Clinical trial NCT02395978
Conditions: Major Depressive Disorder
Sponsor: BioLite, Inc.
Start date: 2015-04-10; Completion date: 2019-03-18
Enrollment: 72 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the safety and efficacy in patients with major depressive disorder.

Detailed description:
The screening phase is intended for diagnosing and assessing the patient for possible inclusion in the study and for providing an adequate washout period. The following study will be conducted in two parts. Part I is an open-label study, multiple center and dose escalation evaluation in twelve patients. Six subjects each will be evaluated for safety and efficacy assessments at 1 or 2 capsules TID dose for 28 days, sequentially. Each of them will be assessed twice in the first week after administration of PDC-1421 Capsules and once a week in the following treatment.

Part II is a randomized, double-blind, placebo-controlled, parallel-group study. 60 subjects will be randomly assigned on a 1:1:1 basis to one of the three arms (1 PDC-1421 Capsule plus 1 placebo TID, 2 PDC-1421 Capsules TID, 2 placebo TID) for 6 weeks and evaluated the safety and efficacy every two weeks during the treatment period.

Arms: arm 1: 1 PDC-1421 Capsule TID, p.o. after meal for 28 days arm 2: 2 PDC-1421 Capsule TID, p.o. after meal for 28 days arm 3: 2 PDC-1421 Capsule TID, p.o. after meal for 42 days arm 4: 1 PDC-1421 Capsule plus 1 placebo TID, p.o. after meal for 42 days arm 5: 2 placebo TID, p.o. after meal for 42 days
Interventions: intervention 1: PDC-1421 Capsule intervention 2: placebo
Intervention descriptions: intervention 1: PDC-1421 Capsule is a botanical investigational new drug containing the extract of Radix Polygalae (Polygala tenuifolia Willd.) as active ingredient. intervention 2: Placebo contained corn starch.

Protocol documents:
Prot_001.pdf: 
  
 

Protocol Number: BLI-1005-002 
Protocol Version: 2.3 
Date: 2018/03/16 
Confidential
BioLite, Inc.                                 
萊特先進生醫股份有限公司 
 
Section 4. PROTOCOL  
 
Investigational New Drug (IND) 
PDC-1421 Capsule 
(Polygala tenuifolia Willd.) 
 
EDITION NUMBER : Version 2.3 
SPONSOR 
 
 
: BioLite, Inc. 
RELEASE DATE  
: 2018/03/16 
 
 
 
A Phase II Study of PDC-1421 Capsule to Evaluate the Safety 
and Efficacy in Patients with Major Depressive Disorder
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NCT02395978


 
   
       
                  
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Protocol 
I 
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Protocol Number: BLI-1005-002 
Protocol Version: 2.3 
Date: 2018/03/16 
Confidential 
BioLite, Inc.                 
萊特先進生醫股份有限公司 
 
 
Table of Contents  
Page 
PROTOCOL SYNOPSIS ..................................................................................................... 1 
LIST OF ABBREVIATIONS/DEFINITIONS..................................................................... 3 
1 BACKGROUND INFORMATION .................................................................................. 6 
1.1 Description of PDC-1421 Capsule ......................................................................... 6 
1.1.1 Preparation ......................................................................................................... 6 
1.1.2 Composition ...................................................................................................... 7 
1.1.3 Storage and Handling ........................................................................................ 8 
1.2 Non-clinical Study of PDC-1421 ........................................................................... 8 
1.2.1 Efficacy Pharmacology...................................................................................... 8 
1.2.2 Safety Pharmacology ....................................................................................... 10 
1.2.3 Cytochrome P450 Interaction with PDC-1421 ................................................ 12 
1.2.4 Toxicology ....................................................................................................... 12 
1.3 Results of Phase I Clinical Trial Study of PDC-1421 .......................................... 14 
1.4 Potential Risk and Benefit ................................................................................... 16 
1.4.1 Potential Risk ................................................................................................... 16 
1.4.2 Potential Benefit .............................................................................................. 17 
1.4.3 Risk Benefit Ratio ........................................................................................... 17 
1.5 Dosage Regimen .................................................................................................. 17 
1.6 Compliance with Protocol, Good Clinical Practice (GCP) and Applicable 
Requirement ............................................................................................................... 19 
1.7 Description of the Population to be Studied ........................................................ 19 
2 TRIAL OBJECTIVE ....................................................................................................... 20 
3 TRIAL DESIGN ............................................................................................................. 20 
3.1 General Design ..................................................................................................... 20 
3.2 Primary Endpoint ................................................................................................. 22 
3.3 Secondary Endpoint ............................................................................................. 23 
3.4 Randomization and Blinding ............................................................................... 23 
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BioLite, Inc.                 
萊特先進生醫股份有限公司 
3.5 Investigational Drug ............................................................................................. 24 
3.5.1 Dosage Form and Strength .............................................................................. 24 
3.5.2 Manufacturer ................................................................................................... 24 
3.5.3 Route of Administration .................................................................................. 24 
3.5.4 Dosing Regimen, packing and labeling ........................................................... 24 
3.5.5 Study Drug Storage ......................................................................................... 28 
3.6 Premature Termination or Suspension of the Study ............................................. 29 
4 SUBJECTS SELECTION AND WITHDRAWAL ......................................................... 30 
4.1 Inclusion Criteria ................................................................................................. 30 
4.2 Exclusion Criteria ................................................................................................ 30 
4.3 Subject Recruitment and Screening ..................................................................... 31 
4.4 Subject Identification ........................................................................................... 31 
4.4.1 Subject Initial Allocation ................................................................................. 32 
4.4.2 Subject Number Allocation ............................................................................. 32 
4.5 Early Withdrawal of Subjects .............................................................................. 33 
5 TREATMENT OF SUBJECTS ....................................................................................... 34 
5.1 Description of Study Drug ................................................................................... 34 
5.2 Treatment Schedule .............................................................................................. 34 
5.2.1 Screening Phase (Visit 1) ................................................................................. 37 
5.2.2. Part I. - Treatment Period (Visit 2~7) and Follow-up (Visit 8) ...................... 38 
5.2.3 Part II.- Treatment Period (Visit 2~4) and Follow-up (Visit 5) ....................... 39 
5.3 Other Medication During the Study ..................................................................... 41 
6 EFFICACY ASSESSMENTS ......................................................................................... 41 
6.1 Specification of the efficacy parameters .............................................................. 41 
6.2 Methods and Timing for Assessing, Recording, and Analyzing of Efficacy 
Parameters. ................................................................................................................. 41 
7 SAFETY ASSESSMENTS ............................................................................................. 44 
7.1 Specification of Safety Parameters ...................................................................... 44 
7.2 Methods and Timing for Assessing, Recording, and Analyzing of Safety 
Parameters .................................................................................................................. 44 
7.3 Adverse Events (AEs) .......................................................................................... 44 
7.4 Serious Adverse Events (SAE) ............................................................................ 45 
7.5 Serious and Unexpected Suspected Adverse Reaction (SUSAR) ........................ 46 
xiv


 
   
       
                  
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Protocol Version: 2.3 
Date: 2018/03/16 
Confidential 
BioLite, Inc.                 
萊特先進生醫股份有限公司 
7.6 SAE Report Procedure ......................................................................................... 46 
7.6.1 Expedited Reporting of SAEs ......................................................................... 46 
7.6.2 IRB Notification .............................................................................................. 46 
7.6.3 Record Retention ............................................................................................. 47 
8 STATISTIC METHODS ................................................................................................. 48 
8.1 Sample Size Determination .................................................................................. 48 
8.2 Statistical Method ................................................................................................ 48 
8.3 Analysis of Efficacy and Safety ........................................................................... 48 
8.4 Premature Termination and Handling of Missing Data ....................................... 49 
9 QUALITY CONTROL AND QUALITY ASSURANCE ............................................... 50 
9.1 Study Monitoring ................................................................................................. 50 
9.2 Sponsor Auditing ................................................................................................. 50 
9.3 Inspected by Regulatory Authorities .................................................................... 50 
10 ETHICAL CONSIDERATIONS .................................................................................. 51 
10.1 Confidential ........................................................................................................ 51 
10.2 Protocol Amendment ......................................................................................... 51 
10.3 Informed Consent ............................................................................................... 51 
10.4 Institutional Review Board (IRB) ...................................................................... 52 
11 DATA HANDLING AND RECORD KEEPING .......................................................... 53 
11.1 Data Handling and Collection ............................................................................ 53 
11.1.1 Study Specific Binders .................................................................................. 53 
11.1.2 Responsibilities of Investigators .................................................................... 53 
11.1.3 Responsibilities of Clinical Monitor .............................................................. 54 
11.2 Records Retention .............................................................................................. 54 
11.2.1 Source Document Retention .......................................................................... 54 
11.2.2 CRF Retention ............................................................................................... 55 
11.2.3 Record Maintenance ...................................................................................... 55 
11.3 Study Center File Management .......................................................................... 56 
12 PUBLICATION PLAN ................................................................................................. 57 
13 REFERENCES ............................................................................................................. 57 
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Protocol 
1 
 
 
BioLite, Inc.           
萊特先進生醫股份有限公司 
Protocol Number: BLI-1005-002 
Protocol Version: 2.2 
Date: 2017/08/18 
Confidential 
PROTOCOL SYNOPSIS 
Name of sponsor 
BioLite, Inc. 
Name of finished 
product 
PDC-1421 Capsule 
Name of active 
ingredient 
PDC-1421 
Protocol title 
A phase II study of PDC-1421 Capsule to evaluate the 
safety and efficacy in patients with major depressive 
disorder (MDD) 
Clinical trial phase 
Phase II 
Study site 
Multiple sites 
Study period 
2 years  
Study population 
Patients with MDD according to the Diagnosis and 
Statistical Manual of Mental Disorders-IV, text revision 
(DSM-IV-TR) criteria. 
Primary study 
objective 
To assess the efficacy profile of PDC-1421 Capsule in 
major depressive disorder with Montgomery-Å sberg 
Depression Rating Scale (MADRS). 
Secondary study 
objective 
To evaluate the efficacy and safety profile of PDC-1421 
Capsule in major depressive disorder with other rating 
scales.  
Study design 
Part I: open label 
Part II: Randomized, double-blind, placebo-controlled, 
parallel groups  
Sample size 
72 subjects  
Test product 
PDC-1421 Capsule 
Dose and regimen 
1 and 2 capsules thrice daily, p.o., after meal 
Duration of treatment 
42 days  
Study intervention  
The screening phase is intended for diagnosing and 
assessing the patient for possible inclusion in the study 
and for providing an adequate washout period. The 
following study will be conducted in two parts. Part I is an 
open-label study, multiple center and dose escalation 
evaluation in twelve patients. Six subjects each will be 
evaluated for safety and efficacy assessments at 1 or 2 
capsules TID dose for 28 days, sequentially. Each of them 


 
   
       
                  
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BioLite, Inc.                 
萊特先進生醫股份有限公司 
will be assessed twice in the first week after 
administration of PDC-1421 Capsules and once a week in 
the following treatment. Part II is a randomized, 
double-blind, placebo-controlled, parallel-group study. 60 
subjects will be randomly assigned on a 1:1:1 basis to one 
of the three arms (1 PDC-1421 Capsule plus 1 placebo 
TID, 2 PDC-1421 Capsules TID, 2 placebo TID) for 6 
weeks and evaluated the safety and efficacy every two 
weeks during the treatment period.  
Primary endpoint  
˙ Change in Montgomery-Å sberg Depression Rating 
Scale (MADRS) total score from baseline to week 6 
compared to placebo. 
Secondary endpoints 
˙ Change in MADRS total score from baseline to week 
2 and 7. 
˙ Change in Hamilton Rating Scale for Depression 
(HAM-D-17), Hamilton Rating Scale for Anxiety 
(HAM-A), Depression and Somatic Symptoms Scale 
(DSSS), Clinical Global Impression Scale (CGI) total 
score from baseline to week 2, 4, 6 and 7.  
˙ Percentage of partial responders (defined as a 
participant with a 25-50% decrease from baseline in 
total score) and responders (defined as a participant 
with ≧50% decrease from baseline in total score) in 
MADRS by week 2, 4, 6 and 7. 
˙ Evaluate Safety Assessments and Columbia-Suicide 
Severity Rating Scale (C-SSRS) from screening stage 
to the last visit 
˙ Difference in the mean changes of MADRS, 
HAM-D-17, HAM-A, DSSS, CGI and C-SSRS from 
the baseline to week 2, 4, 6 and 7 between the 
PDC-1421 Capsule and placebo groups. 
Safety Evaluation 
˙ Change from baseline in physical examination, vital 
sign, electrocardiogram (ECG), hematology and 
blood chemistry 
˙ Incidence of AE/SAE 
Statistical method 
Descriptive Statistics 


 
   
       
                  
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Protocol 
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Protocol Version: 2.3 
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Confidential 
BioLite, Inc.                 
萊特先進生醫股份有限公司 
 LIST OF ABBREVIATIONS/DEFINITIONS 
˙ AE  
Adverse Events, whether or not considered related to the investigational drug, 
must be recorded in CRF. 
˙ CGI 
Clinical Global Impression Scale (see Attachment III) 
˙ CHO  
Chinese Hamster Ovary 
˙ Clinical monitor 
The designated CRA monitoring this study for the sponsor 
˙ CRA 
Clinical Research Associate 
˙ CRC 
Clinical Research Coordinator 
˙ CRF 
Case Report Form 
˙ CRO 
Contract Research Organization 
˙ C-SSRS 
Columbia-Suicide Severity Rating Scale (see Attachment VI) 
˙ DSSS 
Depression and Somatic Symptoms Scale (see Attachment V) 
˙ ECG 
The Electrocardiogram (ECG) is a graphical recording of the cardiac cycle 
produced by an electrocardiograph. 
˙ HAM-D-17 
Hamilton Depression Rating Scale (see Attachment I) 
˙ HAM-A 
Hamilton Anxiety Rating Scale (see Attachment IV) 
˙ HDL 
High-Density Lipoprotein 
˙ HPLC 
High Performance Liquid Chromatography 
˙ ICF 
Informed Consent Form 


 
   
       
                  
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Protocol Version: 2.3 
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BioLite, Inc.                 
萊特先進生醫股份有限公司 
˙ ICH-GCP 
International Conference of Harmonization-Good Clinical Practice) 
˙ IEC 
Independent Ethics Committee 
˙ IRB 
Institutional Review Board 
˙ LDH 
Lactate Dehydrogenase 
˙ LDL 
Lower-Density Lipoprotein 
 
˙ MADRS 
Montgomery and Å sberg Depression Rating Scale (see Attachment II) 
˙ MOHW 
Minister of Health and Welfare 
˙ NET 
Norepinephrine Transporter 
˙ NLT 
Not Less Than 
˙ NMT 
Not More Than 
˙ NOAEL 
No Observable Adverse Effect Level 
˙ NRI 
Norepinephrine Reuptake Inhibitor 
˙ PITDC 
Medical and Pharmaceutical Industry Technology and Development Center 
˙ SAEs 
Serious Adverse Event(s), whether or not considered as related to the 
investigational drug must be recorded and reported. 
The serious adverse event is defined as following: 
Death 
Life-threatening condition 
Inpatient hospitalization or prolongation of existing hospitalization 
Persistent or significant disability/incapacity 
Congenital anomaly/birth defect 
Required intervention to prevent permanent impairment/damage 
˙ Severity Rating of AE 


 
   
       
                  
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BioLite, Inc.                 
萊特先進生醫股份有限公司 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
Grade 2    Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living 
(ADL)*. 
Grade 3 
Severe or medically significant but not immediately 
life-threatening; hospitalization or prolongation of hospitalization 
indicated; disabling; limiting self care ADL†. 
Grade 4    Life-threatening consequences; urgent intervention indicated. 
Grade 5    Death related to AE. 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
†Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, 
and not bedridden. 
˙ SOP 
Standard Operation Procedure 
˙ Study Cohort 
The Study Cohort is defined as a group or cohort of subjects who are assigned to 
take the same dose level of the study drug. 
˙ TLC 
Thin Layer Chromatography 
˙ TBZ 
Tetrabenazine 
 


 
   
       
                  
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BioLite, Inc.                 
萊特先進生醫股份有限公司 
1 BACKGROUND INFORMATION 
1.1 Description of PDC-1421 Capsule 
PDC-1421 Capsule is a botanical investigational new drug containing the extract of 
Radix Polygalae (Polygala tenuifolia Willd.) as active ingredient. Radix Polygalae is 
a traditional herb commonly prescribed in China to induce sedation, benefit the 
mentality and to promote expectoration. It has also been used for insomnia, anxiety, 
and heart palpitations1. 
 
1.1.1 Preparation 
Raw materials originated from P. tenuifolia were obtained from Shanxi, China. After 
having been cleaned, and residual stems removed, the root was sun-dried and become 
the botanical raw material for producing the study drug (PDC-1421 capsule). Raw 
materials shall comply with physical/chemical specifications, and fingerprint 
determination via HPLC and TLC shall show desired contents. The materials shall 
comply criteria for heavy metal, pesticide residues and aflatoxins to avoid 
contaminations. Acceptable raw materials were water extracted, partially purified by 
column chromatography, concentrated, and spray-dried to become the drug substance 
PDC-1421, a yellowish powder. The yield rate from raw materials to PDC-1421 is 
about 1.4 %. Formulation and encapsulation of drug substance PDC-1421 produced 
the final product of PDC-1421 Capsule. Specifications of PDC-1421 Capsule are 
tabulated in Table 1. 
 
Table 1. Specifications of PDC-1421 Capsule  
Test Items 
Specifications 
Physical 
Appearance 
Yellowish Granules in brownish capsule. 
Loss on Drying 
NMT 6% 
Water Extractives 
NLT 80% 
Dilute-Alcohol 
Extractives 
NLT 70% 
Total Ash 
NMT 5% 
Acid-Insoluble Ash 
NMT 4% 
Alcohol Extractives 
NLT 38% 


 
   
       
                  
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BioLite, Inc.                 
萊特先進生醫股份有限公司 
TLC 
1. One grayish blue band has same Rf  value as reference 
standard (3',6-disinapoylsucrose);  
2. One watchet blue band has same Rf  value as reference 
standard (Glomeratose A). 
HPLC of markers 
1. 
7.0 mg/g ≤ Glomeratose A ≤ 17.5 mg/g.  
2. 
38 mg/g ≤ 3',6-Disinapoylsucrose ≤ 95 mg/g. 
UV Spectrum  
λmax: 230 – 240 nm; 315 – 325 nm 
IR Spectrum (cm-1, 
%T) 
Peak at: 3380±100 Broad, 2938±20 Sharp, 1605±10 Sharp, 
1455±10 Sharp, 833±10 Sharp. 
pH 
Dissolved in distill deionized water at a concentration of 0.1 
g/ml, 3.8 ≤ pH ≤5.8. 
Uniformity 
90-110% 
Weight Variation 
90-110% 
Heavy Metal 
Cu < 20 ppm, As < 1 ppm,  
Pb < 5 ppm, Cd < 0.2 ppm, 
Hg < 0.1 ppm 
Microbial Purity 
Total aerobic plate count: NMT 103 CFU/g 
Mold and yeast count: NMT 100 CFU/g 
Echerichia coli: Undetectable 
Staphylococcus aureus: Undetectable 
Salmonella: Undetectable 
NMT: not more than; NLT: not less than  
 
PDC-1421 used in phase I clinical trial was manufactured at the Medical and 
Pharmaceutical Industry Technology and Development Center (PITDC) in New 
Taipei City, Taiwan. In order to scale up the production and in compliant with GMP 
(Good Manufacturing Procedures), the producer has been changed to the Herbal 
Medicine GMP Plant of the Industrial Technology Research Institute (ITRI) in 
Hsinchu County, Taiwan. Products produced at ITRI Plant have been tested and meet 
defined specifications prior to be used in this study. 
 
1.1.2 Composition 
Each PDC-1421 Capsule consists of 380 mg PDC-1421 drug substance and 20 mg of 
excipients. The composition of PDC-1421 Capsule is shown in Table 2. 
 
 
 


 
   
       
                  
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Protocol Number: BLI-1005-002 
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萊特先進生醫股份有限公司 
Table 2. Composition of PDC-1421 Capsule 
Name of Ingredient 
mg per Capsule 
Function 
PDC-1421 
380 mg 
Active ingredient 
Silicon dioxide 
10 mg 
Excipient 
Magnesium stearate 
10 mg 
Excipient 
 
1.1.3 Storage and Handling 
During stability test, physical examination, loss on drying and contents assays of the 
characteristic markers (3',6-disinapoylsucrose and Glomeratose A) were conducted. 
The results indicated that PDC-1421 Capsule is stable when stored in a well-closed 
brown bottle at room temperature (15 ~ 25℃) for at least 24 months. 
 
1.2 Non-clinical Study of PDC-1421 
Pharmacology studies were conducted at MDS Pharma Services, Taiwan. Non-clinical 
toxicity studies were conducted in accordance with Good Laboratory Practice at the 
Development Center for Biotechnology, Taiwan. Safety pharmacology studies were 
compliance with Good Laboratory Practice by Level Biotechnology, Inc. and Charles 
River Laboratory, Inc. 
 
1.2.1 Efficacy Pharmacology 
Two in vitro studies and one in vivo study have been completed to evaluate 
pharmacological activities of PDC-1421. 
 
