Conditions: Attention-Deficit Hyperactivity Disorder (ADHD)
Keywords: ADHD
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 6
Healthy volunteers: no

Brief summary:
The primary objective of this trial was to determine the effective doses and treatment period of PDC-1421 Capsule in subjects with ADHD.

The secondary objective was to evaluate the safety of PDC-1421 Capsule in subjects receiving PDC-1421 at various dose levels.

Detailed description:
This study was a Part I of Phase II study designed to evaluate the safety and efficacy in adult patients with ADHD. 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 targeted population of this Part I study is six subjects who met the intent-to-treat per-protocol basis.

Part I study is an open-label study, single-center, and dose escalation evaluation in six patients.

1. Low dose: Six subjects will be initially evaluated for safety and efficacy assessments at low-dose (1 PDC-1421capsule TID) for 28 days. The subject will return for visit once a week during the treatment period.
2. Checkpoint #1: There will be an evaluation with all safety assessments data to decide whether subjects pass the checkpoint to enter high-dose treatment or continue to receive a low-dose treatment by the investigator.
3. High dose: The subjects who pass Checkpoint #1 will be initially evaluated for safety and efficacy assessments at high-dose (2 PDC-1421 capsules TID) for 28 days. Subjects will return for visit biweekly during the treatment period.
4. Checkpoint #2: There will be an evaluation with all safety assessments data to decide whether this study passes the checkpoint to enter Part II by the investigators.

Arms:
arm 1: 1 PDC-1421 Capsule, trice daily, p.o. after meal for 28 + 28 days arm 2: 1 PDC-1421 Capsule for 28 days + 2 PDC-1421 Capsules for 28 days, trice daily, p.o. after meals

Interventions: intervention 1: PDC-1421 Capsule
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.

Protocol document:
Prot_000.pdf: 
 
   
                   
 
Protocol 
I 
 
Protocol Number: BLI-1008-001 
Protocol Version: 2.0  
Date: 2020/06/30 
Confidential 
BioLite, Inc. 
萊特先進生醫股份有限公司 
 
 
Section 5. PROTOCOL  
 
Investigational New Drug (IND) 
PDC-1421 Capsule 
(Polygala tenuifolia Willd.) 
 
EDITION NUMBER : Version 2.0 
SPONSOR 
 
 
: BioLite, Inc. 
RELEASE DATE  
: 2020/06/30 
 
 
 
A Phase II Tolerability and Efficacy Study of PDC-1421 
Treatment in Adult Patients with Attention-Deficit 
Hyperactivity Disorder (ADHD), Part I 
 
 
NCT Number: NCT0269908 


 
   
                   
 
Protocol 
II 
 
Protocol Number: BLI-1008-001 
Protocol Version: 2.0  
Date: 2020/06/30 
Confidential 
BioLite, Inc. 
萊特先進生醫股份有限公司 
STUDY CONTACT INFORMATION 
 
SPONSOR 
Company: BioLite, Inc. 
Address: 2F, 20, Sec. 2, Shengyi Rd., Zhubei City, 
Hsinchu County, 30261, Taiwan  
Phone: +886-3-668-5386 
FAX: +886-3-657-9632 
PRINCIPAL 
INVESTIGATOR 
Name: Keith McBurnett, Ph.D. 
Title: Professor, Psychiatry, Psychiatry Department, 
University of California San Francisco, School of 
Medicine 
Address: 401 Parnassus Ave., Langley Porter Building, 
San Francisco, California, USA    
Phone: +1-415-476-7892 
CLINICAL 
MONITOR 
CRO to be retained. 
STUDY SITE 
Hospital: UCSF Medical Center  
Address: 401 Parnassus Ave., Langley Porter Building, 
San Francisco, California, USA     
 
 
 


 
   
                   
 
Protocol 
III 
 
Protocol Number: BLI-1008-001 
Protocol Version: 2.0  
Date: 2020/06/30 
Confidential 
BioLite, Inc. 
萊特先進生醫股份有限公司 
SIGNATURE PAGE 
 
Study Title:  
     A Phase II Tolerability and Efficacy Study of PDC-1421 Treatment in 
Adult Patients with Attention-Deficit Hyperactivity Disorder (ADHD), Part 
I 
 
 
I have read this protocol and confirm that to the best of my knowledge it accurately 
describes the conduct of the study. 
 
