]) 
and Visits 6-11 (Day 60 to Day 270 [±7 days]): 
Follow-up Period
Visit 12 (Day 360 [±7]): Exit Visit
Measures Taken to 
Reduce Bias:
Stratified randomization will be used to avoid bias in the 
assignment of subjects to treatment, to increase the 
likelihood that known and unknown subject attributes 
(eg, demographics and baseline characteristics) are 
evenly balanced across treatment groups, to reduce the 
possible influence of covariates on the drug evaluation, 
and to enhance the validity of statistical comparisons 
across treatment groups. Masked treatment will be used 
to reduce the potential of bias during data collection and 
evaluation of clinical endpoints. The subject, the masked 
Evaluating Investigator (Principal investigator or his/her 
designees), the best-corrected visual acuity (BCVA)
technician, the photographer, and any other site staff 
involved in performing visit assessments are masked to 
the study treatment.
Study Population Characteristics:
Number of Subjects:
Part 1: 31 subjects
Part 2: Up to 30 subjects
Condition/Disease:
Macular edema due to central retinal vein occlusion 
(CRVO) or branch retinal vein occlusion (BRVO)
Inclusion Criteria:
1. Male or female, at least 18 years of age.
2. Subjects with macular edema due to CRVO or 
BRVO diagnosed within 18 months prior to the 
Screening Visit with:
y Visual acuity decreases attributable to the edema 
in the study eye; and
y Non-ischemic type by fluorescein angiography 
(FA) in the study eye.
3. BCVA score of 20/40 (73 letters) to 20/400
(19 letters) by Early Treatment of Diabetic 
Retinopathy Study (ETDRS) chart in the study eye 
at the Screening Visit and on Day 1.
4. Mean central subfield thickness (CST) 350 Pm on 
spectral domain optical coherence tomography 
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TLC399 (ProDex)
Taiwan Liposome Company, Ltd.
Clinical Trial Protocol: TLC399A2002
12 October 2018, v5.0
(SD-OCT) measurements in the study eye at the 
Screening Visit as determined by the site’s OCT 
machine.
5. Willing and able to comply with the study 
procedure and sign a written informed consent.
6. Must agree to use a medically acceptable form of 
birth control throughout the study duration unless 
the subject or his/her partner(s) is sterile*.
*Sterile is defined as a woman who has experienced 
menopause (as defined by amenorrhea for greater 
than 12 consecutive months) or has undergone 
successful surgical sterilization (hysterectomy, 
bilateral tubal ligation, or bilateral oophorectomy);
or a man who has undergone successful 
orchiectomy.
Note: If both eyes are eligible for the study, the eye with 
the shorter duration of disease will be used as the study 
eye.
Exclusion Criteria:
1. History of diabetic retinopathy in the study eye.
2. Presence of a brisk afferent pupillary defect (ie, 
obvious and unequivocal) in the study eye.
3. Stroke or myocardial infarction within 3 months 
prior to the Screening Visit.
4. Poorly controlled hypertension (defined as 
systolic blood pressure [BP] >160 mm Hg and/or 
diastolic BP >90 mm Hg) at the Screening Visit or 
at Day 1.
5. Poorly controlled diabetes (defined as 
hemoglobin A1c level > 9.5%) at the Screening 
Visit.
6. Uncontrolled systemic disease.
7. Any ocular condition that in the opinion of the 
masked Evaluating Investigator would prevent a 
15-letter gain in visual acuity in the study eye (eg, 
severe macular ischemia).
8. Presence of an epiretinal membrane in the study 
eye which, in the opinion of masked Evaluating 
Investigator, is the primary cause of macular 
edema, or is severe enough to prevent gain in 
visual acuity despite reduction in macular edema.
9. History of clinically significant (CS) intraocular 
pressure (IOP) elevation (ie, a rise of >10 mm Hg 
or an absolute IOP PP+JZKLFKUHTXLUHG
treatment) in response to topical or systemic 
steroid treatment in either eye.
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TLC399 (ProDex)
Taiwan Liposome Company, Ltd.
Clinical Trial Protocol: TLC399A2002
12 October 2018, v5.0
10. History of ocular hypertension, glaucoma, or optic 
nerve head change consistent with glaucomatous 
damage in the study eye.
11. Active ocular hypertension (with or without 
WUHDWPHQWPP+J in the study eye at the 
Screening or Day 1 visit.
12. Aphakia or presence of anterior chamber 
intraocular lens in the study eye.