1.2.1.1 Radio-ligand Binding Assay 
Radio-ligand binding assays were performed on 168 molecular targets, including 
receptors, ion channels and transporters, to discover the possible functional agonism 
and/or antagonism of PDC-1421 at concentration of 100 μg/ml. Table 3 showed the 
result in this study, indicating that PDC-1421 specifically inhibited norepinephrine 
transporter. Other molecules, such as histamine receptor or cholinergic receptor, were 
not significantly influenced. The results suggested that PDC-1421 shall not induce 
side effects such as hypersomnia or dry month. Subsequent studies applying different 
concentration showed that the inhibition of norepinephrine transporter by PDC-1421 
is dose-dependent, within 3 to 100 μg/ml. Norepinephrine transporter inhibitors have 
developed as antidepressants, such as imipramine, venlafaxine and reboxetine2. 
Therefore, PDC-1421 has the potential to be used as an antidepressant drug. The 


 
   
       
                  
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Protocol Number: BLI-1005-002 
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BioLite, Inc.                 
萊特先進生醫股份有限公司 
subsequent studies were performed to investigate the antidepressant activities of 
PDC-1421. 
 
Table 3. Summary of Significant Activities in radio-ligand binding assay 
Assay Name 
IC50 (μg/ml) 
Norepinephrine Transporter (NET) Binding 
11.8 
 
1.2.1.2 Neurotransmitter Uptake Assay 
Many antidepressants, including selective serotonin reuptake inhibitor or 
serotonin/norepinephrine reuptake inhibitor, are related to the inhibition of 
neurotransmitter reuptake3. Uptake assays were conducted to study the effect of 
PDC-1421 on the reuptake of norepinephrine, serotonin and dopamine. The results of 
uptake assay are summarized in Table 4.  
 
Table 4. Summary for neurotransmitter uptake assay 
Assay Name 
Test Substance 
Dose 
Inhibition 
% 
IC50 
Norepinephrine 
Uptake 
PDC-1421 
Desipramine 
1 μg/mL 
52 
0.70 μg/mL 
0.44 μg/mL 
(1.66 nM) 
Dopamine 
Uptake 
PDC-1421 
Nomifensine 
300 μg/mL 
55 
246 μg/mL 
1.62 μg/mL 
(6.83 nM) 
Serotonin 
Uptake 
PDC-1421 
Fluoxetine 
100 μg/mL 
52 
107 μg/mL 
0.87 μg/mL 
(2.83 nM) 
 
PDC-1421 inhibited Norepinephrine reuptake at a 0.70 μg/mL, much lower than of 
the concentration to inhibit dopamine (246 μg/mL) or serotonin (107 μg/mL). The 
results indicated that primary pharmacological effect of PDC-1421 may be with its 
norepinephrine reuptake inhibition, rather than serotonin or dopamine reuptake 
inhibition. The results are consistent with radio-ligand binding assay, indicated that 
PDC-1421 is highly specific in the inhibition of norepinephrine transporter.  
 


 
   
       
                  
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Protocol Number: BLI-1005-002 
Protocol Version: 2.3 
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Confidential 
BioLite, Inc.                 
萊特先進生醫股份有限公司 
1.2.1.3 Tetrabenazine (TBZ)-induced Hypothermia Model 
According to above assays, PDC-1421 is a selective norepinephrine reuptake inhibitor. 
A previous study has shown that the elevated concentration of norepinephrine 
produced by norepinephrine reuptake inhibitor (NRI) resulted in elevation of body 
temperature in reserpine-induced hypothermia animal model4. Reversed temperature 
in hypothermia model is an index to quantify the effect of NRI. Several studies have 
been conducted using this model to evaluate the antidepressant effects of 
investigational drugs5, 6and support the usefulness of the TBZ Hypothermia model. 
 
PDC-1421 was tested by the TBZ-induced hypothermia model to study the possible 
effect on depression. Vehicle, PDC-1421 and imipramine (positive control) were 
orally administrated to individual groups of experimental mice one hour before TBZ 
treatment and body temperatures were recorded at appropriate time point. The results 
were summarized in Table 5. 
 
Table 5. Summary for pharmacology study of antidepressant-like effect 
Treatment 
Dose 
(mg/kg) 
% Inhibition in Body Temperature 
60 min after TBZ 90 min after TBZ 120 min after TBZ 
PDC-1421 
10 
5 
0 
0 
PDC-1421 
30 
30 
33 
27 
PDC-1421 
100 
      55* 
      59* 
       63* 
PDC-1421 
300 
      77* 
      74* 
       80* 
Imipramine 
3 
      89* 
      84* 
       83* 
* The inhibition of TBZ-induced hypothermic response by ≧50% is considered as 
significant response 
 
The results suggest that PDC-1421 at 100 mg/kg p.o. may be associated with 
antidepressant activity as evidenced by effect on TBZ-induced hypothermia in mice.  
 
1.2.2 Safety Pharmacology 
In order to verify the possible effects other than antidepressant, five studies were 
conducted to evaluate the effects of PDC-1421 on central nervous system, autonomic 
system, cardiovascular function, respiratory function, gastrointestinal system, renal 
function, allergy, inflammation, metabolism and hERG tail current assay: 
• 
EfficacyProfiling in vivo® 


 
   
       
                  
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• 
Safety Pharmacology Testing Package 
• 
AdverseEventProfiling in vivo®  
• 
Safety Pharmacology test in Central Nervous System, Cardiovascular 
System and Respiratory System 
• 
hERG tail current assay 
The significant findings were summarized in Table 6. 
 
Table 6. Summary of the finding in safety pharmacology 
Study package 
Study condition and findings 
EfficacyProfiling  
˙ Oral administration of PDC-1421 at 3000 
mg/kg did not cause any significant change in 
vivo studies. 
˙ PDC-1421 at 300 μg/ml did not demonstrate 
any significant activity (≧50% change) in vitro 
studies. 
Safety Pharmacology 
Testing Package 
PDC-1421 concentration at 300 μg/mL: 
˙ Decrease in acetylcholine and BaCl2-induced 
constriction in guinea pig ileum. 
AdverseEventProfiling 
in vivo® 
PDC-1421 oral dose at 3000 mg/kg: 
˙ Inhibition of gastric emptying in fasted rats 
(-45%) 
PDC-1421 oral dose at 3000 mg/kg for 7 days: 
˙ Increase in RBC on day 2 in blood chemistry 
˙ Increase in K+ and decrease in glucose on day 
2 in blood chemistry 
˙ Decrease in LDH (lactate dehydrogenase) on 
day 8 in blood chemistry 
Safety Pharmacology 
test in Cardiovascular 
System 
˙ RR interval elongation, heart rate decrease, 
diastolic 
arterial 
pressure 
decrease 
and 
increased sinoatrial arrest incidence were 
found in dogs in 2500mg/kg group.  
 
˙ Diastolic arterial pressure decrease was found 
in dogs in 2500mg/kg group. 
hERG tail current assay Below the dosage, 0.8mg/ml PDC-1421, should be 
viewed as the “no effect concentration” in this 
assay. 


 
   
       
                  
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Few effects, including gastrointestinal effects, electrolytes equilibrium, blood sugar 
value, heart rate decrease and diastolic arterial pressure decrease were found in safety 
pharmacology. These findings provided scientific evidence in further clinical study to 
evaluate the influence of PDC-1421. 
 
1.2.3 Cytochrome P450 Interaction with PDC-1421 
Cytochrome P450 (CYP450) enzyme assay was conducted for PDC-1421 to evaluate 
existence of potential drug interaction. The IC50 values of each CYP450 isozymes are 
summarized in Table 7.  
 
Table 7. Summary of IC50 values of CYP450 isozymes 
CYP isozyme 
Species 
Concentration 
Inhibition % 
IC50 
CYP 1A2 
Human 
100 μg/mL 
54 
84 μg/mL 
CYP 2C9 
Human 
100 μg/mL 
57 
74 μg/mL 
CYP 2C19 
Human 
100 μg/mL 
67 
51 μg/mL 
CYP 2D6 
Human 
100 μg/mL 
69 
53 μg/mL 
CYP 3A4 
Human 
100 μg/mL 
58 
67 μg/mL 
 
A lower potential of causing drug-drug interaction was verified with lower CYP450 
inhibition in this study. IC50 of CYP inhibition is higher than IC50 of in vitro 
pharmacological study (11.8 and 0.7 μg/mL in NET radioligand binding assay and 
reuptake assay, respectively), indicating that taking PDC-1421 with substrate of these 
CYP enzymes, including imipramine, paroxetine and warfarin, may not influence the 
blood concentration of these prescribed drugs. 
1.2.4 Toxicology 
Toxic effects of investigational drug are important considerations for human use. 
Several toxicology studies have been conducted to evaluate the toxic effects of 
PDC-1421. 
 
1.2.4.1 Single Dose Acute Toxicity Study in Rats 
Acute toxicity of test drug may predict effect of over dose. Four doses of PDC-1421 
at 0, 1250, 2500 and 5000 mg/kg p.o. were given to different groups of rats. General 
demeanor, clinical signs, mortality, body weight and gross necropsy findings were 
evaluated and recorded. There has been no treatment-related pharmacological effect 


 
   
       
                  
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found with all 4 doses. Therefore, the “no observable adverse effect level” (NOAEL) 
is set at 5000 mg/kg in rats based on the results of this study. 
 
1.2.4.2 28-day Repeated Dose Subacute Toxicity Study in Rats 
The duration of repeated dose toxicity study will be extrapolated to human therapeutic 
duration. Thus, toxic effects related to test drug dose in long term administration and 
determination of NOAEL are very important in further clinical study. Four groups of 
rats were administered with 0, 750, 1500 and 3000 mg/kg /once daily p.o. for 28 days 
respectively. Moribundity/mortality, clinical signs, body weight, food consumption, 
ophthalmology, clinical pathology (including urinalysis, hematology and serum 
chemistry), gross necropsy, organ weight and histopathology, were evaluated on those 
experimental rats. No death nor severe side effects had been observed. However, 
some effects were considered treatment-related as shown in Table 8: 
 
Table 8. Summary of 28-day repeated dose toxicity study in rats 
Group 
1 
2 
3 
4 
Dose (mg/kg/day) 
0 
750 
1500 
3000 
Male 
 
 
 
 
Calcium (mg/dL)1 
10.7 ± 0.7 
10.8 ± 0.8 
10.4 ± 0.9 
9.6 ± 0.5* 
Female 
 
 
 
 
Sodium (mEq/L)2 
147.4 ± 1.8 
148.1 ± 1.6 
147.8 ± 1.8 
150.5 ± 2.1* 
Thymus weight (mg) 
501.3 ± 122.9 449.4 ± 91.7 
418.4 ± 66.7 
377.2 ± 81.2* 
Reference range: 1: 10.5~12.2; 2: 136~156 
*: p < 0.05 
Concluded by the investigating institute, those abnormal are mild and did not 
influence the physical condition of experimented rats. Therefore, NOAEL for 
PDC-1421 in rats under this study condition is 3000 mg/kg/day. 
 
1.2.4.3 28-day Repeated Dose Subacute Toxicity Study in Dogs 
In order to determine NOAEL in dogs, PDC-1421 was repeatedly administered to 4 
groups of dogs at dose levels of 0, 300, 1000, 3000 mg/kg once daily for 28 days. Soft 
feces were found in male dogs at 3000 mg/kg. There are several differences of 
physical value, lower mean corpuscular volume and monocytes in males and lower 
cholesterol and triglyceride in females, between test groups and control group, but these 
effects are not treatment-related or dose-dependent and within DCB (Development 
Center for Biotechnology) historical data range. Therefore, NOAEL for PDC-1421 in 
dogs is set at 3000 mg/kg. 


 
   
       
                  
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1.2.4.4 13-week Repeated Dose Subchronic Toxicity Study in Rats 
To evaluate the subchronic toxicity of PDC-1421, four groups of rats were 
administered with 0, 750, 1500 and 2500 mg/kg/once daily p.o. for 13 weeks (90 
days). There are no treatment-related mortality, clinical signs of toxicity and 
ophthalmologic abnormality in the study. And no significant toxicity evidences in 
mean body weights, mean body weight gains and food consumption in all treatment 
groups were noted.  
 
In clinical pathology, no toxicity evidences were noted for all parameters (hematology, 
serum chemistry and urinalysis), no treatment-related gross abnormality was found at 
necropsy, and no significant toxicity evidences in organ weights evaluation. And the 
histopathological findings showed that no treatment-related changes in vehicle control 
and PDC-1421 treated groups.  
 
It was estimated that the NOAEL of PDC-1421 of the 13-week repeated dose toxicity 
study is 2500 mg/kg/day for both males and females. 
 
1.2.4.5 Genotoxicity 
Three studies, including Ames test, micronucleus test and chromosome aberration 
assay, were conducted to evaluate the genotoxicity of PDC-1421. In Ames test, five 
different strains of Salmonella typhimurium were used to evaluate the mutagenic 
potential when incubated at different concentration of PDC-1421. No mutation 
induced by PDC-1421 was observed. In micronucleus test, three doses of PDC-1421 
at 500, 1000, 2000 mg/kg p.o. were administered to three different groups of BALB/c 
mice and the ability of PDC-1421 to induce micronucleated reticulocytes in mouse 
peripheral blood was measured. The results of this study indicated that PDC-1421 
posed-negative response to clastogenic micronucleated reticulocytes in mice. In 
chromosome aberration assay, clastogenic activity was evaluated in Chinese hamster 
ovary (CHO) cells after adding the different concentration of PDC-1421. Based on the 
results of this study, chromosomes in CHO cells are not affected by PDC-1421. In 
conclusion, PDC-1421 does not pose any risk of genotoxicity.  
 
1.3 Results of Phase I Clinical Trial Study of PDC-1421  
In phase I trial, all total of 85 subjects were screened at study site and 30 subjects 
were enrolled. They were 9 subjects in cohort A with 7 administered PDC-1421 (380 
mg) and 2 administered placebo, 1 of 7 PDC-1421 subjects (P01) had no laboratory 


 
   
       
                  
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test data at baseline; 8 subjects in cohort B with 6 administered PDC-1421 (1140 mg) 
and 2 administered placebo; 4 subjects in cohort C with 3 administered PDC-1421 
(2280 mg) and 1 administered placebo; 9 subjects in cohort D with 7 administered 
PDC-1421(3800 mg) and 2 administered placebo, 1 of 7 PDC-1421 subjects (P27) 
had abnormal laboratory data at screening visit. 
 
Physical examination was determined to be “normal” on every Body System in each 
cohort and no subject had DLT and toxicity grade. 
 
All of the changes of vital signs from baseline of PDC-1421 and placebo group were 
mild and did not exceed the limit of normal range. Furthermore, all of the toxicity 
grades of vital signs were the lowest, systolic blood pressure in grade 1, increase >20 
mm/Hg than baseline at 4 hour. No medical intervention/therapy was required. There 
were no correlation of changes from baseline or changes in the toxicity grade of vital 
signs between doses of PDC-1421. 
 
All changes of laboratory test data from baseline of PDC-1421 group were mild and 
no clinically significant deviation from the normal range. Furthermore, the toxicity 
grades of laboratory test data of PDC-1421 and placebo groups were the lowest, grade 
1. No medical intervention/therapy was required. There were no correlation of change 
from baseline or change in the toxicity grade of laboratory test between doses of 
PDC-1421. Only two grade 2 toxicity (at 24 hour in glucose in cohort A and at 4 hour 
in glucose in cohort B) occurred in placebo group and no medical intervention/therapy 
were required for these cases. 
 
ECG was determined to be “normal” in each time point and in each cohort. No subject 
had DLT and toxicity grade. 
 
C-SSRS were all 0 point on Suicidal ideation, Intensity of ideation, Suicidal behavior 
in each cohort. 
 
No subject had serious adverse event and no subject discontinued due to adverse 
event, no clinically significant finding in physical examinations, vital signs, 
electrocardiogram, laboratory measurements, and C-SSRS was observed throughout 
the treatment period, and the oral administration of PDC-1421 in healthy volunteers 
was safe and well-tolerated for the dose from 380 mg to 3800 mg. During the 
treatment period, 5 subjects reported to experience 8 mild adverse events shown as 


 
   
       
                  
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Table 9. The severity of these 8 adverse events was all mild and no medical action 
required. There was no correlation between number, severity, relationship and 
outcome of adverse events found between doses of PDC-1421 and placebo. Further, 
there was no clinically significant finding in electrolyte level and gastrointestinal 
discomfort during monitoring in the clinical trial. There were two mild adverse events 
such as lower heart rate and higher systolic blood pressure. Lower heart rate was that 
coupled to the dog telemetry study but not higher systolic blood pressure.  
 
Table 9. Frequencies of Adverse Events 
Adverse events 
Frequency 
BODY System 
 
Cohort A 
(380 mg) 
N=7 
Cohort B 
(1140 mg) 
N=6 
Cohort C 
(2280 mg) 
N=3 
Cohort D 
(3800 mg) 
N=7 
Placebo 
N=7 
Digest System 
3/7 
0 
0 
0 
1/7 
     FLATULENCE 
2/7 
0 
0 
0 
1/7 
CONSTIPATION 
1/7 
0 
0 
0 
0 
Nervous System 
0 
0 
2/3 
0 
2/7 
SOMNOLENCE 
0 
0 
1/3 
0 
2/7 
STOMATITIS 
ULCER 
0 
0 
1/3 
0 
0 
 
1.4 Potential Risk and Benefit 
1.4.1 Potential Risk 
The toxicological profile of PDC-1421 was characterized in single and repeat oral 
dose studies of up to 13 weeks in rats and repeat oral dose studies of up to 28 days in 
dogs. Genetic toxicology and safety pharmacology have also been conducted. 
PDC-1421 was observed to be associated with some adverse effects in serum 
electrolytes and GI function, but none were clinically significant. Therefore, potential 
risks of PDC-1421 are fluctuated electrolyte level and gastrointestinal discomfort. We 
monitored these in the Phase I study and there was no deviation of electrolyte level 
and no significant gastrointestinal discomfort during monitoring in the clinical trial. 
However, there were non-clinically significant mild lower diastolic blood pressure 
and lower heart rate in dog telemetry study and it has been only with the 2500 mg/kg, 
which is around the NOAEL for dogs. The cardiovascular systems will be monitored 
in the clinical study. 


 
   
       
                  
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1.4.2 Potential Benefit 
According to nonclinical study results, the results of two in vitro assays support the 
fact that PDC-1421 is a selective norepinephrine reuptake inhibitor and its potency are 
not inferior to other antidepressants. A TBZ-induced hypothermia study has shown 
that PDC-1421 is associated with antidepressant activity. Furthermore, PDC-1421 
will not pose the adverse effects caused by the molecules which possess 
anticholinergic or antihistamine activities due to its selectivity on norepinephrine 
transporter. 
 
1.4.3 Risk Benefit Ratio 
Potential risks in nonclinical results outlined above are minor and easy to monitor. 
Even though there were adverse events in phase I trial, they were no consistent 
findings in the direction of changes of potential risks in nonclinical studies. Therefore, 
the subsequent trial could be benefited from the information obtained from this study.  
 
1.5 Dosage Regimen  
Based on the FDA’s guidance documents, NOAELs from toxicity studies were used to 
estimate the starting dose in our study. Table 10 summarizes the MRSD for 60 kg 
human/day calculated from the NOAEL of 28 day repeating dose studies in rats and in 
dogs using safety margin at 75-fold. 
 
Table 10. Calculation of starting dose 
Study 
Species 
Dosage 
HED 
Dose for 60 kg 
human/day 
28-day repeated dose subacute oral 
toxicity study in rats 
rat 
3000 mg/kg 
(NOAEL) 
483.9 mg/kg 
387 mg/day 
(MRSD) 
28-day repeated dose subacute oral 
toxicity study in dogs 
dog 
3000 mg/kg 
(NOAEL) 
1666.7 mg/kg 
1333 mg/day 
(MRSD) 
Based on these calculations, we proposed the starting dose of PDC-1421 to be at 380 
mg/day. In the phase I study, a single dose of PDC-1421 (oral administration) was 
used to evaluate the safety when taken by healthy subjects. The starting dose and 
dosage regimen are:  
    
380 mg PDC-1421 (one capsule of PDC-1421 Capsule) once daily after meal. 
  
The dose escalation as follows. 
Cohort A (one capsule; 380 mg):  


 
   
       
                  
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Cohort A enrolled 9 subjects. Seven subjects received PDC-1421 Capsule and two 
received placebo. There was only one of placebo subjects who met a DLT due to the 
glucose value at 24 hours after drug administration. We continued the study to the 
next higher dosage, cohort B.  
Cohort B (three capsules; 1140 mg): 
Cohort B enrolled 8 subjects. Six subjects received PDC-1421 Capsule and two 
received placebo. There was only one of placebo subjects who met a DLT due to the 
glucose value at 4 hours after drug administration. We continued the study to the next 
higher dosage, cohort C. 
Cohort C (six capsules; 2280 mg): 
Cohort C enrolled 4 subjects. Three subjects received PDC-1421 Capsule and one 
received placebo. There was no DLT in this cohort. We continued the study to the next 
higher dosage, cohort D. 
Cohort D (ten capsules; 3800 mg): 
Cohort D enrolled 9 subjects. Seven received PDC-1421 Capsule and two received 
placebo. There is no DLT in the final cohort.  
Based on the results, the maximum tolerated dose (MTD) is ≧3800 mg of PDC-1421 
Capsule so that the safe and well-tolerated for PDC1-421 Capsule is from 380 mg to 
3800 mg. According to studies in mouse model system to evaluate efficacious dose, 
TBZ-induced hypothermia assay, PDC-1421 was indicated to be efficient at 100 
mg/kg and 300 mg/kg doses which are equivalent to about 480 mg and 1400 mg in 
human subjects. We choose 1140 mg (3 capsules), between the efficient dosage, and 
2280 mg (6 capsules), above the efficient dosage, which is based on the mice study as 
the dosage regimen of Phase II trial.  