 
SPONSOR’S REPRESENTATIVE 
 
 
 
TYPED NAME (S) 
 
TITLE 
 
SIGNATURE 
 
DATE 
Chi-Hsin R. King 
 
Study Director 
 
 
 
 
 
 


 
   
                   
 
Protocol 
IV 
 
Protocol Number: BLI-1008-001 
Protocol Version: 2.0  
Date: 2020/06/30 
Confidential 
BioLite, Inc. 
萊特先進生醫股份有限公司 
SIGNATURE PAGE 
 
Study Title:  
     A Phase II Tolerability and Efficacy Study of PDC-1421 Treatment in 
Adult Patients with Attention-Deficit Hyperactivity Disorder (ADHD), Part 
I 
 
 
INVESTIGATOR (S) 
I agree to conduct this clinical study in accordance with the design and specific provisions 
of this protocol; deviations from the protocol are acceptable only with a mutually agreed 
upon protocol amendment.  I also agree to report all information or data in accordance 
with the protocol and, in particular, I agree to report any serious adverse experiences as 
defined in this protocol. I also agree to handle all clinical supplies provided by the Sponsor.  
 
Principal Investigator 
 
 
TYPED NAME (S) 
 
TITLE 
 
SIGNATURE 
 
DATE 
 
 
Keith McBurnett, Ph.D.  
Professor, Psychiatry  
 
 
 
 
 


 
   
                   
 
Protocol 
V 
 
Protocol Number: BLI-1008-001 
Protocol Version: 2.0  
Date: 2020/06/30 
Confidential 
BioLite, Inc. 
萊特先進生醫股份有限公司 
Table of Contents  
Page 
PROTOCOL SYNOPSIS ..................................................................................................... 8 
LIST OF ABBREVIATIONS/DEFINITIONS................................................................... 10 
1. Background Information ................................................................................................ 13 
1.1 Description of PDC-1421 Capsule .......................................................................... 13 
1.1.1 Preparation ....................................................................................................... 13 
1.1.2 Composition .................................................................................................... 15 
1.1.3 Storage and Handling ...................................................................................... 15 
1.2 Non-clinical Study of PDC-1421 ............................................................................. 15 
1.2.1 Efficacy Pharmacology.................................................................................... 15 
1.2.2 Safety Pharmacology ....................................................................................... 19 
1.2.3 Cytochrome P450 Interaction with PDC-1421 ................................................ 21 
1.2.4 Toxicology ....................................................................................................... 21 
1.3 Results of Phase I Clinical Trial Study of PDC-1421 .............................................. 23 
1.4 Potential Risk and Benefit ....................................................................................... 25 
1.4.1 Potential Risk ................................................................................................... 25 
1.4.2 Potential Benefit .............................................................................................. 25 
1.4.3 Risk Benefit Ratio ........................................................................................... 25 
1.5 Dosage Regimen ...................................................................................................... 25 
1.6 Compliance with Protocol, Good Clinical Practice (GCP) and Applicable 
Requirement ............................................................................................................ 27 
1.7 Description of the Population to be Studied ............................................................ 27 
2. Trial Objective ............................................................................................................... 28 
3. Trial Design .................................................................................................................... 28 
3.1 General Design ........................................................................................................ 28 
3.2 Primary Endpoint ..................................................................................................... 30 
3.3 Secondary Endpoint ................................................................................................. 30 
3.4 Randomization and Blinding ................................................................................... 30 
3.5 Investigational Drug ................................................................................................ 30 
3.5.1 Dosage Form and Strength .............................................................................. 30 
3.5.2 Manufacturer ................................................................................................... 30 
3.5.3 Route of Administration .................................................................................. 30 


 
   
                   
 