13. Active retinal neovascularization in the study eye.
14. Active or history of choroidal neovascularization 
in the study eye.
15. History of central serous chorioretinopathy in 
either eye.
16. Presence of rubeosis iridis in the study eye.
17. Any active ocular infection (ie, bacterial, viral, 
parasitic, or fungal) in either eye at the Screening 
Visit or on Day 1.
18. History of herpetic ocular infection in the study 
eye or adnexa.
19. Presence of active or inactive toxoplasmosis in 
either eye at the Screening Visit or on Day 1.
20. Presence of visible significant scleral thinning or 
ectasia in the study eye that would preclude safe 
IVT injection.
21. Media opacity in the study eye that precludes
clinical and photographic evaluation (including 
but not limited to preretinal or vitreous 
hemorrhage, lens opacity).
22. Cataract surgery in the study eye within 3 months, 
or other intraocular surgery in the study eye 
within 6 months prior to the Screening Visit; or 
these surgeries are planned during the course of 
the study.
23. Anticipated need for ocular surgery in the study 
eye during the 12-month study period.
24. History of pars plana vitrectomy, radial optic 
neurotomy, or sheathotomy in the study eye.
25. Use of hemodilution for the treatment of RVO 
within 3 months prior to the Screening Visit.
26. Use of IVT ranibizumab or bevacizumab in the 
study eye within 6 weeks prior to the Screening 
Visit; or IVT aflibercept in the study eye within 
8 weeks prior to the Screening Visit.
27. Use of laser of any type in the study eye within 
3 months prior to the Screening Visit.
28. Previous use of non-depot IVT steroids in the 
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TLC399 (ProDex)
Taiwan Liposome Company, Ltd.
Clinical Trial Protocol: TLC399A2002
12 October 2018, v5.0
study eye within 3 months prior to the Screening 
Visit.
29. IVT Ozurdex in the study eye within 6 months
prior to the Screening Visit.
30. Any prior use of Retisert or Iluvien in the study 
eye.
31. Use of systemic steroids or heparin within 
1 month prior to the Screening Visit; or 
anticipated use at any time during the study.
32. Use of immunosuppressants, immunomodulators, 
antimetabolites, and/or alkylating agents within 
6 months prior to the Screening Visit; or 
anticipated use at any time during the study.
33. BCVA score < 34 letters (approximately 20/200 
Snellen equivalent) in the non-study eye using the 
ETDRS chart method at the Screening Visit or at 
Day 1.
34. Known allergy or hypersensitivity to the study 
medication or its components.
35. Known allergy or contraindication to the use of 
fluorescein or povidone iodine or contraindication 
to pupil dilation in either eye.
36. Female subjects who are pregnant, nursing, or 
planning a pregnancy.
37. Treatment with an investigational drug within 
90 days or 5 half-lives of the investigational 
product ([IP]; whichever is longer) prior to the 
Day 1 visit.
38. Any participation in a clinical trial within 30 days 
of the Screening Visit.
39. Subject has a condition or is in a situation which, 
in the masked Evaluating Investigator’s opinion, 
will interfere with the subject’s ability to comply 
with the dosing and visit schedules and the 
protocol evaluations or may not be suitable for this 
study.
Study Formulations and 
Mode of Administration:
TLC399 (ProDex) is designed as a 2-vial system; 
1 with DSP and 1 with PL containing lipid excipients.
On Day 1, subjects will be administered a single dose 
IVT injection according to the randomized group.
Mode of Administration: IVT injection to the study eye 
to be administered by the unmasked Injecting 
Physician.
Evaluation Criteria:
Efficacy Measures:
Primary:
x
Proportion of subjects with BCVA gain of 15 or 
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TLC399 (ProDex)
Taiwan Liposome Company, Ltd.