 
   
       
                  
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1.6 Compliance with Protocol, Good Clinical Practice (GCP) 
and Applicable Requirement 
This study and all operating procedures will be conducted in accordance with GCP 
guidelines, protocol and all applicable regulatory requirements issued by the Minister 
of Health and Welfare (MOHW) in Taiwan and US FDA, to protect the rights, safety 
and well-being of the studying subjects. 
 
1.7 Description of the Population to be Studied 
We chose patients with major depressive disorder as our subjects in this phase II trial. 


 
   
       
                  
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2 TRIAL OBJECTIVE 
The primary objective of this trial was to determine the effective doses and treatment 
period of PDC-1421 Capsule in subjects with MDD. The secondary objective was to 
evaluate the safety of PDC-1421 Capsule in subjects receiving PDC-1421at various 
dose levels. 
3 TRIAL DESIGN 
3.1 General Design 
Table 11. Summary of general design 
 
Part I 
Part II 
Design 
Open label, multiple center, 
dose escalation 
Double-blind, randomized, 
parallel group, 
placebo-controlled 
MDD patients 
12 
60 
Treatment 
(1) 1 capsule TID, 6 MDD 
patients, 28 days 
(2) Checkpoints 
(3) If passing the checkpoint:  
2 capsules TID, another 6 
MDD patients, 28 days 
(4) Checkpoints 
Randomly assigned on a 
1:1:1 basis to one of the 
three arms: 
(1) 1 PDC-1421 Capsule 
plus 1 placebo TID 
(2) 2 PDC-1421 Capsule 
TID 
(3) 2 Placebo TID 
for 42 days 
Assessment 
interval 
First week: twice, 3-4 days 
interval; Once a week during 
the following second to fourth 
week 
Biweekly 
Efficacy and safety 
evaluation 
˙ Safety evaluation  
˙ Efficacy evaluation 
˙ Primary endpoint: 
efficacy measurement 
(MADRS) 
˙ Secondary endpoints: 
other efficacy and safety 
measurements (MADRS, 
DSSS, HAM-D-17, 


 
   
       
                  
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HAM-A, CGI, C-SSRS, 
ECG, vital sign, physical 
examination, hematology, 
blood chemistry and 
concomitant medication 
evaluation) 
The screening phase is intended for diagnosing and assessing the patient for possible 
inclusion in the study and for providing an adequate washout period. The following 
study will be conducted in two parts. The targeted population of this study is 72 
subjects who met the intent-to-treat (ITT) basis, in which 12 are assigned to part I, 60 
are assigned to part II. Part I is an open-label study, multiple center and dose 
escalation evaluation in twelve patients. Six subjects each will be evaluated for any 
safety concerns at 1 or 2 capsules TID dose for 28 days, sequentially. Each of them 
will be assessed twice in the first week after administration of PDC-1421 Capsules 
and once a week in the following treatment. Part II is a randomized, double-blind, 
placebo-controlled, parallel-group study. 60 subjects will be randomly assigned on a 
1:1:1 basis to one of the three treatment arms (1 PDC-1421 Capsule plus 1 placebo 
TID, 2 PDC-1421 Capsule TID, 2 placebo TID) for 6 weeks (42 days) and evaluated 
the safety and efficacy every two weeks during the treatment period. The 
performance of PDC-1421 Capsule on MDD subjects will provide us with valuable 
information for our next phase of the study. 


 
   
       
                  
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Figure 1. General design of procedure 
Part I. 
 
Part II.  
 
 
3.2 Primary Endpoint  
In part II, the primary endpoint is the change of Montgomery-Å sberg Depression 
Rating Scale (MADRS) total score from baseline to Week 6 compared to placebo. 
 
 
 


 
   
       
                  
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3.3 Secondary Endpoint  
Table 12   The secondary efficacy endpoints in part II 
Number 
Items 
1 
MADRS total score－change from baseline to Visit 3 and 6 (Week 2 and 
7). 
2 
HAM-D-17, CGI, DSSS and HAM-A－change from baseline to Visit 3, 
4, 5 and 6 (Week 2, 4, 6 and 7) 
3 
Percentage of partial responders and responders (defined as participants 
with a 25-50% decrease and a ≧50% decrease from baseline in total 
score, respectively) in MADRS total score by Week 2, 4, 6 and 7. 
4 
Safety evaluation－measurements of physical examination, vital signs, 
laboratory data, ECG, Columbia-Suicide Severity Scale (C-SSRS) and 
adverse events reports from screening stage to the last visit. 
5 
Difference in the mean changes of MADRS, HAM-D-17, HAM-A, 
DSSS, CGI and C-SSRS from baseline to week 2, 4, 6 and 7 between 
PDC-1421 Capsule and placebo groups. 
 
3.4 Randomization and Blinding 
Table 13. Summary of randomization and blinding 
 
Part I 
Part II 
Randomization 
None (open label) 
Randomized; 
1 capsule TID: 2 capsules TID: 
placebo = 1:1:1 
Blinding 
None (open label) 
Double-blind; 
(1) Unblinding at the end of 
trial 
(2) Emergency unblinding at a 
serious adverse event. 
 
The randomization scheme generated by computer will be prepared by the CRO prior 
to the start of the study. In part II, subjects will be randomly allocated to the group of 
one of PDC-1421 Capsule (3 or 6 capsules) or placebo in a ratio of 1:1:1. All subjects 
and medical staff will be blinded to the treatment assigned till the end of the trial. All 
emergency unblinding (e.g., due to a serious adverse event) should be reported 
immediately to the BioLite, Inc. Codes linking randomization number to actual 


 
   
       
                  
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treatment for each subject will be secured in a sealed, opaque envelop and maintained 
in the study site and research department of BioLite, Inc. 
 
3.5 Investigational Drug 
Investigational drug (PDC-1421 Capsule or placebo) will be maintained and dispensed 
by the Department of Pharmacy of all clinical sites. No one but the Investigator and/or 
his/her designee is permitted to access the investigational drug. 
 
3.5.1 Dosage Form and Strength 
PDC-1421 Capsule: 380 mg PDC-1421/capsule 
Placebo: 380 mg corn starch/capsule 
 
3.5.2 Manufacturer 
ITRI (Industrial Technology Research Institute), Hsinchu County, Taiwan 
 
3.5.3 Route of Administration 
Oral administration 
 
3.5.4 Dosing Regimen, packing and labeling 
Table 14. Summary of dosing regimen  
 
Part I 
Part II 
Visits 
Once a week (twice in the first 
week) for 28 days 
Biweekly for 42 days 
Study drug bags 
21 packs for the following 
week, total 84 packs 
42 packs for the following two 
weeks, total 126 packs 
Dosing regimen 
Each pack including (1) or (2): 
 
(1) 1 capsule of PDC-1421 
(380 mg), TID 
 
(2)  After passing the 
checkpoint, 2 capsules of 
PDC-1421 (380 mg), TID 
Each pack including (1), (2) or 
(3): 
 2 capsules, TID:  
1 capsule of PDC-1421 (380 
mg) and 1 capsule of placebo 
TID 
 2 capsules, TID:  
2 capsules of PDC-1421 (380 
mg) and 0 capsule of placebo 
TID 
 Placebo: 


 
   
       
                  
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0 capsule of PDC-1421 (380 
mg) and 2 capsules of placebo 
TID 
 
In part I, six subjects each will take 1 or 2 capsules thrice daily for 28 days, 
sequentially. Subjects are assessed twice in the first week after drug administration 
and they will receive the study drug bag for the following 7 days every week. In part 
II, eligible subjects are randomized into one of three treatment arms in a 1:1:1 ratio 
(one capsule of PDC-1421 Capsule and placebo thrice daily; two capsules of 
PDC-1421 Capsule thrice daily; two capsules of placebo thrice daily) for 42 days. 
After the two weeks of drug administration, subjects will return to the center for 
assessments then get another study drug bag for the following 14 days. The biweekly 
clinic visits are three times and one week later after the last dose for follow-up.  
 
Investigational drug (PDC-1421 Capsule or placebo) are provided by BioLite, Inc. 
and stored in Department of Pharmacy of each clinical site. In part I, the first six 
subjects will take 21 packs with 21 capsules of PDC-1421 Capsule and another six 
take 21 packs with 42 capsules of PDC-1421 Capsule in every week of trial. In part II, 
subjects will be dispensed with study drug per 2 weeks which are packaged in a drug 
bag. A drug bag will contain 42 packs. Depending on the study arms, each pack may 
contain 2 PDC-1421 Capsules, 2 placebos or 1 PDC-1421 Capsule plus 1 placebo. 
Each subject will be administered 126 packs in the end of trial. The drug bag of 
investigational drug is clearly labeled as following:  


 
   
       
                  
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Protocol Number: BLI-1005-002 
Protocol Version: 2.3 
Date: 2018/03/16 
Confidential 
BioLite, Inc.                 
萊特先進生醫股份有限公司 
For Part I-low dose (380 mg TID): 
Test Drug: PDC-1421 Capsule 
Amount:       capsules (     reserved capsules included) 
Subject Number: 
Drug Pack Number: 
 
Study Protocol: BLI-1005-002 
Drug Appearance: Brown capsule containing yellow powder 
Major Component: Each capsule contains 380 mg of PDC-1421 
Dosing: 1 capsule thrice daily after meal for OO days and with extra OO days for 
reserved 
Storage Condition: Store at a dry place at room temperature (15~25℃) 
Lot Number:  
Manufacturer: Industrial Technology Research Institute 
Date of Manufacture:  
Date of Expiration:  
Sponsor: BioLite, Inc. 
Clinical Site: Taipei Veterans General Hospital, Linkou Chang Gung Memorial 
Hospital and Taipei City Hospital, Songde Branch. 
 
"Caution: New drug - Limited by Federal Law to investigational use". 
注意：試驗新藥僅限特定臨床試驗使用 
試驗藥物: PDC-1421 膠囊 
數量:     顆膠囊 (含    顆備用膠囊) 
藥物編號:  
受試者編號:  
回診次別: Visit    
計畫書編號: BLI-1005-002 
藥物外觀: 棕色膠囊內含黃色粉末 
主成份: 每顆膠囊含有380 mg PDC-1421  
劑量: 三餐飯後服用1 顆膠囊，OO 日份 (外加OO 日備用藥) 
儲存條件: 儲存於乾燥常溫之環境 (15~25℃) 
批號:  
製造商: 工業技術研究院 
製造日期:  
有效日期:  
廠商: 萊特先進生醫股份有限公司 
試驗機構:  臺北榮民總醫院，林口長庚紀念醫院，臺北市立聯合醫院松德院區 
 
"Caution: New drug - Limited by Federal Law to investigational use". 
注意：試驗新藥僅限特定臨床試驗使用 


 
   
       
                  

Protocol 
27 

Protocol Number: BLI-1005-002 
Protocol Version: 2.3 
Date: 2018/03/16 
Confidential 
BioLite, Inc.                 
萊特先進生醫股份有限公司 
For Part I-high dose (760 mg TID): 
Test Drug: PDC-1421 Capsule 
Amount:       capsules (     reserved capsules included) 
Subject Number:  
Drug Pack Number: 
 
Study Protocol: BLI-1005-002 
Drug Appearance: Brown capsule containing yellow powder 
Major Component: Each capsule contains 380 mg of PDC-1421 
Dosing: 2 capsules thrice daily after meal for OO days and with extra OO days for reserved 
Storage Condition: Store at a dry place at room temperature (15~25℃) 
Lot Number:  
Manufacturer: Industrial Technology Research Institute 
Date of Manufacture:  
Date of Expiration:  
Sponsor: BioLite, Inc. 
Clinical Site: Taipei Veterans General Hospital, Linkou Chang Gung Memorial Hospital and 
Taipei City Hospital, Songde Branch. 
 
"Caution: New drug - Limited by Federal Law to investigational use". 
注意：試驗新藥僅限特定臨床試驗使用 
試驗藥物: PDC-1421 膠囊 
數量:     顆膠囊 (含    顆備用膠囊) 
藥物編號:  
受試者編號: 
回診次別: Visit    
計畫書編號: BLI-1005-002 
藥物外觀: 棕色膠囊內含黃色粉末 
主成份: 每顆膠囊含有380 mg PDC-1421 
劑量: 三餐飯後服用2 顆膠囊，OO 日份 (外加OO 日備用藥) 
儲存條件: 儲存於乾燥常溫之環境 (15~25℃) 
批號:  
製造商: 工業技術研究院 
製造日期:  
有效日期:  
廠商: 萊特先進生醫股份有限公司 
試驗機構:  臺北榮民總醫院，林口長庚紀念醫院，臺北市立聯合醫院松德院區 
 
"Caution: New drug - Limited by Federal Law to investigational use". 
注意：試驗新藥僅限特定臨床試驗使用 


 
   
       
                  

Protocol 
28 

Protocol Number: BLI-1005-002 
Protocol Version: 2.3 
Date: 2018/03/16 
Confidential 
BioLite, Inc.                 
萊特先進生醫股份有限公司 
For Part II: 
Test Drug: PDC-1421 Capsule/placebo 
Amount:       capsules (     reserved capsules included) 
Subject Number:  
Drug Pack Number:  
Visit Number: 
Study Protocol: BLI-1005-002 
Drug Appearance: Brown capsule containing yellow powder 
Major Component: Each capsule contains 380 mg of PDC-1421/placebo 
Dosing: 2 capsules thrice daily after meal for OO days and with extra OO day for reserved 
Storage Condition: Store at a dry place at room temperature (15~25℃) 
Lot Number:  
Manufacturer: Industrial Technology Research Institute 
Date of Manufacture:  
Date of Expiration:  
Sponsor: BioLite, Inc. 
Clinical Site:  
"Caution: New drug - Limited by Federal Law to investigational use". 
注意：試驗新藥僅限特定臨床試驗使用 
試驗藥物: PDC-1421 膠囊/安慰劑 
數量:     顆膠囊 (含    顆備用膠囊) 
藥包編號:  
受試者編號: 
回診次別: Visit    
計畫書編號: BLI-1005-002 
藥物外觀: 棕色膠囊內含黃色粉末 
主成份: 每顆膠囊含有380 mg PDC-1421 或安慰劑 
劑量: 三餐飯後服用2 顆膠囊，OO 日份 (外加 OO 日備用藥) 
儲存條件: 儲存於乾燥常溫之環境 (15~25℃) 
批號:  
製造商: 工業技術研究院 
製造日期:  
有效日期:  
廠商: 萊特先進生醫股份有限公司 
試驗機構:  
"Caution: New drug - Limited by Federal Law to investigational use". 
注意：試驗新藥僅限特定臨床試驗使用 
 
3.5.5 Study Drug Storage 
Investigational drugs will be stored in a locked cabinet at room temperature (15~25℃) 


 
   
       
                  

Protocol 
29 

Protocol Number: BLI-1005-002 
Protocol Version: 2.3 
Date: 2018/03/16 
Confidential 
BioLite, Inc.                 
萊特先進生醫股份有限公司 
in Department of Pharmacy of each clinical site.  
3.6 Premature Termination or Suspension of the Study 
The Investigator and/or the Sponsor may decide to stop the trial if: 
• 
Safety assessment clearly indicates that one study arm is associated with more 
severe or serious adverse experiences. 
• 
The Sponsor decides to terminate the trial if necessary.


 
   
       
                  

Protocol 
30 

Protocol Number: BLI-1005-002 
Protocol Version: 2.3 
Date: 2018/03/16 
Confidential 
BioLite, Inc.                 
萊特先進生醫股份有限公司 
 
4 SUBJECTS SELECTION AND WITHDRAWAL 
Inclusion and exclusion criteria in part I and part II are as follows.  
4.1 Inclusion Criteria 
1. Outpatients aged 20-65 years. 
2. Subjects must be able to understand and willing to sign informed consent. 
3. Female subjects of child-bearing potential must test negative to pregnancy and 
use appropriate birth control method from the beginning of study to the 15 days 
later after ending of study. 
4. Met criteria for MDD without psychotic features as defined by the Diagnostic and 
Statistical Manual of Mental Disorders, Fourth Edition Text Revision® 
(DSM-IV-TR) and confirmed by use of the Mini International Neuropsychiatric 
Interview (MINI). 
5. 17-item HAM-D (Hamilton Rating Scale for Depression) total score ≧20 and 
CGI (Clinical Global Impression) total score ≧4. 
4.2 Exclusion Criteria 
1.  Have a current or previous major psychiatric disorders which be defined to be per 
the DSM-IV-TR, including obsessive-compulsive disorder, posttraumatic stress 
disorder, bipolar I or II, manic or hypomanic episode, schizophrenia, major Axis II 
disorders which might compromise the study, and major depression with 
psychotic symptoms, mental retardation.  
2.  Use of any treatment for MDD in the last 2 weeks before visit 1 (4 weeks for 
fluoxetine). 
3.  Use of psychoactive drugs within the last 2 weeks before visit 1 other than that 
subjects had insomnia who need the treatment as determined by the Investigator.  
4.  Subjects who were non-responsive to two or more courses of antidepressant 
medications given an adequate dosage* for symptom treatment within four 
weeks, or by the judgment of the investigator considered to have treatment 
resistant depression (TRD), or a history of electroconvulsive therapy (ECT), 
transcranial magnetic stimulation (TMS) or psychosurgery within the last year. 
5.  Have a history of any seizure disorder. 
6.  Any clinically significant abnormal vital sign, ECG, laboratory values as 
determined by the investigator which might interfere with the study. 


 
   
       
                  

Protocol 
31 

Protocol Number: BLI-1005-002 
Protocol Version: 2.3 
Date: 2018/03/16 
Confidential 
BioLite, Inc.                 
萊特先進生醫股份有限公司 
7. Any organic disorder caused medical related depression which cannot be under 
well-controlled such as clinically significant in neurological, gastrointestinal, 
renal, hepatic, cardiovascular, respiratory, metabolic, endocrine, hematological or 
other major disorders. 
8. Have a high suicidal risk as measured by MINI. 
9. Have a history of substance dependence/abuse** within the past 6 months or any 
positive drug screen result is determined to be caused by subject’s drug abuse at 
visit 1. 
10. 
Have a history of severe allergies to more than 1 class of medication or multiple 
adverse drug reactions. 
* The adequate dosage of the antidepressant medication is defined as the average of the 
usual dose (mg/day) recommended in American Psychiatric Association (APA) Practice 
Guideline for the Treatment of Patients with Major Depressive Disorder, Third Edition. 
E.g. the usual dose of Citalopram is 20-60 mg/day, the adequate dosage is 40 mg/day. 
** Tobacco is excluded here, and alcohol abuse is defined as average pure alcohol intake 
is more than 112 g (for male) or 56 g (for female) per week and/or with Alcohol 
withdrawal syndrome. Pure alcohol intake =% (Concentration or alcohol content) x c.c. 
(volume)x 0.79 (density of alcohol). Result of serum ethanol test should be equal to 
or lower than 10.0 mg/dL to be determined as eligible for the trial.  If test result is 
between 10.1 to 29.9 mg/dL, only one re-test is allowed per subject to meet the 
criterion. Subject with test result equal to or higher than 30.0 mg/dL is to be 
excluded. 
4.3 Subject Recruitment and Screening 
At Visit 1, Investigator will introduce the proposed clinical study to subjects who are 
interesting in this study. If a subject is willing to undergo an informed consent process 
based on GCP and participate in our study, the subject will be examined as described 
in section 5.2. At Visit 2, based on Visit 1 measurements, subject who meets the 
recruitment criteria will be enrolled in this study. 
 
4.4 Subject Identification 
In order to protect each subject’s privacy, only subjects’ initials will be used as part of 
subjects’ identifications. In addition, a subject number will be assigned to each subject 
who signed the ICF and each subject who is eligible to enroll in the study. 
 


 
   
       
                  

Protocol 
32 

Protocol Number: BLI-1005-002 
Protocol Version: 2.3 
Date: 2018/03/16 
Confidential 
BioLite, Inc.                 
萊特先進生醫股份有限公司 
4.4.1 Subject Initial Allocation  
A subject’s initial will be assigned to each subject by the clinical research coordinator 
(CRC). Remain blank in the 3rd and 4th space if there have no more initial(s) to be 
filled in. 
□ □ □ □ 
4.4.2 Subject Number Allocation 
Each subject will be assigned a number by the CRC. All subject numbers will have six 
digits. 
□□-□□-□□ 
 
 
 
 
 
 
 
 
English initial of the first character in the name 
English initial of the second character in the name 
English initial of the third character in the name 
English initial of the fourth character in the name 
The fifth and sixth digits: the randomized number will be 
consecutive numbers commencing with “01”. At screening visit, 
these should be blank. 
The third and fourth digits: the screening number will be consecutive 
numbers commencing with “01” 
The second digit: the site number. 
The first digit: the part number; Part I will be assigned to “1”, Part II will be 
assigned to “2”. 


 
   
       
                  

Protocol 
33 

Protocol Number: BLI-1005-002 
Protocol Version: 2.3 
Date: 2018/03/16 
Confidential 
BioLite, Inc.                 
萊特先進生醫股份有限公司 
4.5 Early Withdrawal of Subjects 
Subjects are not obligated to give reasons for discontinuation from this study. 
Investigator can ask a subject to be withdrawn from study in the best interest of the 
subject. Subjects withdrawn from the study due to adverse event(s) must be followed 
until the events are resolved or stabilized. The discontinuation will result from the 
following reasons: 
˙ Subjects wish to withdraw. 
˙ Subjects can’t obey the regulation of the study. 
˙ Investigator consider that withdrawal from study is the best interest of a subject. 
˙ The subject is pregnant during the trial. 
 