Protocol 
VI 
 
Protocol Number: BLI-1008-001 
Protocol Version: 2.0  
Date: 2020/06/30 
Confidential 
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3.5.4 Dosing Regimen, packing and labeling ........................................................... 31 
3.5.5 Study Drug Storage ......................................................................................... 34 
3.6 Premature Termination or Suspension of the Study ................................................ 34 
4. Subjects Selection and Withdrawal ................................................................................ 35 
4.1 Inclusion Criteria ..................................................................................................... 35 
4.2 Exclusion Criteria .................................................................................................... 35 
4.3 Subject Recruitment and Screening ......................................................................... 36 
4.4 Subject Identification ............................................................................................... 36 
4.4.1 Subject Initial Allocation ................................................................................. 37 
4.4.2 Subject Number Allocation ............................................................................. 37 
4.5 Early Withdrawal of Subjects .................................................................................. 38 
5. Treatment of Subjects .................................................................................................... 38 
5.1 Description of Study Drug ....................................................................................... 38 
5.2 Treatment Schedule ................................................................................................. 38 
5.2.1 Screening Phase (Visit 1) ................................................................................. 39 
5.2.2. Part I Study. - Treatment Period (Visit 2~8) and Follow-up (Visit 9) ............ 40 
5.3 Other Medication During the Study ........................................................................ 41 
6. Efficacy Assessments ..................................................................................................... 42 
6.1 Specification of the efficacy parameters .................................................................. 42 
6.2 Methods and Timing for Assessing, Recording, and Analyzing of Efficacy 
Parameters. .............................................................................................................. 42 
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) ........................... 45 
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 ............................................................................................. 46 
8. Statistic Methods ............................................................................................................ 47 
8.1 Sample Size Determination ..................................................................................... 47 


 
   
                   
 
Protocol 
VII 
 
Protocol Number: BLI-1008-001 
Protocol Version: 2.0  
Date: 2020/06/30 
Confidential 
BioLite, Inc. 
萊特先進生醫股份有限公司 
8.2 Statistical Method .................................................................................................... 47 
8.3 Analysis of Efficacy and Safety ............................................................................... 47 
8.4 Premature Termination and Handling of Missing Data ........................................... 48 
9. Quality Control and Quality Assurance ......................................................................... 49 
9.1 Study Monitoring ..................................................................................................... 49 
9.2 Sponsor Auditing ..................................................................................................... 49 
9.3 Inspected by Regulatory Authorities ....................................................................... 49 
10. Ethical Considerations ................................................................................................. 50 
10.1 Confidential ........................................................................................................... 50 
10.2 Protocol Amendment ............................................................................................. 50 
10.3 Informed Consent .................................................................................................. 50 
10.4 Institutional Review Board (IRB) .......................................................................... 51 
11. Data Handling and Record Keeping ............................................................................ 52 
11.1 Data Handling and Collection ................................................................................ 52 
11.1.1 Study Specific Binders .................................................................................. 52 
11.1.2 Responsibilities of Investigators .................................................................... 52 
11.1.3 Responsibilities of Clinical Monitor .............................................................. 53 
11.2 Records Retention .................................................................................................. 53 
11.2.1 Source Document Retention .......................................................................... 53 
11.2.2 CRF Retention ............................................................................................... 54 
11.2.3 Record Maintenance ...................................................................................... 54 
11.3 Study Center File Management ............................................................................. 54 
12. Publication Plan ........................................................................................................... 56 
13. References .................................................................................................................... 56 
 
Appendix 1 
1. Form FDA 1572 of Principal-Investigator, Keith McBurnett, Ph.D.    
2. Curriculum Vitae of Keith McBurnett, Ph.D.    
Appendix 2 
Informed Consent Form 
 


 
   
                   
 
Protocol 
   
 
Protocol Number: BLI-1008-001 
Protocol Version: 2.0  
Date: 2020/06/30 
Confidential 
BioLite, Inc. 
萊特先進生醫股份有限公司 
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 Tolerability and Efficacy Study of PDC-1421 
Treatment in Adult Patients with Attention-Deficit 
Hyperactivity Disorder (ADHD), Part I 
Clinical trial phase 
Phase II 
Study site 
Single site 
Study period 
1 year 
Study population 
Patients with ADHD according to the Diagnosis and 
Statistical Manual of Mental Disorders, 5th Edition 
Primary study 
objective 
To determine the efficacy profile of PDC-1421 Capsule in 
ADHD with ADHD Rating Scale-IV (ADHD-RS-IV). 
Secondary study 
objective 
To determine the efficacy and safety profile of PDC-1421 
Capsule in ADHD with other rating scales.  
Study design 
Part I: open label, dose-escalating study 
Sample size 
Maximum 6 subjects  
Test product 
PDC-1421 Capsule 
Dose and regimen 
1 and 2 capsules thrice daily, p.o., after meal 
Duration of treatment 
56 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.  
Part I is an open-label study, single center and dose 
escalation evaluation in six subjects. Six subjects will be 
initially evaluated for safety and efficacy assessments at 
low-dose (1 capsules TID) for 28 days. A safety checkpoint 
will be evaluated at day-28 for entering the high-dose (2 
capsules TID). The subjects who pass the checkpoint will 
be initially evaluated for safety and efficacy assessments at 
high-dose (2 capsules TID) for 28 days. There will be an 
evaluation with all safety assessments data to decide 
whether this study passes the checkpoint to enter Part II. 
 