Clinical Trial Protocol: TLC399A2002
12 October 2018, v5.0
more letters from baseline in the study eye at 
6 months
Secondary:
x
Change from baseline of retinal CST (using SD-
OCT) in the study eye at scheduled visits
x
Proportion of subjects with retinal CST (using 
SD-OCT) <300 Pm in the study eye at scheduled 
visits
x
Change from baseline in number of letters read 
correctly (using BCVA) in the study eye at 
scheduled visits
x
Proportion of subjects with BCVA gain of 15 or 
more letters from baseline in the study eye at 
scheduled visits
x
Proportion of subjects with BCVA letter score 
>73 (20/40 Snellen equivalent) in the study eye at 
scheduled visits
x
Time to achieve a treatment response of gain of 
15 or more letters from baseline BCVA in the 
study eye
Safety Measures:
x
Adverse Events (AEs)
x
IOP
x
Slit lamp biomicroscopy (SLB)
x
Indirect ophthalmoscopy (dilated)
x
Fundus photography (FP)
x
FA 
x
Physical examination
x
Vital signs (BP, pulse)
x
Clinical laboratory evaluations (routine 
hematology, chemistry, and urinalysis)
General Statistical Methods and Types of Analyses
Sample Size Calculation
This is an exploratory study and there is no formal sample size evaluation. For Part 1, 
approximately 20 subjects are expected to be enrolled in each study group completing 
the 12-month follow-up period after study drug administration. Given a drop-out rate 
of 10%, approximately 22 subjects in each group will be enrolled. A total of 
approximately 66 subjects will be randomly assigned to 1 of 3 different strengths of 
TLC399 (ProDex).
Based on the SMC recommendation, following review of data for 31 subjects from 
Part 1 (10, 10, and 11 in Groups 1, 2, and 3, respectively), up to 30 additional subjects 
will be randomly assigned in Part 2 to one of 2 different strengths of TLC399 
(ProDex).
General Statistical Considerations
All efficacy and safety variables will be summarized using descriptive statistics and 
presented by treatment groups. Continuous variables will be presented as number of 
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TLC399 (ProDex)
Taiwan Liposome Company, Ltd.
Clinical Trial Protocol: TLC399A2002
12 October 2018, v5.0
observations, mean, standard deviation, median, minimum, and maximum, as well as 
number of missing data (if relevant); while categorical variables will be presented as 
number of observations, count, percentage, and number of missing data (if relevant) in 
a frequency table. In general, missing values will remain as missing. Specific rules for 
handling missing efficacy data are described in Efficacy Analysis.
Analysis Population
The populations for analysis applied in this study are defined as follows: 
Safety population: All randomized subjects who receive any dose of study drug 
administration.
Modified intent-to-treat (mITT) population: A subset of the safety population 
comprised of subjects who have at least 1 post-treatment efficacy evaluation.
Per protocol (PP) population: A subset of the mITT population comprised of subjects 
who complete the study without any major protocol violations.
Efficacy Analysis
The efficacy data will be descriptively summarized with the mITT and PP analysis 
populations and presented by study part and treatment group. Data for the Group 3 dose 
in both study parts will be pooled and summarized as well.
The mITT analysis will be considered primary and the PP supportive.
For all analyses of BCVA data, missing data will be imputed using multiple imputation 
methods. Patients who receive rescue medication/procedures within 6 months after the 
study treatment is initiated will be considered failure to achieve a gain of at least 
15 BCVA letters. For continuous measures, all data points after a subject starts rescue 
medication will be replaced with the last observation prior to rescue medication
administration.
Sensitivity analyses on the primary endpoint will be performed as follows:
1) On observed data only, with subjects requiring rescue medications prior to 
Month 6 included as treatment failures (mITT and PP populations)
2) Imputing missing data using the last observation carried forward, with subjects 
requiring rescue medications prior to Month 6 included as treatment failures 
(mITT population)
3) On observed data only, with subjects who require rescue medications prior to 
Month 6 using their Month 6 data (mITT population)
The same approach to missing data as described for BCVA data will apply to CST 
data.
The time to achieve a treatment response of gain of 15 or more letters from baseline 
BCVA will be analyzed using the Kaplan-Meier method. Survival plots will be created 
and the survival time will be presented as mean, median, 95% confidence intervals 
(CIs) for the median, and the range.
Change from baseline in number of letters read correctly (using BCVA) and change 
from baseline of retinal CST (by using SD-OCT scan) in the study eye during the 
12-month period will be summarized by treatment groups at scheduled visits.
Additionally, 95% CIs for the treatment estimates in changes from baseline will be 
constructed.
Subgroup Analysis
Subgroup analyses will be performed for the primary efficacy endpoint and selected
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TLC399 (ProDex)
Taiwan Liposome Company, Ltd.
Clinical Trial Protocol: TLC399A2002
12 October 2018, v5.0
secondary endpoints by RVO type.