 
   
       
                  

Protocol 
34 

Protocol Number: BLI-1005-002 
Protocol Version: 2.3 
Date: 2018/03/16 
Confidential 
BioLite, Inc.                 
萊特先進生醫股份有限公司 
5 TREATMENT OF SUBJECTS 
5.1 Description of Study Drug 
PDC-1421 Capsule is a botanical investigational new drug. Each PDC-1421 Capsule 
contains 380 mg PDC-1421 drug substance extracted from dry root of P. tenuifolia. 
The detailed information of PDC-1421 Capsule is described in section 1.1. Placebo 
contains 380 mg corn starch and 20 mg excipient (10 mg silicon dioxide and 10 mg 
magnesium stearate); the appearance of placebo capsule and composition of excipient 
are the same as PDC-1421 Capsule. 
 
5.2 Treatment Schedule 
Potential subjects will be introduced by Investigator of the study design at Screening. 
If the subject agrees to participate and signs the consent form, the screening process 
will begin. Suitability of the subject will be evaluated by inclusion/exclusion criteria. 
In part I, sequentially, six eligible subjects each take 1 or 2 capsules of PDC-1421 
Capsule thrice daily and will be assessed twice in the first week (Visit 3 and 4), every 
week (Visit 5, 6 and 7) for the following treatment and one week later after the last 
dose for follow-up (Visit 8). In part II, at the beginning of randomization (Visit 2), 
subjects who met eligibility criteria will be enrolled into this trial and take the study 
drug in the assigned dose. Subjects will be assessed biweekly (Visit 3, 4 and 5) and a 
follow-up (Visit 6). Screening, safety and efficacy assessments will be performed as 
Table 15 and 16. 


 
   
       
                  

Protocol 
35 

Protocol Number: BLI-1005-002 
Protocol Version: 2.3 
Date: 2018/03/16 
Confidential 
BioLite, Inc.                 
萊特先進生醫股份有限公司 
Table 15. Part I-schedule of assessments 
*On ±2 days.  
*V3 (Week 1/2) only can be conducted in Day 3 or Day 4.  
 
 
Screening 
Treatment Period 
Follow-up 
Visit 
1 
2 
3 
4 
5 
6 
7 
  8 
*Week 
-2 to -1 ~0 
0 
1/2 
1 
2 
3 
4 
  5 
Informed consent 
˙ 
 
 
 
 
 
 
 
Subject information 
˙ 
 
 
 
 
 
 
 
Medical history 
˙ 
˙ 
 
 
 
 
 
 
DSM-IV-TR 
˙ 
 
 
 
 
 
 
 
HAM-D-17 
˙ 
˙ 
 
˙ 
˙ 
˙ 
˙ 
˙ 
CGI 
˙ 
˙ 
 
˙ 
˙ 
˙ 
˙ 
˙ 
MADRS 
˙ 
˙ 
 
˙ 
˙ 
˙ 
˙ 
˙ 
DSSS 
˙ 
˙ 
 
˙ 
˙ 
˙ 
˙ 
˙ 
HAM-A 
˙ 
˙ 
 
˙ 
˙ 
˙ 
˙ 
˙ 
C-SSRS 
˙ 
˙ 
˙ 
˙ 
˙ 
˙ 
˙ 
˙ 
Concomitant 
medication 
˙ 
˙ 
˙ 
˙ 
˙ 
˙ 
˙ 
˙ 
Physical 
examination 
˙ 
˙ 
˙ 
˙ 
˙ 
˙ 
˙ 
˙ 
Vital sign 
˙ 
˙ 
˙ 
˙ 
˙ 
˙ 
˙ 
˙ 
ECG 
˙ 
˙ 
˙ 
˙ 
˙ 
˙ 
˙ 
˙ 
Laboratory 
examination 
 
 
 
 
 
 
 
 
Drug screen 
˙ 
 
 
 
 
 
 
 
Pregnancy test 
˙ 
 
 
 
 
 
 
˙ 
Hematology 
˙ 
˙ 
 
 
˙ 
 
˙ 
˙ 
Blood chemistry 
˙ 
˙ 
 
 
˙ 
 
˙ 
˙ 
Eligibility evaluation 
˙ 
 
 
 
 
 
 
 
Drug accountability 
 
˙ 
˙ 
˙ 
˙ 
˙ 
˙ 
 
AE/SAE evaluation 
 
 
˙ 
˙ 
˙ 
˙ 
˙ 
˙ 


 
   
       
                  

Protocol 
36 

Protocol Number: BLI-1005-002 
Protocol Version: 2.3 
Date: 2018/03/16 
Confidential 
BioLite, Inc.                 
萊特先進生醫股份有限公司 
Table 16. Part II-schedule of assessments 
*On ±2 days.  
** If the interval of visit 1 and visit 2 is within 7 days, Hematology and Blood 
chemistry test of visit 2 can be skipped.  
 
 
 
 
 
Screening 
Treatment Period 
Follow-up 
Visit 
1 
2 
3 
4 
  5 
6 
*Week 
-2 to -1 ~ 0 
0 
2 
4 
6 
7 
Informed consent 
˙ 
 
 
 
 
 
Subject information 
˙ 
 
 
 
 
 
Medical history 
˙ 
˙ 
 
 
 
 
DSM-IV-TR 
˙ 
 
 
 
 
 
HAM-D-17 
˙ 
˙ 
˙ 
˙ 
˙ 
˙ 
CGI 
˙ 
˙ 
˙ 
˙ 
˙ 
˙ 
MADRS 
˙ 
˙ 
˙ 
˙ 
˙ 
˙ 
DSSS 
˙ 
˙ 
˙ 
˙ 
˙ 
˙ 
HAM-A 
˙ 
˙ 
˙ 
˙ 
˙ 
˙ 
C-SSRS 
˙ 
˙ 
˙ 
˙ 
˙ 
˙ 
Concomitant 
medication 
˙ 
˙ 
˙ 
˙ 
˙ 
˙ 
Physical examination 
˙ 
˙ 
˙ 
˙ 
˙ 
˙ 
Vital sign 
˙ 
˙ 
˙ 
˙ 
˙ 
˙ 
ECG 
˙ 
˙ 
˙ 
˙ 
˙ 
˙ 
Laboratory 
examination 
 
 
 
 
 
 
Drug screen 
˙ 
 
 
 
 
 
Pregnancy test 
˙ 
 
 
 
 
˙ 
Hematology 
˙ 
˙** 
˙ 
˙ 
˙ 
˙ 
Blood chemistry 
˙ 
˙** 
˙ 
˙ 
˙ 
˙ 
Eligibility evaluation 
˙ 
 
 
 
 
 
Drug accountability 
 
˙ 
˙ 
˙ 
˙ 
 
AE/SAE evaluation 
 
 
˙ 
˙ 
˙ 
˙ 



 
 
Protocol 
37 
 
 
BioLite, Inc.           
萊特先進生醫股份有限公司 
Protocol Number: BLI-1005-002 
Protocol Version: 2.2 
Date: 2017/08/18 
Confidential 
5.2.1 Screening Phase (Visit 1) 
The Screening phase will be done within 1-2 weeks period and intended for diagnosing 
and assessing the patient for possible inclusion in the study and for providing an adequate 
washout period. The items of physical, rating scales, laboratory examination and drug 
accountability at screening are outlined below: 
˙ Informed consent 
˙ Subject information, including date of birth, body height and weight 
˙ Medical history, including any clinically significant psychiatric, neurological, 
gastrointestinal, renal, hepatic, cardiovascular, respiratory, metabolic, endocrine, 
hematological or other major disorders 
˙ Drug screen, including alcohol, benzodiazepine, amphetamine/MDMA, opiates, 
cannabinoid, cocaine, phencyclidine, and barbiturate.  If a positive result is 
determined to be caused by prescription of benzodiazepine instead of subject’s drug 
abuse, a 10-day washout period of the prescribed benzodiazepine is required before 
being treated with investigational products. 
˙ Pregnancy test 
˙ Physical examination: skin, head, neck, eyes, ears, nose, throat, heart, lungs, 
abdomen (liver, spleen), neurological examination, lymph node and extremities. 
˙ Vital sign: heart rate, blood pressure, body temperature 
˙ ECG 
˙ Hematology: RBC, WBC, platelets, hematocrit, hemoglobin, prothrombin time (PT), 
partial thromboplastin time (aPTT) 
˙ Blood chemistry: AST, ALT, LDH, total bilirubin, BUN, serum creatinine, free 
thyroxine (FT4), TSH, sodium, calcium, potassium, HbA1c, LDL, HDL, 
triglyceride, cholesterol. 
˙ DSM-IV-TR, HAM-D-17, CGI, MADRS, DSSS, HAM-A, C-SSRS and 
concomitant medication evaluation. 
 
 


 
   
       
                  
 
Protocol 
 
 
Protocol Number: BLI-1005-002 
Protocol Version: 2.3 
Date: 2018/03/16 
Confidential 
BioLite, Inc.                 
萊特先進生醫股份有限公司 
5.2.2. Part I. - Treatment Period (Visit 2~7) and Follow-up (Visit 8) 
Laboratory data , other tests and evaluation results shall be obtained at Screening to 
determine the appropriateness of subject enrolled in this study. Subjects who meet the 
eligibility criteria will be enrolled and take test drug at this period. First six eligible 
subjects will take 1 capsule of PDC-1421 Capsule thrice daily in the first week and be 
assessed twice in the first week after drug administration. They will receive 21 packs of 
PDC-1421 Capsule for the following week and be evaluated every week till visit 8. After 
one week of the last dose administration, subjects are assessed for a follow-up. Then, a 
checkpoint will be conducted. If subjects have no serious adverse event, the trial can 
continue to next step. If subjects have serious adverse events, there should be a meeting 
to consider the possibility of continuing the next step of the study or not. Another six 
subjects will take 2 capsules of PDC-1421 Capsule and all the visits are the same as 
previous three subjects’. Then, another checkpoint will be conducted as mentioned above. 
If subjects have no serious adverse events, the schedule can be conducted to the part II. If 
subjects have serious adverse events, there should be a meeting to consider the possibility 
of continuing part II of the study or not. The items of safety and efficacy parameters at 
treatment period are outlined below: 
˙ Physical examination: skin, head, neck, eyes, ears, nose, throat, heart, lungs, 
abdomen (liver, spleen), neurological examination, lymph node and extremities. 
˙ Vital sign: heart rate, blood pressure, body temperature 
˙ ECG 
˙ Hematology: RBC, WBC, platelets, hematocrit, hemoglobin, prothrombin time (PT), 
partial thromboplastin time (aPTT) 
˙ Blood chemistry: AST, ALT, LDH, total bilirubin, BUN, serum creatinine, free 
thyroxine (FT4), TSH, sodium, calcium, potassium, LDL, HDL, triglyceride, 
cholesterol 
˙ HAM-D-17, CGI, HAM-A, DSSS, MADRS, C-SSRS and concomitant medication 
evaluation. (At visit 3, subjects will not need to be assessed for above scales except 
C-SSRS and concomitant medication evaluation.) 
˙ AE/SAE evaluation  
˙ Drug accountability 
 


 
   
       
                  
 
Protocol 
 
 
Protocol Number: BLI-1005-002 
Protocol Version: 2.3 
Date: 2018/03/16 
Confidential 
BioLite, Inc.                 
萊特先進生醫股份有限公司 
Follow-up visit will be performed at visit 8 after one week of the last dose administration. 
The test items are outlined in the following: 
˙ Physical examination: skin, head, neck, eyes, ears, nose, throat, heart, lungs, 
abdomen (liver, spleen), neurological examination, lymph node and extremities. 
˙ Vital sign: heart rate, blood pressure, body temperature 
˙ ECG 
˙ Hematology: RBC, WBC, platelets, hematocrit, hemoglobin, prothrombin time (PT), 
partial thromboplastin time (aPTT) 
˙ Blood chemistry: AST, ALT, LDH, total bilirubin, BUN, serum creatinine, free 
thyroxine (FT4), TSH, sodium, calcium, potassium, LDL, HDL, triglyceride, 
cholesterol. 
˙ HAM-D-17, MADRS, DSSS, HAM-A, CGI and C-SSRS and concomitant 
medication evaluation.  
˙ Pregnancy test 
˙ AE/SAE evaluation 
 
A Data and Safety Monitoring Plan (DSMP) will be provided in this study and approved 
by IRB. It describes the risk and benefit to subjects, the type of data or events to be 
captured under the monitoring plan, the frequency of reporting to IRB, etc. 
 
5.2.3 Part II.- Treatment Period (Visit 2~5) and Follow-up (Visit 6) 
Laboratory data and results of other tests and evaluation shall be obtained at screening to 
determine the appropriateness of subject enrolled in this study. Subjects who meet the 
eligibility criteria will be enrolled and take study drugs. Baseline data (Visit 2), including 
physical examination, vital sign, ECG, hematology, blood chemistry, HAM-D-17, CGI, 
HAM-A, MADRS, DSSS, C-SSRS and concomitant medication evaluation, will be 
collected before dosing study drug. At visits 2, 3 and 4 (weeks 0, 2 and 4), each subject 
will be dispensed a supply of study drug sufficient for 2-week treatment period. The 
subjects will be instructed to take one dose (i.e., two capsules) after a meal thrice daily 
for every week. Subjects will be assessed every two weeks and receive the study drug for 
next two weeks till the end of trial. At visits 2, 3, 4 and 5, the safety and efficacy 
parameters will be evaluated by the following items.  


 
   
       
                  
 
Protocol 
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Protocol Number: BLI-1005-002 
Protocol Version: 2.3 
Date: 2018/03/16 
Confidential 
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˙ Physical examination: skin, head, neck, eyes, ears, nose, throat, heart, lungs, 
abdomen (liver, spleen), neurological examination, lymph node and extremities. 
˙ Vital sign: heart rate, blood pressure, body temperature 
˙ ECG 
˙ Hematology: RBC, WBC, platelets, hematocrit, hemoglobin, prothrombin time (PT), 
partial thromboplastin time (aPTT). If the interval of visit 1 and visit 2 is within 7 
days, Hematology test of visit 2 can be skipped. 
˙ Blood chemistry: AST, ALT, LDH, total bilirubin, BUN, serum creatinine, free 
thyroxine (FT4), TSH, sodium, calcium, potassium, LDL, HDL, triglyceride, 
cholesterol. If the interval of visit 1 and visit 2 is within 7 days, Blood chemistry test 
of visit 2 can be skipped. 
˙ HAM-D-17, CGI, HAM-A, DSSS, MADRS, C-SSRS and concomitant medication 
evaluation.  
˙ AE/SAE evaluation  
˙ Drug accountability 
 
Follow-up visit will be performed at visit 6 after one week of the last dose administration. 
The test items are outlined in the following: 
˙ Physical examination: skin, head, neck, eyes, ears, nose, throat, heart, lungs, 
abdomen (liver, spleen), neurological examination, lymph node and extremities. 
˙ Vital sign: heart rate, blood pressure, body temperature 
˙ ECG 
˙ Hematology: RBC, WBC, platelets, hematocrit, hemoglobin, prothrombin time (PT), 
partial thromboplastin time (aPTT) 
˙ Blood chemistry: AST, ALT, LDH, total bilirubin, BUN, serum creatinine, free 
thyroxine (FT4), TSH, sodium, calcium, potassium, LDL, HDL, triglyceride, 
cholesterol. 
˙ HAM-D-17, MADRS, DSSS, CGI, HAM-A and C-SSRS and concomitant 
medication evaluation.  
˙ Pregnancy test 
˙ AE/SAE evaluation 


 
   
       
                  
 
Protocol 
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Protocol Number: BLI-1005-002 
Protocol Version: 2.3 
Date: 2018/03/16 
Confidential 
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5.3 Other Medication During the Study 
To avoid conflict or unknown effects with the study drug, subjects are prohibited from 
taking any antidepressants and psychoactive drugs, as per the exclusion criteria, including 
MAOIs (monoamine oxidase inhibitor), NRIs (norepinephrine reuptake inhibitor) and 
norepinephrine receptor agonist/antagonist. Subjects can’t combine the newly-initiated 
psychotherapy. If subjects have severe insomnia, Zolpidem, Zopiclone or Zaleplon can be 
used in four nights per week from V1 to the first week after V2. (The maximum daily 
dose in Zolpidem, Zopiclone and Zaleplon are 10 mg, 7.5 mg and 10 mg respectively.) 
 
6 EFFICACY ASSESSMENTS 
6.1 Specification of the efficacy parameters 
Efficacy parameters are outlined as follows:  
˙ MADRS evaluation  
˙ CGI evaluation  
˙ HAM-D-17 evaluation 
˙ HAM-A evaluation 
˙ DSSS evaluation 
 
 
6.2 Methods and Timing for Assessing, Recording, and 
Analyzing of Efficacy Parameters. 
The data obtained from eligible subjects before study drug administration in Visit 2 are 
set as baseline. After the beginning of treatment, the collection of data of efficacy 
parameters are performed at planned treatment schedule as section 5.2. CRC shall record 
these data in CRF in detail after each visit during the treatment period. In part I, efficacy 
assessments are conducted from screening stage to the last visit. In part II, data 


 
   
       
                  
 
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Protocol Number: BLI-1005-002 
Protocol Version: 2.3 
Date: 2018/03/16 
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comparison between group of 1 capsule TID, 2 capsules TID of PDC-1421 Capsule and 
placebo will be conducted in final report of this study to evaluate which group(s) of 
PDC-1421 Capsule are efficient. The rating scales are as follows: 
 
˙ MADRS (Montgomery- Å sberg Depression Rating Scale) 
The MADRS is a 10-item checklist including 1) depression [apparent]; 2) 
depression [reported]; 3) loss of interest; 4) suicidal ideation; 5) tension; 6) reduced 
appetite; 7) insomnia; 8) difficulty in activities; 9) concentration; and 10) pessimism. 
Each Item is rated on a scale of 0-6, with anchors at 2-point intervals; higher scores 
indicating more severity (i.e., ranging from 0 [no sadness] to 6 [extremely 
despondent]). Percentage of partial responders (defined as a participant with a 
25-50%decrease from baseline in total score) and responders (defined as a participant 
with ≧50%decrease from baseline in total score.). The following are as an 
interpretation of scores:  
Recovered, 7 
Mild, 15 
Moderate, 25 
Severe, 31 
Very severe, 44 
 
˙ CGI (Clinical Global Impression) 
The CGI actually comprises two companion one-item measures evaluating the 
following: (a) CGI-Severity (CGI-S) which rates illness severity of psychopathology 
from 1 to 7 and (b) CGI-Improvement (CGI-I) which rates change from the 
initiation (baseline) of treatment. 
 
˙ HAM-D-17 (Hamilton Rating Scale for Depression) 
This is one of the earliest scales to be developed for depression, and is a clinician 
rated scale aimed at assessing depression severity among patients for treatment. 
There are four specific HAM-D symptom groups: psychomotor retardation, anxiety, 
cognitive disturbance and insomnia. The depression score ranges from 0 to 52. The 
following are as an interpretation of scores: 


 
   
       
                  
 
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Protocol Number: BLI-1005-002 
Protocol Version: 2.3 
Date: 2018/03/16 
Confidential 
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萊特先進生醫股份有限公司 
0-7: Normal 
8-16: Mild 
17-23: Moderate 
≧24: Severe 
 
˙ HAM-A (Hamilton Rating Scale for anxiety) 
HAM-A is a series of questions related to symptoms of anxiety. It rates the individual 
on a five-point scale (0~4) for each of the 14 items. Seven of the items specifically 
address psychic anxiety and the remaining seven items address somatic anxiety. The 
anxiety score ranges from 0 to 56, lower scores are better. The following are as an 
interpretation of scores: 
0-13: Normal 
14-17: Mild 
18-24: Moderate 
≧25: Severe 
 
˙ DSSS (Depression and Somatic Symptoms Scale) 
The scale includes a simultaneous measure of depression and somatic symptoms that 
two issues frequently co-occur. Though many preexisting questionnaires for 
depression contain items relating to somatic complaints, the DSSS is specifically 
concerned with the relationship between the two. Consisting of 22 items, the DSSS 
includes 12 depression-related items and 10 somatic items. Evaluation of the severity 
of the symptoms are the following:  
Absent: no symptoms 
Mild: symptoms caused slight discomfort or disturbance 
Moderate: symptoms caused significant discomfort or disturbance 
Severe: symptoms caused very significant discomfort or disturbance 
 
 


 
   
       
                  
 
Protocol 
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Protocol Number: BLI-1005-002 
Protocol Version: 2.3 
Date: 2018/03/16 
Confidential 
BioLite, Inc.                 
萊特先進生醫股份有限公司 
7 SAFETY ASSESSMENTS 
7.1 Specification of Safety Parameters 
Safety parameters are outlined as follows:  
˙ Data collected from the physical examinations, vital sign, ECG and laboratory test in 
scheduled visit 
˙ Adverse events reported 
˙ Serious adverse events reported 
˙ C-SSRS evaluation 
7.2 Methods and Timing for Assessing, Recording, and 
Analyzing of Safety Parameters 
The data obtained before study drug administration in Visit 2 are set as baseline. After the 
beginning of treatment, the collection of data of safety parameters are performed at 
planned treatment schedule as section 5.2. AE or SAE will be closely monitored during 
the study period. CRC shall record these data in CRF in detail. In part I and part II, data 
are recorded from screening stage to the last visit. 
7.3 Adverse Events (AEs) 
Adverse event is any unfavorable and unintended symptom, syndrome, medical condition 
or experience that develops or worsens within the study period. In this Phase II trial, any 
clinically significant abnormal findings, including causing the subject to withdraw from 
the study, requiring treatment or causing apparent clinical manifestations, or judged 
relevant by the investigator, are considered to be AEs and will be monitored and recorded. 
AE may not be causal relationship with study medication or clinical study. Whether 
related to study medication or not, CRC shall record the information of AEs in CRF. The 
information of AEs contains characteristic, onset and duration, frequency, the 
Investigator’s opinion of the relationship to the study drug (unrelated, unlikely, possibly, 
probably, definitely), outcome (recovered, recovered with residual effects, continuing, 


 
   
       
                  
 
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Protocol Number: BLI-1005-002 
Protocol Version: 2.3 
Date: 2018/03/16 
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death, lost to follow-up) and severity. Common Terminology Criteria for Adverse Events 
v4.03 (CTCAE Table.17) is a descriptive terminology and the grading (severity) scale is 
provided for each AE term.  
 