 
   
                   
 
Protocol 
   
 
Protocol Number: BLI-1008-001 
Protocol Version: 2.0  
Date: 2020/06/30 
Confidential 
BioLite, Inc. 
萊特先進生醫股份有限公司 
Primary endpoint  
 
 
˙ Improvement of 40% or greater in ADHD Rating 
Scale-Investigator Rated (ADHD-RS-IV) from baseline 
up to 8 weeks treatment 
Secondary endpoints 
˙ Change from baseline in the Conners' Adult Attention-
Deficit/Hyperactivity 
Disorder 
Rating 
Scale-Self 
Report: Short Version (CAARS-S:S) to 8 weeks 
treatment. 
˙ Clinical Global Impression-ADHD- Severity (CGI-
ADHD-S) and Clinical Global Impression-ADHD- 
improvement (CGI-ADHD-I) score of 2 or lower. 
Safety Evaluation 
A. Change from baseline in: 
1. vital sign 
2. physical examination 
3. electrocardiogram (ECG) 
4. laboratory tests (hematology and biochemistry) 
B. 
Incidence of AE/SAE 
C. 
Suicidal ideation and behavior by Columbia-Suicide 
Severity Rating Scale (C-SSRS) 
Statistical method 
Descriptive Statistics 
 


 
   
                   
 
Protocol 
   
 
Protocol Number: BLI-1008-001 
Protocol Version: 2.0  
Date: 2020/06/30 
Confidential 
BioLite, Inc. 
萊特先進生醫股份有限公司 
 LIST OF ABBREVIATIONS/DEFINITIONS 
˙ ADHD 
Attention-Deficit/Hyperactivity Disorder 
˙ ADHD-RS-IV 
Attention-Deficit/Hyperactivity Disorder Rating Scale-IV 
˙ AE  
Adverse Events, whether or not considered related to the investigational drug, must 
be recorded in CRF. 
˙ CAARS-S:S 
Conners' Adult Attention-Deficit/Hyperactivity Disorder Rating Scale-Self Report: 
Short Version 
˙ CGI-ADHD-I 
Clinical Global Impression- Attention-Deficit/Hyperactivity Disorder –Improvement 
˙ CGI-ADHD-S  
Clinical Global Impression- Attention-Deficit/Hyperactivity Disorder - Severity 
˙ 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 
˙ DSM-5 
The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
˙ ECG 
The Electrocardiogram (ECG) is a graphical recording of the cardiac cycle produced 
by an electrocardiograph. 


 
   
                   
 
Protocol 
   
 
Protocol Number: BLI-1008-001 
Protocol Version: 2.0  
Date: 2020/06/30 
Confidential 
BioLite, Inc. 
萊特先進生醫股份有限公司 
˙ HDL 
High-Density Lipoprotein 
˙ HPLC 
High Performance Liquid Chromatography 
˙ ICF 
Informed Consent Form 
˙ ICH-GCP 
International Conference of Harmonization-Good Clinical Practice 
˙ IEC 
Independent Ethics Committee 
˙ IRB 
Institutional Review Board 
˙ LDH 
Lactate Dehydrogenase 
˙ LDL 
Lower-Density Lipoprotein 
 
˙ 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 


 
   
                   
 
Protocol 
   
 
Protocol Number: BLI-1008-001 
Protocol Version: 2.0  
Date: 2020/06/30 
Confidential 
BioLite, Inc. 
萊特先進生醫股份有限公司 
Persistent or significant disability/incapacity 
Congenital anomaly/birth defect 
Required intervention to prevent permanent impairment/damage 
˙ Severity Rating of AE 
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. 
˙ SHR 
Spontaneous hypertensive rat 
˙ 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. 
˙ TID 
Three times a day 
˙ WKY rat 
Wistar-Kyoto rat 
˙ TLC 
Thin Layer Chromatography 
 


 
   
                   
 
Protocol 
   
 
Protocol Number: BLI-1008-001 
Protocol Version: 2.0  
Date: 2020/06/30 
Confidential 
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 became 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 with 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. 
 