Safety Analysis
All safety data analyses will be performed on the safety population and displayed in 
subject data listings and summarized in tables. Treatment-emergent adverse events 
(TEAEs) will be listed and categorized by start date, stop date, seriousness, severity, 
relationship to IP, action taken, and outcome. TEAEs with a missing relationship to 
study treatment will assume greatest relationship to study treatment. TEAEs with 
missing severity grades will be categorized as “missing” for tabulation of TEAEs by 
severity. Summary tables will display the total number of TEAEs and the number of 
subjects with each TEAE by treatment groups. TEAEs will be summarized by the 
Medical Dictionary for Regulatory Activities (MedDRA) system organ class and 
preferred term for all TEAEs, serious adverse events (SAEs), and TEAEs leading to 
study withdrawal. In addition, TEAEs will be summarized by day of onset relative to 
the injection day of IP.
Safety data including physical examination, vital signs, clinical laboratory data, IOP 
assessments, SLB, indirect ophthalmology, FA, and FP evaluations will be 
descriptively summarized by treatment group.
Continuous safety data will be summarized by visit and include changes from baseline.
Continuous data will also be converted to categorical values where possible (ie, 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.
Interim Analysis
An interim analysis for the primary efficacy evaluation was planned to be conducted 
after all subjects have completed at least 6 months in the study or had been withdrawn. 
For this Phase 2 trial, efficacy and safety evaluation beyond Month 6 will be 
considered exploratory.
Safety monitoring committee (SMC) reviews will be performed throughout the study.
The unmasked SMC reviewed unmasked listings for 31 subjects on 29 March 2018 
(data cutoff 09 March 2018), and requested that recruitment be temporarily paused 
pending further data analysis. Additional descriptive efficacy summaries were provided 
to the SMC for a review meeting on 25 April 2018. An unmasked team from the 
sponsor presented further data for an unmasked SMC meeting held on 18 August 2018 
(data cutoff 06 August 2018). Following this meeting, the SMC approved the sponsor’s 
proposal to enroll additional subjects treated with the Group 3 dose and a new Group 4 
dose (containing a greater volume of the same formulation of Group 3).
As of Protocol Amendment 3 (v4), data from Part 1 (31 subjects) will be unmasked. 
Given that, as of protocol preparation, 1) all 31 subjects randomized in Part 1 have 
completed at least Month 7.5 in the trial or have been withdrawn (and evaluations 
beyond 6 months were considered exploratory); 2) no formal statistical comparisons 
will be made between the groups in Part 1 or Part 2; and 3) the selection of dose to 
carry forward from Part 1 has already been decided, it was deemed that minimal bias 
will be introduced by unmasking the data. The sponsor intends to disclose key 
unmasked efficacy and safety data from Part 1 with the investigators and other 
stakeholders so that they can adequately understand the benefits and risks of the study 
treatment.
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TLC399 (ProDex)
Taiwan Liposome Company, Ltd.
Clinical Trial Protocol: TLC399A2002
12 October 2018, v5.0
For Part 2, no formal interim analysis is planned.
Summary of Known and Potential Risks and Benefits to Human Subjects
ProDex is developed to provide an ideal, safe, long-acting, DSP delivery system for the 
treatment of macular edema.
Subjects receiving ProDex IVT injection may be at risk for transient vitreous opacity, 
which might result in transient visual acuity decrease but would be expected to resolve
within 2-6 weeks after study drug dosing. IVT injections have been associated with
endophthalmitis, eye inflammation, increased IOP, vitreous hemorrhage, and retinal 
detachments. Subjects should be monitored following the injection. Use of 
corticosteroids may produce posterior subcapsular cataracts, increased IOP, glaucoma, 
and may enhance the establishment of secondary ocular infections due to bacteria, 
fungi, or viruses.
From the experience of preclinical and preliminary clinical data, the expected adverse 
reactions of ProDex IVT injection on subject with macular edema following CRVO 
and BRVO include vitreous opacity, increased IOP, visual acuity decrease,
conjunctival hemorrhage, eye pain, dry eye, foreign body sensation, conjunctival 
hyperemia, cataract, floaters, and hypertension. Previous human experience from 
Ozurdex shows that potential adverse reactions include vitreous detachment, optic 
nerve damage, visual acuity and field defects, posterior subscapular cataract formation, 
secondary ocular infection, and perforation of the globe where there is thinning of the 
cornea or sclera. The expected systemic adverse reactions such as hypertension, 
hyperglycemia, vasovagal reaction, and facial flushing are also rare, but will be 
monitored carefully.
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