Table 17. Common Terminology Criteria for Adverse Events 
Grade 
Description 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living (ADL)*. 
Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL†. 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE.‡ 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
†Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and 
not bedridden. 
 
7.4 Serious Adverse Events (SAE) 
SAE is defined as any significantly untoward medical occurrence, including: 
˙ Death 
˙ Life-threatening condition 
˙ Inpatient hospitalization or prolongation of existing hospitalization 
˙ Persistent or significant disability/incapacity 
˙ Congenital anomaly/birth defect 
˙ Required intervention to prevent permanent impairment/damage 
 
 


 
   
       
                  
 
Protocol 
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Protocol Number: BLI-1005-002 
Protocol Version: 2.3 
Date: 2018/03/16 
Confidential 
BioLite, Inc.                 
萊特先進生醫股份有限公司 
7.5 Serious and Unexpected Suspected Adverse Reaction 
(SUSAR) 
SUSAR is defined as any significantly untoward medical occurrence, the nature or 
severity of: 
1. Which is not consistent with the applicable product information (e.g., Investigator's 
Brochure) for an unapproved investigational medicinal product. 
2. Which must be causal relationship with study medication or clinical study. 
 
7.6 SAE Report Procedure 
7.6.1 Expedited Reporting of SAEs 
When expedited SAEs meet the informed criteria according to the relevant regulations, 
they will be reported to the regulatory authorities (e.g. Minister of Health and Welfare; 
MOHW, Taiwan and the Food and Drug Administration; FDA, U.S.) by the Sponsor. 
Written reports should be made on the ADR Reporting Form of regulatory authorities (e.g. 
Taiwan MOHW and on Medwatch 3500A Form of US FDA), and submitted in a timely 
fashion according to all relevant regulatory requirements. A copy of this report will also 
be provided to the principal investigator’s local institutional review board if necessary. 
All SAEs will be monitored until they are resolved or until the principal investigator 
assesses them as irreversible, chronic, or stable, or until the subject dies. During the 
clinical trial, if expedited SAEs occur, the investigator should inform the sponsor/CRO 
within 24 hours by fax and/or telephone.  
 
 
7.6.2 IRB Notification  
Reports of serious adverse events will be communicated to IRB: 
• 
Fatal or life-threatening SUSAR: Should be reported to IRB in the 7 calendar days 
and detailed written documents should be provided within 15 days after being aware 
of the event. 
• 
Non-Fatal or life-threatening SUSAR: Should be reported to IRB no later than 15 


 
   
       
                  
 
Protocol 
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Protocol Number: BLI-1005-002 
Protocol Version: 2.3 
Date: 2018/03/16 
Confidential 
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萊特先進生醫股份有限公司 
calendar days. 
• 
Non-SUSAR SAE: Should be reported to IRB following each IRB regulations. 
 
 
7.6.3 Record Retention 
All telephone/fax reports must be followed with a written narrative summary of the 
adverse event and any sequel. These narratives, which confirm the information collected 
by telephone and may provide additional information not available at the time of the 
initial report, must be reviewed by the clinical monitor within 7 calendar days following 
the telephone/fax report to sponsor. 


 
   
       
                  
 
Protocol 
 
 
Protocol Number: BLI-1005-002 
Protocol Version: 2.3 
Date: 2018/03/16 
Confidential 
BioLite, Inc.                 
萊特先進生醫股份有限公司 
8 STATISTIC METHODS 
8.1 Sample Size Determination 
In part I, six subjects each will be evaluated for safety and efficacy assessments at 1 or 2 
capsules TID dose for 28 days, sequentially. 
In part II, this is a small proof-of-concept study to evaluate 2 doses of PDC-1421 and 
placebo in the treatment of major depressive disorder. Based on our study design, it is 
planned to enroll 60 subjects who met the intent-to-treat (ITT) basis.  
 
8.2 Statistical Method 
Simple descriptive statistics with 95% confidence interval will be performed with data 
collected in this study wherever applicable. Treatment effects are evaluated based on 
2-sided test with a 0.05 significant level. All data shall be tabulated and presented in the 
study report. The descriptive statistics will be provided. The safety and efficacy data will 
be analyzed using the non-parametric method. 
 
8.3 Analysis of Efficacy and Safety  
The efficacy measures are conducted on the per-protocol (PP) and intent-to-treat (ITT) 
basis. The per protocol will be defined as (1) The drug compliance is at least 80% (2) 
Subjects have completed data to determine the primary endpoint. (3) Subjects cannot 
have protocol deviation. The protocol deviation will be defined as (1) Inclusion or 
exclusion criteria not satisfied. (2) Not permitted concomitant medications (3) Wrong 
randomized treatment prescribed. An intent-to-treat (ITT) basis will be defined as the 
data are analyzed by the treatment groups to which the randomized patients who take at 
least one dose of study medication and have any post-baseline safety data collected. The 
safety measures are conducted on the ITT basis. The data are analyzed utilizing the last 
observation carried forward (LOCF) technique to impute the missing data. 
 


 
   
       
                  
 
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Protocol Number: BLI-1005-002 
Protocol Version: 2.3 
Date: 2018/03/16 
Confidential 
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萊特先進生醫股份有限公司 
The efficacy and safety information recorded on CRF will be summarized by tables 
presented in frequency and percentage for categorical variables, in mean with SD as well 
as median with the minimum and maximum for continuous variables. The comparison 
between three groups will be analyzed by nonparametric method as appropriate. All 
adverse events will be summarized with coding term, severity, relationship to study drug 
by frequency tables with the counts and percentage. In addition, serious adverse events 
will be listed with event narration. 
 
8.4 Premature Termination and Handling of Missing Data 
Any premature termination of the study therapy will be recorded in CRF. Listing of the 
subjects with premature termination will be provided with the dates and reasons. Missing 
data caused by premature termination will be utilized the last observation carried forward 
(LOCF).  


 
   
       
                  
 
Protocol 
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Protocol Number: BLI-1005-002 
Protocol Version: 2.3 
Date: 2018/03/16 
Confidential 
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萊特先進生醫股份有限公司 
9 QUALITY CONTROL AND QUALITY 
ASSURANCE 
9.1 Study Monitoring 
The clinical monitor from sponsor-designated contract research organization (CRO) will 
be responsible for overseeing the progress of a clinical trial to be conducted, recorded, 
and reported in accordance with the protocol, Standard Operating Procedures (SOPs), 
GCP, and the applicable regulatory requirements. All written informed consent and CRFs 
will be carefully reviewed and the accuracy of the data will be validated by clinical 
monitor. 
 
9.2 Sponsor Auditing 
Prior to locking the database of safety, the representative of Sponsor’s quality assurance 
department will visit the Investigator’s site to implement an audit of study. The audit will 
to determine the compliance of Investigator with protocol, GCP and applicable 
regulations. Besides, auditors will assess the accuracy of clinical data record. The 
Investigator and trial personnel need to cooperate with auditor to facilitate the process of 
audit. 
 
9.3 Inspected by Regulatory Authorities 
Local regulatory authority may visit the Investigator to conduct an inspection of this 
study and the site. The Investigator must make the trial-related records accessible to 
regulatory agency inspectors. In addition, the Investigator needs to notify the Sponsor 
immediately when contacted with regulatory authority for the inspection.  
 


 
   
       
                  
 
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Protocol Number: BLI-1005-002 
Protocol Version: 2.3 
Date: 2018/03/16 
Confidential 
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萊特先進生醫股份有限公司 
10 ETHICAL CONSIDERATIONS 
10.1 Confidential 
All information about study subjects will be kept confidential in accordance with the 
applicable regulatory requirement, to protect and respect the privacy of study subjects. 
Only the members performed study-related processes, including trial-related monitoring, 
audits, IRB/IEC review, and regulatory inspection, could directly access to source 
data/documents. 
 
10.2 Protocol Amendment 
Any amendment to the Protocol which deemed necessary as the study progresses will be 
fully discussed by Investigator and the Sponsor. A written amendment must be submitted 
to US FDA, MOHW and Chairman of the IRB, except when the change(s) involves only 
logistical or administrative aspects of the trial (e.g. change in clinical monitors or change 
of telephone numbers). Investigator must await for their approvals of the protocol 
amendment before implementing the changes. A protocol change intended to eliminate an 
apparent immediate hazard to trial subjects may be implemented immediately while 
simultaneously informing FDA/MOHW/IRB.  
 
When, in the judgment of Chairmen of the IRB, Investigator and/or the Sponsor, the 
amendment to the Protocol substantially alters the study design and/or increases the 
potential risk to the subjects, the currently approved written informed consent form will 
be modified according to the modification. A second informed consent will be obtained 
from subjects enrolled in the study before further participation. 
 
10.3 Informed Consent 
Written informed consent must be reviewed and approved by IRB. Informed consent will 
be designed to provide detailed information, including explanation of the purpose of this 


 
   
       
                  
 
Protocol 
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Protocol Number: BLI-1005-002 
Protocol Version: 2.3 
Date: 2018/03/16 
Confidential 
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萊特先進生醫股份有限公司 
study, the risks and discomforts involved, potential benefits and all basic elements 
required by regulatory agencies, to participants. Investigator (or his or her qualified 
designees) will be responsible for explaining the contents of the informed consent to 
participants as clear as possible. Once it is felt that the subject understands the 
implications of participating, the written informed consent form shall be signed by the 
subject and a witness. The written informed consent will be obtained from each subject 
before any study related procedures (including any pre-treatment procedures) are 
performed.  
 
10.4 Institutional Review Board (IRB) 
This study is conducted to be consistent with the principles of the Declaration of Helsinki 
and GCP. This protocol and any supplementary documents, including written informed 
consent form, subject recruitment advertisements and Investigator’s Brochure, must be 
reviewed and approved by IRB of all clinical sites qualified with local legal prescriptions 
prior to study initiation. The members of IRB are average thirty people, including 
medical doctors, professors of pharmacology and members whose primary area of 
interest is in the nonscientific area such as law and social welfare policy. One group of 
members of IRB meet once a month. Any changes in protocol must be received the IRB 
approval/favorable opinion in advance of use except for the immediate hazards to trial 
subjects. Investigator shall submit a status report to IRB at the end of the study. IRB must 
be notified by the Investigators promptly for all unanticipated problems involving risk to 
human subjects or others. Investigator is required to maintain an accurate and complete 
record of all written submissions made to IRB and must agree to share all such 
documents and reports with the Sponsor and any regulatory agency, for example, MOHW 
in Taiwan. 


 
   
       
                  
 
Protocol 
 
 
Protocol Number: BLI-1005-002 
Protocol Version: 2.3 
Date: 2018/03/16 
Confidential 
BioLite, Inc.                 
萊特先進生醫股份有限公司 
11 DATA HANDLING AND RECORD KEEPING 
An EDC (electronic data capture) system may be used in this study to handle data in an 
electronic CRF. Follow the EDC system guideline when using it. 
11.1 Data Handling and Collection 
11.1.1 Study Specific Binders 
Four types of binder will be utilized in this study: 
 Subject Binder: Containing informed consent, all case report forms and certain 
source documents collected for each subject entered the treatment period of the 
study. Each Subject Binder will have tab dividers for the laboratory printouts. 
Subject Binders will be kept at each study center. 
 
 Screening Binder: Containing all case report forms of subjects participated in the 
screening period but found ineligible for entering the treatment period of the study. 
Screening Binders will be kept at each study center 
 
 Generic Forms Binder: Containing enough blank generic case report forms for all 
subjects participating in the study.  
 
 Study Center File: Documents pertinent to the conduct of this study will be filed in 
this binder.  
 
11.1.2 Responsibilities of Investigators 
 
The Investigator shall process, prepare and maintain complete and accurate study 
procedure and documentation in compliance with GCP standards and local laws, rules 
and regulations. It is the Investigators’ responsibility to ensure that the designated CRC 
for this study at the hospital fully understands his/her responsibilities and has the ability 
to fulfill all the relevant tasks on behalf of the Investigator in many occasions. For each 


 
   
       
                  
 
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Protocol Number: BLI-1005-002 
Protocol Version: 2.3 
Date: 2018/03/16 
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subject enrolled, a CRF must be completed and signed by the Investigator, no matter if 
this subject has completed the study or not. The Investigator agree to fully cooperate and 
assist the clinical monitor in performing their duties, including enabling direct access to 
the relevant hospital and clinic records. Study documentation will be promptly and fully 
disclosed to the Sponsor by the Investigator and also shall be made available at the 
Investigators’ site for inspection, copying, review and audit for a reasonable number of 
times by representatives of the Sponsor or any regulatory agencies. The Investigator 
agrees to promptly take any reasonable steps that are requested by the Sponsor as a result 
of an audit to correct the known error in the study documentation and case report forms. 
The Investigator shall submit to the Sponsor all original case report forms and all reports 
required by the Protocol when the clinical study have been completed or terminated. 
 
11.1.3 Responsibilities of Clinical Monitor 
Clinical monitor shall frequently inspect the source documents (clinic and hospital 
subject records) and compare them with the CRF at regular time interval throughout the 
study, to verify the adherence of study execution to the Protocol and confirm the 
completeness, consistency and accuracy of the data entered. The monitor will perform 
source data verification by visually comparison between the entries of the CRF and 
subjects’ records, including informed consent, inclusion/exclusion criteria, key variables, 
drug administration, adverse experience records and safety variables. Additional 
monitoring will be required if the error rate is unacceptably high. 
 
11.2 Records Retention 
11.2.1 Source Document Retention 
Source documents refer to any record pertained to a given subject in the study from 
which study data is, or could be, obtained or verified. This includes, but not limited to, 
records, charts, notes and laboratory reports. These records, maintained by the 
Investigator, shall comply with applicable regulations. At the aspect of ICF keeping, one 
of the original signed informed consent forms for each participant shall be filed with 
records kept by the Investigator and the other copy should be given to the subject. 
Besides, progress notes on each visit to the clinic will be required. The progress note of 


 
   
       
                  
 
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Protocol Number: BLI-1005-002 
Protocol Version: 2.3 
Date: 2018/03/16 
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萊特先進生醫股份有限公司 
each visit shall at least contain the date of the visit, a general reference to the procedures 
completed, general subject status remarks including any significant medical findings, and 
the signature of the clinician making the entry. In addition, any contact with the subject 
via telephone or other means that provides significant clinical information, such as 
adverse events, will also be documented in the progress notes. These will be filed with 
subject records kept by the Investigator and made available for inspection by authorized 
personnel. 
 
11.2.2 CRF Retention 
All information required by the Protocol will be collected on either CRF or source 
documents. Essential documents should be retained until the Sponsor informs the 
Investigator that documents are no longer needed to be kept. 
 
11.2.3 Record Maintenance 
Regulation requires all investigators participating in clinical trials to maintain detailed 
clinical data for the duration of one of the following periods, whichever is shortest: 
 
(1) A period of at least two years following the approval date of an application for a 
marketing permit in support of which the results of the clinical investigation were 
submitted, or  
 
(2) A period of two years after the Sponsor notifies the Investigator that no further 
application is to be filed with the regulatory authority. 
 
The Investigator will not dispose of any record relevant to this study without informing 
the Sponsor and providing an opportunity for the Sponsor personnel to collect such 
record. The Investigator shall take full responsibility for maintaining all documentation 
related to the conduct of this study, including subject records, research data, and pertinent 
correspondence. These documents are subject to inspection by the Sponsor and 
appropriate regulatory authorities. 
 


 
   
       
                  
 
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Protocol Number: BLI-1005-002 
Protocol Version: 2.3 
Date: 2018/03/16 
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萊特先進生醫股份有限公司 
11.3 Study Center File Management 
It will be the responsibility of the clinical monitors/CRC to maintain the study center file. 
The study center file for this study will contain, but not limited to, the information listed 
below: 
 
Investigator Brochure. 
 
Signed Protocol and Amendments approved by both Regulatory Authority 
and IRB. 
 
Copies of Regulatory Authority and IRB approval letter for this study. 
 
Curricula Vitae of Investigator and sub-investigator. 
 
Other documentation of IRB complied with regulations by Regulatory 
Authority. 
 
Copy of Informed Consent Form approved by both Regulatory Authority 
and IRB. 
 
All IRB correspondence (reports to IRB, including reports of all death and 
adverse 
experience, 
annual 
progress 
reports, 
final 
reports, 
acknowledgement of receipt of report and actions taken by IRB). 
 
All IND Efficacy and Safety Reports sent to the Investigator. 
 
Laboratory certification and/or license. 
 
All written correspondence with the Sponsor. 
 
Normal ranges of laboratory value for all laboratory tests required by 
Protocol. 
 
CRA monitoring logs. 
 
Drug Invoices and Drug Dispense/Return Records. 


 
   
       
                  
 
Protocol 
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Protocol Number: BLI-1005-002 
Protocol Version: 2.3 
Date: 2018/03/16 
Confidential 
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萊特先進生醫股份有限公司 
12 PUBLICATION PLAN 
Sponsor and Investigator will determine authorship and govern other aspects of the 
publication process related to this trial. All publications must be approved by the Sponsor 
prior to publication. 
13 REFERENCES 
1. Robert Riesenberg, Joshua Rosenthal, Leslie Moldauer, Christine Peterson. Results 
of a proof-of-concept, dose-finding, double-blind, placebo-controlled study of 
RX-10100 
(Serdaxin® ) 
in 
subjects 
with 
major 
depressive 
disorder. 
Psychopharmacology 2012; 221 (4): 601-610. 
2. Kari R Nations, Peter Dogterom, Larry Ereshefsky et al. Examination of Org 26576, 
an AMPA receptor positive allosteric modulator, in patients diagnosed with major 
depressive disorder: an exploratory, randomized, double-blind, placebo-controlled 
trial. Journal of Psychopharmacology 2012; 26(12): 1525-1539. 
3. Enric Alvarez, Victor Perez, Francesc Artigas, et al. A double-blind, randomized, 
placebo-controlled, active reference study of Lu AA21004 in patients with major 
depressive disorder. International Journal of Neuropsychopharmacology. 2012; 15(5): 
589-600 
4. Sanjay Dube, Mary Anne Della, Prasad Rao, et al. A study of the effects of 
LY2216684, a selective norepinephrine reuptake inhibitor, in the treatment of major 
depression. Journal of Psychiatric Research 2010; 44(6): 356-363 
5. Beth Pangallo, Mary Anne Della, Celine Goldberger, et al. A randomized, 
double-blind study comparing LY2216684 and placebo in the treatment of major 
depressive disorder. Journal of Psychiatric Research 2011; 45(6): 748-755 
6.  Cheng MC, Li CY, Ko HC, Ko FN, Lin YL, Wu TS. Antidepressant principles of the 
roots of Polygala tenuifolia. J Nat Prod. 2006; 69: 1305-1309. 
7. Zhou J. Norepinephrine transporter inhibitors and their therapeutic potential. Drugs 
Future. 2004; 29(12): 1235-44. 
8. Mann JJ. The medical management of depression. N Engl J Med. 2005; 353(17): 


 
   
       
                  
 
Protocol 
 
 
Protocol Number: BLI-1005-002 
Protocol Version: 2.3 
Date: 2018/03/16 
Confidential 
BioLite, Inc.                 
萊特先進生醫股份有限公司 
1819-34. 
9. Englert LF, Ho BT, Taylor D. The effects of (-)-delta9-tetrahydrocannabinol on 
reserpine-induced hypothermia in rats. Br J Pharmacol. 1973; 49(2): 243-52. 
10. Sanchez-Mateo CC, Bonkanka CX, Prado B, Rabanal RM. Antidepressant activity of 
some Hypericum reflexum L. fil. extracts in the forced swimming test in mice. J 
Ethnopharmacol. 2007; 112(1): 115-21. 
11. Gylys JA, Muccia PM, Taylor MK. Pharmacological and toxicological properties of 
2-methyl-3-piperidinopyrazine, a new antidepressant. Ann N Y Acad Sci. 1963; 107: 
899-913. 
12. Suehs BT, et al, Texas Medication Algorithm Project Procedural Manual: Major 
Depressive Disorder Algorithms. The Texas Department of State Health Services. 
2008 
13. Montgomery SA, Å sberg M. A New Depression Scale Designed to be Sensitive to 
Change. British Journal of Psychiatry 1979; 134: 382-389.  
14. Mark. Zimmerman et al., Severity classification on the Hamilton depression rating 
scale. Journal of Affective Disorders. 2013; 150: 384–388 
15. Hamilton, M. A rating scale for depression. Journal of Neurology, Neurosurgery and 
Psychiatry. 1960; 23: 56-62 
16. Hamilton M. The assessment of anxiety states by rating. British Journal of Medical 
Psychology. 1959; 32:50–55. 
17. Ching-I Hung et al., Preliminary study of a scale measuring depression and somatic 
symptoms. Psychological Reports. 2006; 99: 379-389 
18. Ching-I Hung et al., The cut-off points of the Depression and Somatic Symptoms 
Scale and the Hospital Anxiety and Depression Scale in detecting non-full remission 
and a current major depressive episode. International Journal Psychiatry in Clinical 
Practice. 2011; 00: 1-8 
19. Ching-I Hung et al., Depression and somatic symptoms scale: A new scale with both 
depression 
and 
somatic 
symptoms 
emphasized. 
Psychiatry 
and 
Clinical 
Neurosciences. 2006; 60: 700-708 
 