 
 


 
   
                   
 
Protocol 
   
 
Protocol Number: BLI-1008-001 
Protocol Version: 2.0  
Date: 2020/06/30 
Confidential 
BioLite, Inc. 
萊特先進生醫股份有限公司 
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% 
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. 
10.0 mg/g ≤ Glomeratose A ≤ 30.0 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 


 
   
                   
 
Protocol 
   
 
Protocol Number: BLI-1008-001 
Protocol Version: 2.0  
Date: 2020/06/30 
Confidential 
BioLite, Inc. 
萊特先進生醫股份有限公司 
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 
use 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. 
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 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. Pharmacodynamics studies were conducted at PITDC, Taiwan.  
 
1.2.1 Efficacy Pharmacology 
Two in vitro studies and one in vivo study have been completed to evaluate 
pharmacological activities of PDC-1421. 
 


 
   
                   
 
Protocol 
   
 
Protocol Number: BLI-1008-001 
Protocol Version: 2.0  
Date: 2020/06/30 
Confidential 
BioLite, Inc. 
萊特先進生醫股份有限公司 
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 been developed as the ADHD 
treatment, such as Atomoxetine. Therefore, PDC-1421 has the potential to be used as an 
ADHD medication. The subsequent studies were performed to investigate the activities of 
PDC-1421 used to treat ADHD. 
 
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 
Atomoxetine, which is one of ADHD medications on market, is a potent 
norepinephrine uptake inhibitor in vitro and in vivo with relatively low affinity for serotonin 
and dopamine uptake processes2,3. 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.  
 
 
 


 
   
                   
 
Protocol 
   
 
Protocol Number: BLI-1008-001 
Protocol Version: 2.0  
Date: 2020/06/30 
Confidential 
BioLite, Inc. 
萊特先進生醫股份有限公司 
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.  
 
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. 
 
PDC-1421 was tested by the TBZ-induced hypothermia model to study the effect on 
norepinephrine reuptake inhibition. 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. 
 


 
   
                   
 
Protocol 
   
 
Protocol Number: BLI-1008-001 
Protocol Version: 2.0  
Date: 2020/06/30 
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Table 5. Summary for pharmacology study on norepinephrine reuptake inhibition. 
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 NRI 
activity as evidenced by effect on TBZ-induced hypothermia in mice.  
 
1.2.1.4 Spontaneous hypertensive rat (SHR) Model 
According to above assays, PDC-1421 is a selective norepinephrine reuptake inhibitor. 
Norepinephrine has also been proposed to play a key role in the pathophysiology and 
pharmacotherapy of ADHD5,6,7. The SHR is a valid and currently accepted model for the 
study of ADHD9. The SHRs are known to display hyperactivity, impulsivity, poor sustained 
attention, and deficits in learning and memory processes in comparison with normotensive 
Wistar-Kyoto (WKY) rats10. In order to proof of concept that PDC-1421 possesses the 
potential of treating ADHD, a local motor activity assay was performed by using SHR. 
Horizontal activity of SHR is recorded within one hour in Automated Locomotor Activity 
Analysis System Chamber. Intraperitoneal injection of 5 mg/kg atomoxetine, as a positive 
control, inhibited total activity of SHR rats significantly after 1 and 4 days administration. 
Atomoxetine is oral capsule in treatment usage. The course of treatment of atomoxetine 
needs one to three weeks for a good therapeutic response. The absorption of intraperitoneal 
injection is better than oral administration. PDC-1421 was designed as an oral drug 
substance. To determine PDC-1421’s anti-ADHD effective dose, male SHR were orally 
given PDC-1421 dissolved in Saline at a dosage of 75, 225 or 675 mg/kg bodyweight at 
each exposure. The data revealed that oral administration of PDC-1421 for 1 and 4 days 
significantly inhibit total activity of SHR at the concentration of 675 mg/kg.  
 