SAP_000.pdf: 
 
CONFIDENTIAL 
 “Final” Page 1 of 34 
 
Project No. BLI-1005-002 
Protocol Version: 2.3 
 
Statistical Analysis Plan for PDC-1421 
SAP Version: 20180626_01 
 
Sponsor: BioLite, Inc. 
Prepared by: Virginia Contract Research Organization Co., Ltd. 
\\hp_server\ingly lee$\STA\BOLPDCA20141117\07_SAP\20190611 
(Amendment)\SAP_BOLPDCA20141117_20180626_01_final_20190611.doc  
 
Template 200912
1. 
TITLE PAGE 
STATISTICAL ANALYSIS PLAN (SAP) 
A Phase II Study of PDC-1421 Capsule to Evaluate the Safety and Efficacy in Patients with 
Major Depressive Disorder 
Protocol No.: 
BLI-1005-002 
 
 
 
 
First subject first visit: 
May-19-2015 
Last visit of the study: 
Mar-18-2019 
Sponsor: 
BioLite, Inc. 
CRO: 
Virginia Contract Research Organization Co., Ltd. 
3F, No. 2, Lane 258, Ruiguang Rd., Neihu District, 
Taipei 114, Taiwan 
 
 
 
 
Final 
Date of issue: 
June-14-2019 
 
 
 
NCT02395978


 
CONFIDENTIAL 
 “Final” Page 2 of 34 
 
Project No. BLI-1005-002 
Protocol Version: 2.3 
 
Statistical Analysis Plan for PDC-1421 
SAP Version: 20180626_01 
 
Sponsor: BioLite, Inc. 
Prepared by: Virginia Contract Research Organization Co., Ltd. 
\\hp_server\ingly lee$\STA\BOLPDCA20141117\07_SAP\20190611 
(Amendment)\SAP_BOLPDCA20141117_20180626_01_final_20190611.doc  
 
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2. 
TABLE OF CONTENTS  
1. 
TITLE PAGE .......................................................................................................................................... 1 
2. 
TABLE OF CONTENTS ....................................................................................................................... 2 
3. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ........................................................ 4 
4. 
PROTOCOL AMENDMENTS ............................................................................................................. 5 
5. 
INVESTIGATIONAL PLAN .............................................................................................................. 14 
5.1 
OBJECTIVE.......................................................................................................................................... 14 
5.1.1 
Primary objective ..................................................................................................................... 14 
5.1.2 
Secondary objective .................................................................................................................. 14 
5.2 
STUDY DESIGN ................................................................................................................................... 14 
5.2.1 
Schematic Diagram of The Study: ............................................................................................ 15 
5.2.2 
Study Medication Administration ............................................................................................. 16 
5.2.3 
Flowchart of study procedures ................................................................................................. 16 
5.3 
STATISTICAL METHODS PLANNED IN THE PROTOCOL AND DETERMINATION OF SAMPLE SIZE ........... 17 
5.3.1 
Populations for analysis ........................................................................................................... 17 
5.3.2 
Endpoints .................................................................................................................................. 17 
5.3.3 
Statistical Evaluation................................................................................................................ 18 
5.3.4 
Determination of sample size ................................................................................................... 18 
5.4 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES ................................................. 19 
6. 
STATISTICAL EVALUATIONS ....................................................................................................... 20 
6.1 
DATA SETS ANALYZED ...................................................................................................................... 20 
6.2 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ............................................................... 20 
6.2.1 
Demographic data .................................................................................................................... 20 
6.2.2 
Major Depressive Disorder History and Medical history ........................................................ 20 
6.2.3 
Concomitant medications ......................................................................................................... 21 
6.3 
STUDY TREATMENT ADMINISTRATION ............................................................................................... 21 
6.3.1 
Treatment Compliance ............................................................................................................. 21 
6.3.2 
Extent of Exposure .................................................................................................................... 21 
6.3.3 
Mean Daily Dose ...................................................................................................................... 21 
6.4 
ANALYSIS OF EFFICACY ..................................................................................................................... 22 
6.4.1 
Primary Efficacy Endpoint ....................................................................................................... 22 
6.4.2 
Secondary efficacy endpoints: .................................................................................................. 22 
6.5 
ANALYSIS OF SAFETY ......................................................................................................................... 23 
6.5.1 
Adverse events (AEs) ................................................................................................................ 23 
6.5.2 
Serious adverse events (SAEs) .................................................................................................. 23 
6.5.3 
Laboratory data ........................................................................................................................ 24 
6.5.4 
Physical Examination (PE) ...................................................................................................... 24 
6.5.5 
Vital Signs ................................................................................................................................ 24 
6.5.6 
ECG .......................................................................................................................................... 24 
6.5.7 
C-SSRS ..................................................................................................................................... 24 
6.6 
STATISTICAL / ANALYTICAL ISSUES ................................................................................................... 25 
6.6.1 
Adjustments for covariates ....................................................................................................... 25 
6.6.2 
Handling of Dropouts or Missing Data .................................................................................... 25 
6.6.3 
Interim Analyses and Data Monitoring .................................................................................... 25 
6.6.4 
Multicenter Studies ................................................................................................................... 25 
6.6.5 
Multiple Comparisons / Multiplicity ......................................................................................... 25 
6.6.6 
Use of An “Efficacy Subset” of Subjects .................................................................................. 25 
6.6.7 
Active-Control Studies Intended to Show Equivalence ............................................................. 26 
6.6.8 
Examination of Subgroups ....................................................................................................... 26 
NCT02395978


 
CONFIDENTIAL 
 “Final” Page 3 of 34 
 
Project No. BLI-1005-002 
Protocol Version: 2.3 
 
Statistical Analysis Plan for PDC-1421 
SAP Version: 20180626_01 
 
Sponsor: BioLite, Inc. 
Prepared by: Virginia Contract Research Organization Co., Ltd. 
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6.6.9 
Relocation of Visit Data by Time Window ................................................................................ 26 
6.6.10 
Random effect and fixed effect when modeling ......................................................................... 26 
6.6.11 
Outliers ..................................................................................................................................... 26 
6.6.12 
Calibration of Laboratory Data Between Centers ................................................................... 26 
7. 
DOCUMENTATION OF STATISTICAL METHODS .................................................................... 27 
7.1 
DOCUMENTATION OF STATISTICAL METHODS .................................................................................... 27 
8. 
DATA HANDLING PROCEDURE .................................................................................................... 28 
8.1 
CODING SYSTEM ................................................................................................................................ 28 
8.2 
DATA STORAGE AND ANALYSIS ......................................................................................................... 28 
9. 
STUDY SUBJECTS ............................................................................................................................. 29 
9.1 
DISPOSITION OF SUBJECTS .................................................................................................................. 29 
9.2 
WITHDRAWAL OF SUBJECTS ............................................................................................................... 29 
9.3 
PROTOCOL DEVIATIONS ..................................................................................................................... 29 
10. 
REFERENCE LIST ............................................................................................................................. 30 
11. 
APPENDICES ....................................................................................................................................... 31 
11.1 
NORMAL RANGES FOR LABORATORY VARIABLES ............................................................................. 31 
11.2 
TABLE OF CONTENTS (TOC) FOR TABLES, FIGURES AND LISTING ..................................................... 31 
11.3 
MOCK-UP TABLES ............................................................................................................................... 31 
11.4 
VERSION CONTROL INFORMATION OF SAP ........................................................................................ 31 
11.5 
CONTENTS OF AMENDMENT OF SAP .................................................................................................. 32 
12. 
SIGNATURE PAGE ............................................................................................................................ 34 
 
NCT02395978


 
CONFIDENTIAL 
 “Final” Page 4 of 34 
 
Project No. BLI-1005-002 
Protocol Version: 2.3 
 
Statistical Analysis Plan for PDC-1421 
SAP Version: 20180626_01 
 
Sponsor: BioLite, Inc. 
Prepared by: Virginia Contract Research Organization Co., Ltd. 
\\hp_server\ingly lee$\STA\BOLPDCA20141117\07_SAP\20190611 
(Amendment)\SAP_BOLPDCA20141117_20180626_01_final_20190611.doc  
 
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3. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AE 
Adverse event 
BMI 
Body mass index 
C.I. 
Confidence interval 
CRF 
Case report form 
CRO 
Contract research organization 
DRCSU 
Depression Research Clinic at Stanford University 
FDA 
Food and Drug Administration 
GCP 
Good clinical practice 
IQR 
Inter-quartile range 
IRB 
Institutional review board 
ITT 
Intent-to-treat 
LCGMH 
Linkou Chang Gung Memorial Hospital 
LOCF 
Last observation carried forward 
PP 
Per-protocol 
Q1 
The first quantile (the 25th percentile) 
Q3 
The third quantile (the 75th percentile) 
TSGH 
Tri-Service General Hospital 
TVGH 
Taipei Veterans General Hospital 
SAE 
Serious adverse event 
SD 
Standard deviation 
WH 
Wanfang Hospital 
VCRO 
Virginia contract research organization 
 
NCT02395978


 
CONFIDENTIAL 
 “Final” Page 5 of 34 
 
Project No. BLI-1005-002 
Protocol Version: 2.3 
 
Statistical Analysis Plan for PDC-1421 
SAP Version: 20180626_01 
 
Sponsor: BioLite, Inc. 
Prepared by: Virginia Contract Research Organization Co., Ltd. 
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4. 
PROTOCOL AMENDMENTS 
The version of approval  protocol after enrolling the first subject was described as follow: 
As no patient were enrolled in Taipei City Hospital, Songde Branch, the site will not be 
included for analysis. 
 
 
This protocol amendment about the statistical analysis is consisted of the following 
(compared to the final approved protocol): 
Page 
Before 
version烉 1.4 
Page 
Content after modification 
Version烉1.5 
2 
Primary endpoint 
Change 
in 
Montgomery-Åsberg 
Depression 
2 
Primary endpoint 
Change 
in 
Montgomery-Åsberg 
Depression 
Approved  
date    
Approved  
by 
 
Final 
(version:<protocol version>) 
 
Amendment 01 
(version: <protocol version>) 
TFDA  
20150727 (Version 1.4) 
20160630 (Version 1.5) 
CGMH-LK 
20150728 (Version 1.4) 
20160511 (Version 1.5) 
TVGH 
20150806 (Version 1.4) 
20160706 (Version 1.5) 
 
 
 
TFDA 
20160630 (Version 1.5) 
20160910 (Version 2.0) 
CGMH-LK 
20160511 (Version 1.5) 
20160824 (Version 2.0) 
TSGH 
20160802 (Version 1.5) 
20161017 (Version 2.0) 
TVGH 
20160706 (Version 1.5) 
20161104 (Version 2.0) 
 
 
 
TFDA 
20160910 (Version 2.0) 
20170517 (Version 2.1) 
CGMH-LK 
20160824 (Version 2.0) 
20170406 (Version 2.1) 
TSGH 
20161017 (Version 2.0) 
20170512 (version 2.1) 
TVGH 
20161104 (Version 2.0) 
20170524 (Version 2.1) 
WFH 
20161007 (version 2.0) 
20170411 (Version 2.1) 
 
 
 
TFDA 
20170517 (Version 2.1) 
20171030 (Version 2.2) 
CGMH-LK 
20170406 (Version 2.1) 
20171113 (Version 2.2) 
TSGH 
20170512 (version 2.1) 
20171128 (Version 2.2) 
WFH 
20170411 (Version 2.1) 
20170411 (Version 2.2) 
 
 
 
TFDA 
20171030 (Version 2.2) 
20190218 (Version 2.3) 
CGMH-LK 
20171113 (Version 2.2) 
20190214 (Version 2.3) 
TVGH 
20170524 (Version 2.1) 
20190318 (Version 2.3) 
WFH 
20170411 (Version 2.2) 
20190331 (Version 2.3) 
 
 
 
FDA 
20170225 (Version 2.1) 
20180513 (Version 2.3) 
Stanford 
20170128 (Version 2.1) 
20180503 (Version 2.3) 
NCT02395978


 
CONFIDENTIAL 
 “Final” Page 6 of 34 
 
Project No. BLI-1005-002 
Protocol Version: 2.3 
 
Statistical Analysis Plan for PDC-1421 
SAP Version: 20180626_01 
 
Sponsor: BioLite, Inc. 
Prepared by: Virginia Contract Research Organization Co., Ltd. 
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Rating Scale (MADRS) total score 
from baseline to week 4 compared to 
placebo. 
 
Secondary endpoint 
 Change in Hamilton Rating Scale 
for 
Depression 
(HAM-D-17), 
Hamilton Rating Scale for Anxiety 
(HAM-A), Depression and Somatic 
Symptoms Scale (DSSS), Clinical 
Global Impression Scale (CGI) total 
score from baseline to week 2, 4 
and 5. 
 Change in MADRS total score from 
baseline to week 2 and 5. 
 Percentage of partial responders 
(defined as a participant with a 25-
50% decrease from baseline in total 
score) and responders (defined as a 
participant with ʁ 50% decrease 
from baseline in total score) in 
MADRS by week 2, 4 and 5. 
 Evaluate Safety Assessments and 
Columbia-Suicide Severity Rating 
Scale (C-SSRS) from screening 
stage to the last visit 
 Difference in the mean changes of 
MADRS, 
HAM-D-17, 
HAM-A, 
DSSS, CGI and C-SSRS from the 
baseline to week 2, 4 and 5 between 
the PDC-1421 Capsule and placebo 
groups. 
Rating Scale (MADRS) total score from 
baseline to week 6 compared to placebo. 
 
Secondary endpoint 
 Change in MADRS total score from 
baseline to week 2 and 7. 
 Change in Hamilton Rating Scale for 
Depression (HAM-D-17), Hamilton 
Rating Scale for Anxiety (HAM-A), 
Depression and Somatic Symptoms 
Scale (DSSS), Clinical Global 
Impression Scale (CGI) total score 
from baseline to week 2, 4, 6 and 7. 
 Percentage of partial responders 
(defined as a participant with a 25-
50% decrease from baseline in total 
score) and responders (defined as a 
participant with ʁ 50% decrease 
from baseline in total score) in 
MADRS by week 2, 4, 6 and 7. 
 Evaluate Safety Assessments and 
Columbia-Suicide Severity Rating 
Scale (C-SSRS) from screening stage 
to the last visit 
 Difference in the mean changes of 
MADRS, 
HAM-D-17, 
HAM-A, 
DSSS, CGI and C-SSRS from the 
baseline to week 2, 4, 6 and 7 
between the PDC-1421 Capsule and 
placebo groups. 
14 
None 
14 
1.2.4.4 13-week Repeated 
Dose Subchronic Toxicity 
Study in Rats 
To evaluate the subchronic toxicity of 
PDC-1421, four groups of rats were 
administered with 0, 750, 1500 and 
2500 mg/kg/once daily p.o. for 13 
weeks 
(90 
days). 
There 
are 
no 
treatment-related 
mortality, 
clinical 
signs of toxicity and ophthalmologic 
abnormality in the study. 
And no significant toxicity evidences in 
NCT02395978


 
CONFIDENTIAL 
 “Final” Page 7 of 34 
 
Project No. BLI-1005-002 
Protocol Version: 2.3 
 
Statistical Analysis Plan for PDC-1421 
SAP Version: 20180626_01 
 
Sponsor: BioLite, Inc. 
Prepared by: Virginia Contract Research Organization Co., Ltd. 
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mean body weights, mean body weight 
gains and food consumption in all 
treatment groups were noted. 
In 
clinical 
pathology, 
no 
toxicity 
evidences were noted for all parameters 
(hematology, 
serum 
chemistry 
and 
urinalysis), no treatment-related gross 
abnormality was found at necropsy, and 
no significant toxicity evidences in 
organ weights evaluation. And the 
histopathological findings showed that 
no treatment-related changes in vehicle 
control and PDC-1421 treated groups. 
It was estimated that the NOAEL of 
PDC-1421 of the 13-week repeated dose 
toxicity study is 2500 mg/kg/day for 
both males and females. 
22 
As Page 2 
22 
As Page 2 
24 
3.5.4 Dosing Regimen, packing and 
labeling Table 14. Summary of 
dosing regimen Visits of Part II 
Biweekly for 28 days 
24 
3.5.4 Dosing Regimen, packing and 
labeling Table 14. Summary of 
dosing regimen Visits of Part II 
Biweekly for 42 days 
25 
In part II, eligible subjects are 
randomized into one of three treatment 
arms in a 1:1:1 ratio [one capsule of 
PDC-1421 Capsule and placebo thrice 
daily; two capsules of PDC-1421 
Capsule thrice daily; two capsules of 
placebo thrice daily] for 28 days. After 
the two weeks of drug administration, 
subjects will return to the center for 
assessments then get another study 
drug bag for the following 14 days. 
The biweekly clinic visits are two 
times and one week later after the last 
dose for follow-up. 
Investigational 
drug 
(PDC-1421 
Capsule or placebo) are provided by 
BioLite, Inc. and stored in Department 
of Pharmacy, Taipei Veterans General 
Hospital, 
Linkou 
Chang 
Gung 
Memorial Hospital and Taipei City 
 
In 
part 
II, 
eligible 
subjects 
are 
randomized into one of three treatment 
arms in a 1:1:1 ratio [one capsule of 
PDC-1421 Capsule and placebo thrice 
daily; two capsules of PDC-1421 
Capsule thrice daily; two capsules 
of placebo thrice daily] for 42 days. 
After 
the 
two 
weeks 
of 
drug 
administration, subjects will return to 
the center for assessments then 
get another study drug bag for the 
following 14 days. The biweekly clinic 
visits are three times and one week later 
after the last dose for follow-up. 
Investigational 
drug 
(PDC-1421 
Capsule or placebo) are provided by 
BioLite, Inc. and stored in Department 
of Pharmacy, Taipei Veterans General 
Hospital, 
Linkou 
Chang 
Gung 
Memorial Hospital, Taipei City 
NCT02395978


 
CONFIDENTIAL 
 “Final” Page 8 of 34 
 
Project No. BLI-1005-002 
Protocol Version: 2.3 
 
Statistical Analysis Plan for PDC-1421 
SAP Version: 20180626_01 
 
Sponsor: BioLite, Inc. 
Prepared by: Virginia Contract Research Organization Co., Ltd. 
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Hospital, Songde Branch. In part I, the 
first six subjects will take 21 packs 
with 21 capsules of PDC-1421 Capsule 
and another six take 21 packs with 42 
capsules of PDC-1421 Capsule in 
every week of trial. 
In part II, subjects will be dispensed 
with study drug per 2 weeks which are 
packaged in a drug bag. A drug bag 
will contain 42 packs. Depending on 
the study arms, each pack may contain 
2 PDC-1421 Capsules, 2 placebos or 1 
PDC-1421 Capsule plus 1 placebo. 
Each subject will be administered 
84 packs in the end of trial. The drug 
bag of investigational drug is clearly 
labeled as following 
Hospital, Songde Branch and Tri-
Service General Hospital, Neihu Main 
Facility and Tingjhou Branch. In part I, 
the first six subjects will take 21 packs 
with 21 capsules of PDC-1421 Capsule 
and another six take 21 packs with 42 
capsules of PDC-1421 Capsule 
in every week of trial. In part II, 
subjects will be dispensed with study 
drug per 2 weeks which are packaged in 
a drug bag. A drug bag will contain 42 
packs. Depending on the study 
arms, each pack may contain 2 PDC-
1421 Capsules, 2 placebos or 1 PDC-
1421 Capsule plus 1 placebo. Each 
subject will be administered 126 packs 
in the end of trial. 
The drug bag of investigational drug is 
clearly labeled as following 
32 
4.4.2 Subject Number Allocation 
The second digit: the site number; 
Taipei Veterans General Hospital will 
be assigned to “1”, Linkou Chang 
Gung Memorial Hospital will be 
assigned to “2” and Taipei City 
Hospital, Songde Branch will be 
assigned to “3”. 
32 
4.4.2 Subject Number Allocation 
The second digit: the site number; 
Taipei Veterans General Hospital will be 
assigned to Ⱦ1”, Linkou Chang Gung 
Memorial Hospital will be assigned to 
“2” and Taipei City Hospital, Songde 
Branch will be assigned to 3”, Tri-
Service General Hospital, Neihu 
Main Facility will be assigned to “4”. 
Tri-Service General Hospital, Tingjhou 
Branchwill be assigned to “5”. 
52 
10.4 Institutional Review Board (IRB) 
This 
study 
is 
conducted 
to 
be 
consistent with the principles of the 
Declaration of Helsinki and GCP. This 
protocol 
and 
any 
supplementary 
documents, including written 
informed 
consent 
form, 
subject 
recruitment 
advertisements 
and 
Investigator’s 
Brochure, 
must 
be 
reviewed and approved by IRB of 
the Taipei Veterans General Hospital, 
Linkou 
Chang 
Gung 
Memorial 
Hospital and Taipei City Hospital, 
Songde Branch qualified with local 
52 
10.4 Institutional Review Board (IRB) 
This study is conducted to be consistent 
with the principles of the Declaration of 
Helsinki and GCP. This protocol and 
any 
supplementary 
documents, 
including written informed consent 
form, 
subject 
recruitment 
advertisements 
and 
Investigator’s 
Brochure, 
must 
be 
reviewed 
and 
approved by IRB of the 
Taipei 
Veterans 
General 
Hospital, 
Linkou 
Chang 
Gung 
Memorial 
Hospital, Taipei City Hospital, Songde 
Branch 
and 
Tri-Service 
General 
NCT02395978


 
CONFIDENTIAL 
 “Final” Page 9 of 34 
 
Project No. BLI-1005-002 
Protocol Version: 2.3 
 
Statistical Analysis Plan for PDC-1421 
SAP Version: 20180626_01 
 
Sponsor: BioLite, Inc. 
Prepared by: Virginia Contract Research Organization Co., Ltd. 
\\hp_server\ingly lee$\STA\BOLPDCA20141117\07_SAP\20190611 
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legal prescriptions prior to study 
initiation… 
Hospital qualified with local legal 
prescriptions prior to study initiation… 
 
Page 
Before 
version烉 1.4 
Page 
Content after modification 
Version烉1.5 
2 
Primary endpoint 
Change 
in 
Montgomery-Åsberg 
Depression 
Rating Scale (MADRS) total score 
from baseline to week 4 compared to 
placebo. 
 
Secondary endpoint 
 Change in Hamilton Rating Scale 
for 
Depression 
(HAM-D-17), 
Hamilton Rating Scale for Anxiety 
(HAM-A), Depression and Somatic 
Symptoms Scale (DSSS), Clinical 
Global Impression Scale (CGI) total 
score from baseline to week 2, 4 
and 5. 
 Change in MADRS total score from 
baseline to week 2 and 5. 
 Percentage of partial responders 
(defined as a participant with a 25-
50% decrease from baseline in total 
score) and responders (defined as a 
participant with ʁ 50% decrease 
from baseline in total score) in 
MADRS by week 2, 4 and 5. 
 Evaluate Safety Assessments and 
Columbia-Suicide Severity Rating 
Scale (C-SSRS) from screening 
stage to the last visit 
 Difference in the mean changes of 
MADRS, 
HAM-D-17, 
HAM-A, 
DSSS, CGI and C-SSRS from the 
baseline to week 2, 4 and 5 between 
the PDC-1421 Capsule and placebo 
groups. 
2 
Primary endpoint 
Change 
in 
Montgomery-Åsberg 
Depression 
Rating Scale (MADRS) total score from 
baseline to week 6 compared to placebo. 
 
Secondary endpoint 
 Change in MADRS total score from 
baseline to week 2 and 7. 
 Change in Hamilton Rating Scale for 
Depression (HAM-D-17), Hamilton 
Rating Scale for Anxiety (HAM-A), 
Depression and Somatic Symptoms 
Scale (DSSS), Clinical Global 
Impression Scale (CGI) total score 
from baseline to week 2, 4, 6 and 7. 
 Percentage of partial responders 
(defined as a participant with a 25-
50% decrease from baseline in total 
score) and responders (defined as a 
participant with ʁ 50% decrease 
from baseline in total score) in 
MADRS by week 2, 4, 6 and 7. 
 Evaluate Safety Assessments and 
Columbia-Suicide Severity Rating 
Scale (C-SSRS) from screening stage 
to the last visit 
 Difference in the mean changes of 
MADRS, 
HAM-D-17, 
HAM-A, 
DSSS, CGI and C-SSRS from the 
baseline to week 2, 4, 6 and 7 
between the PDC-1421 Capsule and 
placebo groups. 
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CONFIDENTIAL 
 “Final” Page 10 of 34 
 
Project No. BLI-1005-002 
Protocol Version: 2.3 
 
Statistical Analysis Plan for PDC-1421 
SAP Version: 20180626_01 
 
Sponsor: BioLite, Inc. 
Prepared by: Virginia Contract Research Organization Co., Ltd. 
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14 
None 
14 
1.2.4.4 13-week Repeated 
Dose Subchronic Toxicity 
Study in Rats 
To evaluate the subchronic toxicity of 
PDC-1421, four groups of rats were 
administered with 0, 750, 1500 and 
2500 mg/kg/once daily p.o. for 13 
weeks 
(90 
days). 
There 
are 
no 
treatment-related 
mortality, 
clinical 
signs of toxicity and ophthalmologic 
abnormality in the study. 
And no significant toxicity evidences in 
mean body weights, mean body weight 
gains and food consumption in all 
treatment groups were noted. 
In 
clinical 
pathology, 
no 
toxicity 
evidences were noted for all parameters 
(hematology, 
serum 
chemistry 
and 
urinalysis), no treatment-related gross 
abnormality was found at necropsy, and 
no significant toxicity evidences in 
organ weights evaluation. And the 
histopathological findings showed that 
no treatment-related changes in vehicle 
control and PDC-1421 treated groups. 
It was estimated that the NOAEL of 
PDC-1421 of the 13-week repeated dose 
toxicity study is 2500 mg/kg/day for 
both males and females. 
22 
As Page 2 
22 
As Page 2 
24 
3.5.4 Dosing Regimen, packing and 
labeling Table 14. Summary of 
dosing regimen Visits of Part II 
Biweekly for 28 days 
24 
3.5.4 Dosing Regimen, packing and 
labeling Table 14. Summary of 
dosing regimen Visits of Part II 
Biweekly for 42 days 
25 
In part II, eligible subjects are 
randomized into one of three treatment 
arms in a 1:1:1 ratio [one capsule of 
PDC-1421 Capsule and placebo thrice 
daily; two capsules of PDC-1421 
Capsule thrice daily; two capsules of 
placebo thrice daily] for 28 days. After 
the two weeks of drug administration, 
 
In 
part 
II, 
eligible 
subjects 
are 
randomized into one of three treatment 
arms in a 1:1:1 ratio [one capsule of 
PDC-1421 Capsule and placebo thrice 
daily; two capsules of PDC-1421 
Capsule thrice daily; two capsules 
of placebo thrice daily] for 42 days. 
After 
the 
two 
weeks 
of 
drug 
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CONFIDENTIAL 
 “Final” Page 11 of 34 
 
Project No. BLI-1005-002 
Protocol Version: 2.3 
 
Statistical Analysis Plan for PDC-1421 
SAP Version: 20180626_01 
 
Sponsor: BioLite, Inc. 
Prepared by: Virginia Contract Research Organization Co., Ltd. 
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subjects will return to the center for 
assessments then get another study 
drug bag for the following 14 days. 
The biweekly clinic visits are two 
times and one week later after the last 
dose for follow-up. 
Investigational 
drug 
(PDC-1421 
Capsule or placebo) are provided by 
BioLite, Inc. and stored in Department 
of Pharmacy, Taipei Veterans General 
Hospital, 
Linkou 
Chang 
Gung 
Memorial Hospital and Taipei City 
Hospital, Songde Branch. In part I, the 
first six subjects will take 21 packs 
with 21 capsules of PDC-1421 Capsule 
and another six take 21 packs with 42 
capsules of PDC-1421 Capsule in 
every week of trial. 
In part II, subjects will be dispensed 
with study drug per 2 weeks which are 
packaged in a drug bag. A drug bag 
will contain 42 packs. Depending on 
the study arms, each pack may contain 
2 PDC-1421 Capsules, 2 placebos or 1 
PDC-1421 Capsule plus 1 placebo. 
Each subject will be administered 
84 packs in the end of trial. The drug 
bag of investigational drug is clearly 
labeled as following 
administration, subjects will return to 
the center for assessments then 
get another study drug bag for the 
following 14 days. The biweekly clinic 
visits are three times and one week later 
after the last dose for follow-up. 
Investigational 
drug 
(PDC-1421 
Capsule or placebo) are provided by 
BioLite, Inc. and stored in Department 
of Pharmacy, Taipei Veterans General 
Hospital, 
Linkou 
Chang 
Gung 
Memorial Hospital, Taipei City 
Hospital, Songde Branch and Tri-
Service General Hospital, Neihu Main 
Facility and Tingjhou Branch. In part I, 
the first six subjects will take 21 packs 
with 21 capsules of PDC-1421 Capsule 
and another six take 21 packs with 42 
capsules of PDC-1421 Capsule 
in every week of trial. In part II, 
subjects will be dispensed with study 
drug per 2 weeks which are packaged in 
a drug bag. A drug bag will contain 42 
packs. Depending on the study 
arms, each pack may contain 2 PDC-
1421 Capsules, 2 placebos or 1 PDC-
1421 Capsule plus 1 placebo. Each 
subject will be administered 126 packs 
in the end of trial. 
The drug bag of investigational drug is 
clearly labeled as following 
32 
4.4.2 Subject Number Allocation 
The second digit: the site number; 
Taipei Veterans General Hospital will 
be assigned to “1”, Linkou Chang 
Gung Memorial Hospital will be 
assigned to “2” and Taipei City 
Hospital, Songde Branch will be 
assigned to “3”. 
32 
4.4.2 Subject Number Allocation 
The second digit: the site number; 
Taipei Veterans General Hospital will be 
assigned to Ⱦ1”, Linkou Chang Gung 
Memorial Hospital will be assigned to 
“2” and Taipei City Hospital, Songde 
Branch will be assigned to 3”, Tri-
Service General Hospital, Neihu 
Main Facility will be assigned to “4”. 
Tri-Service General Hospital, Tingjhou 
Branchwill be assigned to “5”. 
NCT02395978


 
CONFIDENTIAL 
 “Final” Page 12 of 34 
 
Project No. BLI-1005-002 
Protocol Version: 2.3 
 
Statistical Analysis Plan for PDC-1421 
SAP Version: 20180626_01 
 
Sponsor: BioLite, Inc. 
Prepared by: Virginia Contract Research Organization Co., Ltd. 
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52 
10.4 Institutional Review Board (IRB) 
This 
study 
is 
conducted 
to 
be 
consistent with the principles of the 
Declaration of Helsinki and GCP. This 
protocol 
and 
any 
supplementary 
documents, including written 
informed 
consent 
form, 
subject 
recruitment 
advertisements 
and 
Investigator’s 
Brochure, 
must 
be 
reviewed and approved by IRB of 
the Taipei Veterans General Hospital, 
Linkou 
Chang 
Gung 
Memorial 
Hospital and Taipei City Hospital, 
Songde Branch qualified with local 
legal prescriptions prior to study 
initiation… 
52 
10.4 Institutional Review Board (IRB) 
This study is conducted to be consistent 
with the principles of the Declaration of 
Helsinki and GCP. This protocol and 
any 
supplementary 
documents, 
including written informed consent 
form, 
subject 
recruitment 
advertisements 
and 
Investigator’s 
Brochure, 
must 
be 
reviewed 
and 
approved by IRB of the 
Taipei 
Veterans 
General 
Hospital, 
Linkou 
Chang 
Gung 
Memorial 
Hospital, Taipei City Hospital, Songde 
Branch 
and 
Tri-Service 
General 
Hospital qualified with local legal 
prescriptions prior to study initiation… 
 
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32 
4.4.2 Subject Number Allocation 
The second digit: the site number; 
Taipei Veterans General Hospital will 
be assigned to “1”, Linkou Chang 
Gung Memorial Hospital will be 
assigned to “2” and Taipei City 
Hospital, Songde Branch will be 
assigned to “3”, Tri-Service General 
Hospital, Neihu Main Facility will be 
assigned to “4”. Tri-Service General 
Hospital, Tingjhou Branchwill be 
assigned to “5”. 
32 
4.4.2 Subject Number Allocation 
The second digit: the site number. 
 
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3.1 General Design  
The targeted population of this study is 
72 subjects who met the per-protocol 
basis, in which 12 are assigned to part 
I, 60 are assigned to part II. 
21 
3.1 General Design  
The targeted population of this study is 
72 subjects who met the intent-to-treat 
(ITT) basis, in which 12 are assigned to 
part I, 60 are assigned to part II. 
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CONFIDENTIAL 
 “Final” Page 13 of 34 
 
Project No. BLI-1005-002 
Protocol Version: 2.3 
 
Statistical Analysis Plan for PDC-1421 
SAP Version: 20180626_01 
 
Sponsor: BioLite, Inc. 
Prepared by: Virginia Contract Research Organization Co., Ltd. 
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8.1 Sample Size Determination 
Based on our study design, it is 
planned to enroll 60 subjects who met 
the per-protocol basis. 
48 
8.1 Sample Size Determination 
Based on our study design, it is planned 
to enroll 60 subjects who met the intent-
to-treat (ITT) basis. 
 
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42 
The total score is used to define 
treatment response (ʁ40% reduction 
from baseline) and partial response 
(20-39% reduction from baseline). 
42 
Percentage 
of 
partial 
responders 
(defined as a participant with a 25-50% 
decrease from baseline in total score) 
and responders (defined as a participant 
with ʁ50%decrease from baseline in 
total score. 
 
NCT02395978


 
CONFIDENTIAL 
 “Final” Page 14 of 34 
 
Project No. BLI-1005-002 
Protocol Version: 2.3 
 
Statistical Analysis Plan for PDC-1421 
SAP Version: 20180626_01 
 
Sponsor: BioLite, Inc. 
Prepared by: Virginia Contract Research Organization Co., Ltd. 
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5. 
INVESTIGATIONAL PLAN 
5.1 
Objective 
5.1.1 
Primary objective 
The primary objective of this trial was to determine the effective doses and treatment 
period of PDC-1421 Capsule in subjects with MDD.  
5.1.2 
Secondary objective 
To evaluate the safety of PDC-1421 Capsule in subjects receiving PDC-1421 at various dose 
levels . 
5.2 
Study Design 
The screening phase is intended for diagnosing and assessing the patient for possible 
inclusion in the study and for providing an adequate washout period. The following 
study will be conducted in two parts. The targeted population of this study is 72 
subjects who met the intent-to-treat (ITT) basis, in which 12 are assigned to part I, 
60 are assigned to part II. Part I is an open-label study, multiple center and dose 
escalation evaluation in twelve patients. Six subjects each will be evaluated for any 
safety concerns at 1 or 2 capsules TID dose for 28 days, sequentially. Each of them 
will be assessed twice in the first week after administration of PDC-1421 Capsules 
and once a week in the following treatment. Part II is a randomized, double-blind, 
placebo-controlled, parallel-group study. 60 subjects will be randomly assigned on a 
1:1:1 basis to one of the three treatment arms (1 PDC-1421 Capsule plus 1 placebo 
TID, 2 PDC-1421 Capsule TID, 2 placebo TID) for 6 weeks (42 days) and evaluated 
the safety and efficacy every two weeks during the treatment period. The 
performance of PDC-1421 Capsule on MDD subjects will provide us with valuable 
information for our next phase of the study. 
NCT02395978


 
CONFIDENTIAL 
 “Final” Page 15 of 34 
 
Project No. BLI-1005-002 
Protocol Version: 2.3 
 
Statistical Analysis Plan for PDC-1421 
SAP Version: 20180626_01 
 
Sponsor: BioLite, Inc. 
Prepared by: Virginia Contract Research Organization Co., Ltd. 
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5.2.1 
Schematic Diagram of The Study: 
 
 
 
 
 
 
 
 
 
 
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CONFIDENTIAL 
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Project No. BLI-1005-002 
Protocol Version: 2.3 
 
Statistical Analysis Plan for PDC-1421 
SAP Version: 20180626_01 
 
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Prepared by: Virginia Contract Research Organization Co., Ltd. 
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5.2.2 
Study Medication Administration 
In part I, six subjects each will take 1 or 2 capsules thrice daily for 28 days, 
sequentially. Subjects are assessed twice in the first week after drug administration 
and they will receive the study drug bag for the following 7 days every week. In part 
II, eligible subjects are randomized into one of three treatment arms in a 1:1:1 ratio 
(one capsule of PDC-1421 Capsule and placebo thrice daily; two capsules of 
PDC-1421 Capsule thrice daily; two capsules of placebo thrice daily) for 42 days. 
After the two weeks of drug administration, subjects will return to the center for 
assessments then get another study drug bag for the following 14 days. The biweekly 
clinic visits are three times and one week later after the last dose for follow-up. 
5.2.3 
 Flowchart of study procedures 
Part I-schedule of assessments 
*On ±2 days. 
*V3 (Week 1/2) only can be conducted in Day 3 or Day 4.  
 
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CONFIDENTIAL 
 “Final” Page 17 of 34 
 
Project No. BLI-1005-002 
Protocol Version: 2.3 
 
Statistical Analysis Plan for PDC-1421 
SAP Version: 20180626_01 
 
Sponsor: BioLite, Inc. 
Prepared by: Virginia Contract Research Organization Co., Ltd. 
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Part II-schedule of assessments 
*On ±2 days. 
** If the interval of visit 1 and visit 2 is within 7 days, Hematology and Blood 
chemistry test of visit 2 can be skipped. 
 
5.3 
Statistical Methods Planned in the Protocol and Determination of Sample Size 
5.3.1 
Populations for analysis 
The efficacy measures are conducted on the per-protocol (PP) and intent-to-treat (ITT) 
basis. The per protocol will be defined as (1) The drug compliance is at least 80% (2) 
Subjects have completed data to determine the primary endpoint. (3) Subjects cannot 
have protocol deviation. The protocol deviation will be defined as (1) Inclusion or exclusion 
criteria not satisfied. (2) Not permitted concomitant medications (3) Wrong randomized 
treatment prescribed. An intent-to-treat (ITT) basis will be defined as the data are analyzed 
by the treatment groups to which the randomized patients who take at least one dose of study 
medication and have any post-baseline safety data collected.  
The safety measures are conducted on the ITT basis.  
5.3.2 
Endpoints  
Primary endpoint: 
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CONFIDENTIAL 
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Project No. BLI-1005-002 
Protocol Version: 2.3 
 
Statistical Analysis Plan for PDC-1421 
SAP Version: 20180626_01 
 
Sponsor: BioLite, Inc. 
Prepared by: Virginia Contract Research Organization Co., Ltd. 
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In part II, the primary endpoint is the change of Montgomery-Å sberg Depression 
Rating Scale (MADRS) total score from baseline to Week 6 compared to placebo.  
Secondary endpoints are: 
 MADRS total score炼change from baseline to week 2 and 7 
 HAM-D-17, CGI, DSSS and HAM-A炼change from baseline to week 2, 4, 6 and 7 
 Percentage of partial responders and responders (defined as participants with a 25-50% 
decrease and a ʁ50% decrease from baseline in total score, respectively) in MADRS total 
score by Week 2, 4, 6 and 7 
 Difference in the mean changes of MADRS, HAM-D-17, HAM-A,DSSS, CGI and C-
SSRS from baseline to week 2, 4, 6 and 7 between PDC-1421 Capsule and placebo groups. 
Safety endpoints: 
 physical examination 
 vital signs  
 laboratory data (blood chemistry) 
 ECG  
 Columbia-Suicide Severity Scale (C-SSRS)  
 Incidence of AE/SAE 
5.3.3 
Statistical Evaluation 
Simple descriptive statistics with 95% confidence interval will be performed with data 
collected in this study wherever applicable. Treatment effects are evaluated based on 
2-sided test with a 0.05 significant level. All data shall be tabulated and presented in the 
study report. The descriptive statistics will be provided. The safety and efficacy data will 
be analyzed using the non-parametric method. 
5.3.3.1  Primary analysis methods 
The efficacy and safety information recorded on CRF will be summarized by tables 
presented in frequency and percentage for categorical variables, in mean with SD as well 
as median with the minimum and maximum for continuous variables. The comparison 
between three groups will be analyzed by nonparametric method as appropriate. All 
adverse events will be summarized with coding term, severity, relationship to study drug 
by frequency tables with the counts and percentage. In addition, serious adverse events 
will be listed with event narration. 
5.3.4 
Determination of sample size 
In part I, six subjects each will be evaluated for safety and efficacy assessments at 1 or 2 
capsules TID dose for 28 days, sequentially. 
NCT02395978


 
CONFIDENTIAL 
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Project No. BLI-1005-002 
Protocol Version: 2.3 
 
Statistical Analysis Plan for PDC-1421 
SAP Version: 20180626_01 
 
Sponsor: BioLite, Inc. 
Prepared by: Virginia Contract Research Organization Co., Ltd. 
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In part II, this is a small proof-of-concept study to evaluate 2 doses of PDC-1421 and 
placebo in the treatment of major depressive disorder. Based on our study design, it is 
planned to enroll 60 subjects who met the intent-to-treat (ITT) basis. 
5.4 
Changes in the Conduct of the Study or Planned Analyses 
All the statistical analysis will follow protocolized statistical contents.  
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CONFIDENTIAL 
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Project No. BLI-1005-002 
Protocol Version: 2.3 
 
Statistical Analysis Plan for PDC-1421 
SAP Version: 20180626_01 
 
Sponsor: BioLite, Inc. 
Prepared by: Virginia Contract Research Organization Co., Ltd. 
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6. 
STATISTICAL EVALUATIONS 
The statistical objective of this study is to assess the safety and efficacy profiles in three 
groups - 1 PDC-1421 capsule plus 1 placebo, 2 PDC-1421 Capsule, and 2 placebos. 
6.1 
Data Sets Analyzed 
Two study populations are intention-to-treat (ITT) population and per-protocol (PP) 
populations which are defined in section 5.3.1.  
The efficacy evaluations will be performed on both of the ITT and PP datasets while the 
safety evaluations will be performed on the ITT dataset. The primary conclusion will be 
made for the primary endpoint on the ITT population 
Demographic and baseline (Visit 2) characteristics will be performed on the ITT population. 
Sample size, mean, 95% confidence interval of mean, median, standard deviation, inter-
quartile range, maximum and minimum will be summarized for continuous variables. For 
categorical variables, the frequency and percentage will be provided. 
6.2 
Demographics and Other Baseline Characteristics 
Demography and baseline characteristics will be summarized in descriptive statistics and 
listed by part, center and treatment. 
6.2.1 
Demographic data 
Demographic variables including age(year), height (cm), weight (kg) and BMI (kg/m2) will 
be summarized. Subjects’ gender will be tabulated. 
Age (years) = integer of  (date of initial visit – date of birth) / 365.25  
BMI (Kg/m2) = (weight) / (height)2 rounds to one decimal place 
6.2.2 
Major Depressive Disorder History and Medical history 
Frequency table of Diagnosis and Statistical Manual of Mental Disorders-IV, text revision 
(DSM-IV-TR) will be presented. 
Frequency table of subject with medical history and current medical condition will be 
presented. 
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CONFIDENTIAL 
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Project No. BLI-1005-002 
Protocol Version: 2.3 
 