 
   
                   
 
Protocol 
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Protocol Number: BLI-1008-001 
Protocol Version: 2.0  
Date: 2020/06/30 
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Figure 1. The local motor activity assay in different dose of PDC-1421. 
Asterisk (*) represents P-value <0.05 between control and treatment groups. 
Double-asterisk (**) represents P-value <0.01 between control and treatment groups. 
 
1.2.2 Safety Pharmacology 
In order to verify the possible adverse reactions, 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® 
• 
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. 
 
 
 


 
   
                   
 
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Protocol Number: BLI-1008-001 
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Table 6. Summary of the finding in safety pharmacology 
Study package 
Study condition and findings 
Efficacy Profiling  
˙ 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. 
Adverse Event 
Profiling 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 2500 mg/kg group.  
 
˙ Diastolic arterial pressure decrease was found 
in dogs in 2500 mg/kg group. 
hERG tail current assay Below the dosage, 0.8 mg/ml PDC-1421, should 
be viewed as the “no effect concentration” in this 
assay. 
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. 
 


 
   
                   
 
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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 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. 
 


 
   
                   
 
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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 four 
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 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 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 hours. No medical intervention/therapy was required. There was 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 


 
   
                   
 
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of laboratory test data of PDC-1421 and placebo groups were the lowest, grade 1. No 
medical intervention/therapy was required. There was 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 hours in glucose in cohort A and at 4 hours 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, five subjects reported to 
experience eight mild adverse events shown as Table 9. The severity of these eight 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. In the dog 
telemetry study, only lower heart rate was found 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 


 
   
                   
 
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Protocol Number: BLI-1008-001 
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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 28 days 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. 
 
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 have low affinity 
to serotonin and dopamine. A SHR animal model has shown that PDC-1421 has potential 
to develop as an ADHD medication. 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. As 
there were adverse events in phase I trial, no similar findings were found in nonclinical 
studies. The subsequent trial could be benefited from gathering further safety information 
for PDC-1421 treatment. 
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. 
 


 
   
                   
 
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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 is as follows. 
Cohort A (one capsule; 380 mg):  
Cohort A enrolled nine 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 eight 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 four 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 nine 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.  


 
   
                   
 
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According to studies in mouse model system to evaluate efficacious dose, SHR animal 
model, PDC-1421 was indicated to be efficient at oral administration of 675 mg/kg doses 
which are equivalent to about intraperitoneal injection of 5 mg/kg atomoxetine. The 
consideration is the course of treatment of atomoxetine, ADHD medication which is also a 
selective NRI, need one to three weeks for a good therapeutic response. There will be lower 
effective dose with long-term administration. The positive control, atomoxetine 
administrated by intraperitoneal injection in SHR animal model, and the absorption is 
better than oral. Base on the bioavailability is 63%, and the minimum starting dose is 0.5 
mg/kg of Strattera (the trade name of atomoxetine), we translate the starting dose of PDC-
1421 is 42.56 mg/kg (675 [mg] * 63% * 0.5 [mg/kg] / 5 [mg/kg] = 42.56 mg) and the 
human equivalent dose is about 2553.59 mg in 60 kg weight. 
 
PDC-1421 Recommended Dose in Human 
 
 Atomoxetine Starting Dose in Human by oral 
----------------------------------------------------  =  --------------------------------------------------------- 
PDC-1421 Effective Dose in SHR 
 
      Atomoxetine Effective Dose in SHR by oral 
(Assumption: Atomoxetine’s bioavailability by oral is 63% by injection in SHR.) 
 
According to the result of phase I trial and preclinical study with SHR animal model, 
we choose 1140 mg (3 capsules) and 2280 mg (6 capsules) as the dosage regimen of Phase 
II trial.  
 