Statistical Analysis Plan for PDC-1421 
SAP Version: 20180626_01 
 
Sponsor: BioLite, Inc. 
Prepared by: Virginia Contract Research Organization Co., Ltd. 
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General medical history will be presented in incidence table and listed for each subject. 
Ongoing medical conditions will be presented separately from the cured diseases. 
6.2.3 
Concomitant medications 
Frequency table of subjects with pre-treatment and concomitant medications will be 
presented. WHO Drug Dictionary will be applied. 
Pre-treatment medications are the medications taken before the first dosing of study drug, 
while concomitant medications are those taken during the treatment duration (from first 
dosing date of study drug to the day before exiting from study). 
6.3 
Study Treatment Administration 
6.3.1 
Treatment Compliance 
Subjects’ compliance (%) during the treatment period will be tabulated by part, center, and 
treatment and calculated according to the following formula: 
烌 100* Number of study medication actually took during the extent of exposure 
Number of study medication should be taken during the extent of exposure (#) 
# = (number of study medication should be taken per day) * (extent of exposure, section 6.3.2) 
6.3.2 
Extent of Exposure 
Extent of exposure (days) = date of last drug taken – date of first drug taken + 1 
If the date of first drug taken is not available, the date when the drug was firstly dispensed 
will be used for calculation. 
If the date of last drug taken is not available, the date will be replaced with that of the last 
drug return, previous drug taken, or previous drug return in order. 
6.3.3 
Mean Daily Dose 
Descriptive statistics of mean daily dose of the test drug will be presented by part, center, and 
treatment. 
Mean daily dose烌 Number of study medication taken  
Extent of exposure (section 6.3.2) 
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Project No. BLI-1005-002 
Protocol Version: 2.3 
 
Statistical Analysis Plan for PDC-1421 
SAP Version: 20180626_01 
 
Sponsor: BioLite, Inc. 
Prepared by: Virginia Contract Research Organization Co., Ltd. 
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6.4 
Analysis of Efficacy 
Results of efficacy will be presented with descriptive statistics (i.e. sample size, number of 
missing data, mean, 95% confidence interval of mean, median, standard deviation, inter-
quartile range, maximum and minimum) for continuous parameters by part, visit, and 
treatment. Line charts of all efficacy outcomes will be generated and presented as mean and 
standard deviation. 
6.4.1 
Primary Efficacy Endpoint 
In part II study, the primary endpoint is the net change of the MADRS total score at the 6th 
week after treatment (Mean MADRS total score at week 6 – Mean MADRS total score at 
baseline [Visit 2]). 
Kruskal-Wallis test will be implemented to test the group difference. 
The primary hypothesis will be: 
H0: The mean ranks of the groups are the same  
Ha: The mean ranks of the groups are not the same  
One a significant treatment effect is found, Wilcoxon rank sum test with Holm procedure will 
then be performed for comparisons between two treatment groups and the placebo group. The 
treatment group will be declared superior if null hypothesis is rejected and μt1 and/or μt2 is 
greater than μp. 
6.4.2 
Secondary efficacy endpoints: 
In the part II study, change from baseline in MADRS at week 2/4/7, along with net changes 
in HAM-D-17, HAM-A, DSSS, and CGI at week 2/4/6/7 are the secondary endpoints. Also, 
group differences in net changes of the MADRS, CGI, HAM-D-17, HAM-A, and DSSS at 
the 2nd, 4th, 6th, and 7th week are the secondary efficacy endpoints. For the results with regard 
to MADRS and HAM-D-17, the summary of all sites in Taiwan will also be provided to 
contrast with the one in America. 
Descriptive statistics for original and changes from baseline will be display by part, center, 
visit and treatment. As for the group difference, it will be examined by Kruskal-Wallis test. A 
significant treatment effect will be claimed after the Wilcoxon rank sum test for post-hoc 
tests.  
In addition to the treatment difference, the effect of different product batches (or batch 
number)- the first batch and the second batch, on MADRS will also be examined. Drugs with 
batch number of “HDP-045A-040327” and placebos with batch number of “HDP-045C-
040327” are classified into the first batch of product. The batch numbers included in the 
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CONFIDENTIAL 
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Project No. BLI-1005-002 
Protocol Version: 2.3 
 
Statistical Analysis Plan for PDC-1421 
SAP Version: 20180626_01 
 
Sponsor: BioLite, Inc. 
Prepared by: Virginia Contract Research Organization Co., Ltd. 
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second batch are “HDP-045A-070119” for PDC-1421 and “HDP-045C-070119” for placebo. 
Subjects with baseline visit later than 2018/02/13, or those who were enrolled before 
2018/02/13 and got drugs after 2018/03/15 will be classified into the subgroup of the second 
batch. 
The responder and  partial responder is defined by the net change in total score of MADRS 
(responders are defined as participants with a ʁ50% decrease in total score from baseline; 
partial responders are defined as participants with at least 25% and no more than 50% 
decrease in total score from baseline). The percentage difference between treatment groups 
will be examined by Cochran-Mantel-Haenszel test.  
The same definitions of partial responder will be used for HAM-D-17. The difference 
between the treatment will be compared with Cochran-Mantel-Haenszel test as well. 
All statistical tests used will be two-tailed with α =0.05.  
6.5 
Analysis of Safety 
6.5.1 
Adverse events (AEs) 
The coding system used will be the Medical Dictionary for Regulatory Activities (MedDRA). 
Pre-treatment AE is the AE onset before the first dosing of study drug, while treatment-
emergent AE is the one onset after the first dosing of study drug. Pre-treatment AE and 
treatment emergent AE will be analyzed separately. 
Frequency table of subjects with pre-treatment AE (PTAE) and treatment emergent AE 
(TEAE) will be presented by part, center and treatment.  
For TEAE, adverse event incidents will also be summarized descriptively by system organ 
class and preferred term using MedDRA. If more than one type of event occurred within a 
system organ class/ preferred term for the subject, the subject is counted only once for each 
system organ class/ preferred term. 
For TEAE, incidence tables of severity, action taken, relationship to study drug, outcome and 
serious AE or not will be presented by part, center, preferred term and treatment. 
The frequency distribution of severity, action taken, relationship to study drug, and outcome 
of all AE events will be presented by part, center, and treatment. 
6.5.2 
Serious adverse events (SAEs) 
Incidence of serious adverse event will be tabulated. Serious adverse events incidents will be 
summarized descriptively by part, center, system organ class/ preferred term, and treatment 
group. 
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Project No. BLI-1005-002 
Protocol Version: 2.3 
 
Statistical Analysis Plan for PDC-1421 
SAP Version: 20180626_01 
 
Sponsor: BioLite, Inc. 
Prepared by: Virginia Contract Research Organization Co., Ltd. 
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6.5.3 
Laboratory data 
Descriptive statistics of original data and net changes in hematology and biochemistry data 
will be presented by part, center, visit, and treatment.  
Results of clinical significance with regard to laboratory data will be summarized with 
frequency and percentage. 
6.5.4 
Physical Examination (PE) 
Incidence table including umber and percentage of patient with abnormal PE will be 
tabulated by part, center, visit, and treatment for each body system.  
The corresponding body system will be analyzed and reported using a transition table. The 
type of transition includes no change,  change to normal, change to non-clinical significance, 
(NCS), change to clinical significance (CS) for each body system from baseline (Visit 2). 
6.5.5 
Vital Signs 
Descriptive statistics of net changes in vital signs including systolic and diastolic blood 
pressure, heart rate and body temperature will be presented by part, center, visit, and 
treatment.  
Results of clinical significance with regard to vital sign will be summarized with frequency 
and percentage. 
6.5.6 
ECG 
Frequency table and change in ECG result will be summarized by part, center, visit and 
treatment. The transition of ECG is define as following 4 groups: no change,  change to 
normal, change to non-clinical significance, (NCS), change to clinical significance (CS). 
6.5.7 
C-SSRS 
Results of C-SSRS will be presented by part, center, visit, and treatment. The baseline of C-
SSRS was set at screening visit (Visit 1). 
The analysis for C-SSRS will follow the official guidance “Columbia-Suicide Severity 
Rating Scale - Scoring and Data Analysis Guide.” The 10 categories will be defined 
according to 10 binary responses (yes/no) on the C-SSRS, which are:  
Category 1 – Wish to be Dead 
Category 2 – Non-specific Active Suicidal Thoughts 
Category 3 – Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act  
Category 4 – Active Suicidal Ideation with Some Intent to Act, without Specific Plan  
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CONFIDENTIAL 
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Project No. BLI-1005-002 
Protocol Version: 2.3 
 
Statistical Analysis Plan for PDC-1421 
SAP Version: 20180626_01 
 
Sponsor: BioLite, Inc. 
Prepared by: Virginia Contract Research Organization Co., Ltd. 
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Category 5 – Active Suicidal Ideation with Specific Plan and Intent 
Category 6 – Preparatory Acts or Behavior  
Category 7 – Aborted Attempt 
Category 8 – Interrupted Attempt  
Category 9 – Actual Attempt (non-fatal)  
Category 10 – Completed Suicide 
Suicidal ideation is identified if the total score of the five suicidal ideation questions 
(Categories 1-5)>0. Suicidal behavior is identified if the total score of the five suicidal 
behavior questions (Categories 6-10)>0. Suicidal ideation or behavior is identified if the total 
score of the ten suicidal ideation and behavior questions (Categories 1-10)>0. 
Changes of suicidal ideation, suicidal behavior, and suicidal ideation or behavior from 
baseline during treatment will be summarized in a shift-table by visit, center and treatment. 
6.6 
Statistical / Analytical Issues 
6.6.1 
Adjustments for covariates 
No adjustment for covariates will be performed in this study. 
6.6.2 
Handling of Dropouts or Missing Data 
Missing data caused by premature termination will be utilized the last observation carried 
forward (LOCF). However, the LOCF method will only be applied to data on efficacy. No 
imputation will be done for safety data. 
6.6.3 
Interim Analyses and Data Monitoring 
No interim analysis was planned. 
6.6.4 
Multicenter Studies  
This is a multi-center study, which was conducted in the Depression Research Clinic at 
Stanford University, Tri-Service General Hospital, Taipei Veterans General Hospital, Linkou 
Chang Gung Memorial Hospital, Taipei City Hospital, Songde Branch, and Wanfang Hospital. 
All results will be listed by center. 
6.6.5 
Multiple Comparisons / Multiplicity 
The Holm procedure will be carried out for the post-hoc test of the primary endpoint.  
6.6.6 
Use of An “Efficacy Subset” of Subjects 
All analyzed populations were defined in section 5.3.1; no other population will be utilized in 
statistical analyses. 
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CONFIDENTIAL 
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Project No. BLI-1005-002 
Protocol Version: 2.3 
 
Statistical Analysis Plan for PDC-1421 
SAP Version: 20180626_01 
 
Sponsor: BioLite, Inc. 
Prepared by: Virginia Contract Research Organization Co., Ltd. 
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6.6.7 
Active-Control Studies Intended to Show Equivalence 
Not applicable 
6.6.8 
Examination of Subgroups 
No subgroup analysis was conducted in the study. All center data will be pooled together for 
analyses of efficacy endpoint. 
6.6.9 
Relocation of Visit Data by Time Window 
Subject with visit relocation are listed in table below: 
 
6.6.10 Random effect and fixed effect when modeling 
Not applicable  
6.6.11 Outliers 
Outliers will not be excluded for and some extreme values will be excluded from this study. 
6.6.12 Calibration of Laboratory Data Between Centers 
Units of continuous laboratory data will be unified; the ones used in a plurality of center will 
be the standard.  
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CONFIDENTIAL 
 “Final” Page 27 of 34 
 
Project No. BLI-1005-002 
Protocol Version: 2.3 
 
Statistical Analysis Plan for PDC-1421 
SAP Version: 20180626_01 
 
Sponsor: BioLite, Inc. 
Prepared by: Virginia Contract Research Organization Co., Ltd. 
\\hp_server\ingly lee$\STA\BOLPDCA20141117\07_SAP\20190611 
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7. 
DOCUMENTATION OF STATISTICAL METHODS 
7.1 
Documentation of Statistical Methods 
Following SAS procedures will be applied for statistical methods mentioned in Chapter 6. 
SAS 
procedure 
Statistical Analysis 
Method 
Comment 
Freq 
Frequency table 
 
 
 
Cochran-Mantel-
Haenszel Test 
Test of association between variables by controlling 
for multiple centers 
Sgplot 
Graph 
 
NPAR1WAY Kruskal-Wallis test 
To test group difference of continuous variables 
 
Wilcoxon rank sum test Post-hoc test 
MULTTEST Holm’s Procedure 
Significant level control for Multiplicity  
MEANS 
Descriptive Statistics 
Means, SD, Min, Max, Med, IQR, P1, P3 
*Center effect will be incorporated in only when degree of freedom is sufficient. 
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CONFIDENTIAL 
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Project No. BLI-1005-002 
Protocol Version: 2.3 
 
Statistical Analysis Plan for PDC-1421 
SAP Version: 20180626_01 
 
Sponsor: BioLite, Inc. 
Prepared by: Virginia Contract Research Organization Co., Ltd. 
\\hp_server\ingly lee$\STA\BOLPDCA20141117\07_SAP\20190611 
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8. 
DATA HANDLING PROCEDURE 
8.1 
Coding System 
The MedDRA system (version 20.0) is used to code adverse events.  
Concomitant medication will be coded via WHODRUG.  
General medical history term will be coded via ICD-10 coding system  
8.2 
Data Storage and Analysis 
All data are stored in the VCROCTIS system.  
Statistical evaluation will be performed using SAS 9.4 (SAS-Institute Inc., Cary, NC). 
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CONFIDENTIAL 
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Project No. BLI-1005-002 
Protocol Version: 2.3 
 
Statistical Analysis Plan for PDC-1421 
SAP Version: 20180626_01 
 
Sponsor: BioLite, Inc. 
Prepared by: Virginia Contract Research Organization Co., Ltd. 
\\hp_server\ingly lee$\STA\BOLPDCA20141117\07_SAP\20190611 
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9. 
STUDY SUBJECTS 
9.1 
Disposition of Subjects 
The number and percentage of randomized subject no. and analysis population will be 
tabulated by center and treatment.  
9.2 
Withdrawal of Subjects  
Frequency table of the reasons for subject withdraw from study will be presented by center 
and treatment. 
9.3 
Protocol Deviations  
Protocol deviations will be listed and will be tabulated by center and treatment. 
 
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CONFIDENTIAL 
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Project No. BLI-1005-002 
Protocol Version: 2.3 
 
Statistical Analysis Plan for PDC-1421 
SAP Version: 20180626_01 
 
Sponsor: BioLite, Inc. 
Prepared by: Virginia Contract Research Organization Co., Ltd. 
\\hp_server\ingly lee$\STA\BOLPDCA20141117\07_SAP\20190611 
(Amendment)\SAP_BOLPDCA20141117_20180626_01_final_20190611.doc  
 
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10. 
REFERENCE LIST 
Clenn A. Walker, Common Statistical Methods for Clinical Research with SAS Examples, 
2nd edition, Cary, NC, SAS Institute Inc., 2002  
Shein-Chung Chow, Jen-pei Liu, Design and Analysis of Clinical Trials, John Wiley & Sons, 
Inc., 1998 
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CONFIDENTIAL 
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Project No. BLI-1005-002 
Protocol Version: 2.3 
 
Statistical Analysis Plan for PDC-1421 
SAP Version: 20180626_01 
 
Sponsor: BioLite, Inc. 
Prepared by: Virginia Contract Research Organization Co., Ltd. 
\\hp_server\ingly lee$\STA\BOLPDCA20141117\07_SAP\20190611 
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11. 
APPENDICES 
11.1 
Normal Ranges For Laboratory Variables 
Will be listed in data listings  
11.2 
Table of Contents (TOC) for Tables, Figures and Listing 
Refer to section 14 and 16.2 in clinical study report  
No further SAP amendment will be required for the deviation of TOC when the changes are still 
complied with the main text SAP. 
11.3 
Mock-up tables 
Refer to attachment “MUT_BOLPDCA20141117_20180626_01_final_20190611.pdf” 
11.4 
Version Control Information of SAP 
Document 
Version 
Approved date 
Final 
20180626_00 
Apr-19-2019 
Final 
20180626_01 
June-14-2019 
 
 
 
 
 
 
 
 
 
 
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CONFIDENTIAL 
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Project No. BLI-1005-002 
Protocol Version: 2.3 
 
Statistical Analysis Plan for PDC-1421 
SAP Version: 20180626_01 
 
Sponsor: BioLite, Inc. 
Prepared by: Virginia Contract Research Organization Co., Ltd. 
\\hp_server\ingly lee$\STA\BOLPDCA20141117\07_SAP\20190611 
(Amendment)\SAP_BOLPDCA20141117_20180626_01_final_20190611.doc  
 
Template 200912
 
11.5 
Contents of Amendment of SAP 
Page 
Before 
version烉 00 
Page 
Content after modification 
Version烉01 
20~ 
21 
6.4 Analysis of Efficacy 
Results of efficacy will be presented 
with descriptive statistics (i.e. sample 
size, number of missing data, mean, 
95% confidence interval of mean, 
median, standard deviation, inter-
quartile range, maximum and 
minimum) for continuous parameters 
by part, visit, and treatment. 
20~ 
21 
6.4 Analysis of Efficacy 
Results of efficacy will be presented 
with descriptive statistics (i.e. sample 
size, number of missing data, mean, 
95% confidence interval of mean, 
median, standard deviation, inter-
quartile range, maximum and minimum) 
for continuous parameters by part, visit, 
and treatment. Line charts of all efficacy 
outcomes will be generated and 
presented as mean and standard 
deviation. 
22 
Definition of partial responder 
…partial responder are defined as 
participants with at least 25% and no 
more than 50% decrease in total score 
from baseline) and the 95% confidence 
interval (CI) will be computed.  
22 
Definition of partial responder 
…partial responders are defined as 
participants with at least 25% and no 
more than 50% decrease in total score 
from baseline).  
22 
6.5.1 Adverse events (AEs) 
For TEAE, incidence tables of severity, 
action taken, relationship to study drug, 
outcome and serious AE or not will be 
presented by part, center, and treatment. 
22 
6.5.1 Adverse events (AEs) 
For TEAE, incidence tables of severity, 
action taken, relationship to study drug, 
outcome and serious AE or not will be 
presented by part, center, preferred term 
and treatment. 
The frequency distribution of severity, 
action taken, relationship to study drug, 
and outcome of all AE events will be 
presented by part, center, and treatment. 
23 
6.5.4 Physical Examination (PE) 
Only when abnormality is recorded, the 
corresponding body system will be 
analyzed and reported using a transition 
table. The type of transition includes 
normal -> normal, normal -> abnormal, 
abnormal -> abnormal, and abnormal-> 
normal for each body system from 
baseline (Visit 2). 
23 
6.5.4 Physical Examination (PE) 
The corresponding body system will be 
analyzed and reported using a transition 
table. The type of transition includes no 
change,  change to normal, change to 
non-clinical significance, (NCS), 
change to clinical significance (CS) for 
each body system from baseline (Visit 
2). 
23 
6.5.5 Vital Signs 
Descriptive statistics of net changes in 
vital signs including systolic and 
diastolic blood pressure, heart rate and 
23 
6.5.5 Vital Signs 
Descriptive statistics of net changes in 
vital signs including systolic and 
diastolic blood pressure, heart rate and 
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Project No. BLI-1005-002 
Protocol Version: 2.3 
 
Statistical Analysis Plan for PDC-1421 
SAP Version: 20180626_01 
 
Sponsor: BioLite, Inc. 
Prepared by: Virginia Contract Research Organization Co., Ltd. 
\\hp_server\ingly lee$\STA\BOLPDCA20141117\07_SAP\20190611 
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body temperature will be presented by 
part, center, visit, and treatment.  
body temperature will be presented by 
part, center, visit, and treatment.  
Results of clinical significance with 
regard to vital sign will be summarized 
with frequency and percentage. 
23 
6.5.6 ECG 
Frequency table and change in ECG 
result will be summarized by part, 
center, visit and treatment. The 
transition of ECG is define as following 
4 groups: normal -> normal, normal -> 
abnormal, abnormal -> abnormal, and 
abnormal-> normal. 
23 
6.5.6 ECG 
Frequency table and change in ECG 
result will be summarized by part, 
center, visit and treatment. The 
transition of ECG is define as following 
4 groups: no change,  change to normal, 
change to non-clinical significance, 
(NCS), change to clinical significance 
(CS). 
30 
11.3 Mock-up tables  
Refer to attachment 
“MUT_BOLPDCA20141117_20180626_ 
00_final20190411.pdf” 
30 
11.3 Mock-up tables 
Refer to attachment 
“MUT_BOLPDCA20141117_20180626 
_01_final_20190611.pdf” 
 
 
NCT02395978