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 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 Attention Deficit Hyperactivity 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 ADHD. 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 
Design 
Open label, single center, dose escalation study 
ADHD 
patients 
6 
Treatment 
(1) Low dose: 1 capsule TID, 28 days 
(2) Checkpoint #1 
(3) High dose: 2 capsules TID, 28 days 
(4) Checkpoint #2 
Assessment 
interval 
Low dose: Once a week 
High dose: Biweekly 
Efficacy and 
safety 
evaluation 
˙ Safety evaluation  
˙ Efficacy 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 targeted 
population of this Part I study is six subjects who met the intent-to-treat basis.  
 
Part I study is an open-label study, single center and dose escalation evaluation in six 
patients.  
Low dose: Six subjects will be initially evaluated for safety and efficacy assessments at 
low-dose (1 capsule TID) for 28 days. Subject will return for visit once a week 
during treatment period.  


 
   
                   
 
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Protocol Number: BLI-1008-001 
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Checkpoint #1: There will be an evaluation with all safety assessments data to decide 
whether you pass the checkpoint to enter high-dose treatment or continue 
to receive a low-dose treatment by the investigator.  
High dose: The subjects who pass the checkpoint #1 will be initially evaluated for safety 
and efficacy assessments at high-dose (2 capsules TID) for 28 days. Subject 
will return for visit biweekly during treatment period. 
Checkpoint #2: There will be an evaluation with all safety assessments data to decide 
whether this study passes the checkpoint to enter Part II by the 
investigators. 
 
Figure 2. General design of procedure 
Part I. Study.  
 
 
 
 


 
   
                   
 
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3.2 Primary Endpoint  
Improvement of 40% or greater in ADHD Rating Scale-Investigator Rated (ADHD-
RS-IV) from baseline up to 8 weeks treatment. 
3.3 Secondary Endpoint  
Table 12   The secondary efficacy endpoints 
Number 
Items 
1 
Change from baseline in the Conners' Adult Attention-
Deficit/Hyperactivity Disorder Rating Scale-Self Report: Short Version 
(CAARS-S:S) up to 8 weeks treatment. 
2 
Clinical Global Impression-ADHD- Severity (CGI-ADHD-S) and 
Clinical Global Impression-ADHD- improvement (CGI-ADHD-I) score 
of 2 or lower. 
3.4 Randomization and Blinding 
Table 13. Summary of randomization and blinding 
 
Part I 
Randomization 
None (open label) 
Blinding 
None (open label) 
3.5 Investigational Drug 
Investigational drug (PDC-1421 Capsule) will be maintained and dispensed by UCSF 
Medical Center. 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 
 
3.5.2 Manufacturer 
ITRI (Industrial Technology Research Institute), Hsinchu County, Taiwan 
 
3.5.3 Route of Administration 
Oral administration 


 
   
                   
 
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3.5.4 Dosing Regimen, packing and labeling 
3.5.4.1 Dosing Regimen 
Part I Study: 
Subjects will receive a low-dose treatment with 1 PDC-1421 Capsule thrice 
daily for 28 days (4 weeks). After passing a dose-up checkpoint for the 
safety of individual subjects, they will receive a high-dose treatment with 2 
PDC-1421 Capsules thrice daily for another 28 days (4 weeks). 
Dosing regimen for the study is summarized with drug packing on Table 14. 
3.5.4.2 Packaging 
Investigational drug (PDC-1421 Capsule) are provided by BioLite, Inc. and stored in 
the UCSF Medical Center. Subjects will receive the investigational drug at each visit and 
also be requested to return unused drug at each visit. Drug packing for each part of the 
study is summarized with dosing regimen on Table 14. 
Part I Study: 
➢ 
Low-Dose: Subjects will receive a drug bag with 21 PDC-1421 
Capsules each visit. A total 5 weekly visits will be requested during this 
28-day treatment period. 
➢ 
High-Dose: Subjects will receive 1 drug bag of 84 PDC-1421 
Capsules/bag each visit. A total 3 biweekly visits will be requested 
during this 28-day treatment period. 
 Table 14. Summary of dosing regimen and packaging 
Part no. 
Part I 
Dosing/Arm 
Low-Dose 
High-Dose 
Treatment Duration 
28 days     +     28 days 
Dosing 
Regimen 
Placebo 
N/A 
N/A 
PDC-1421 
1 Cap. TID 
2 Caps. TID 
Packaging 
21 PDC-1421 Caps./bag 
84 PDC-1421 Caps./bag 
Visit Frequency 
Weekly 
Biweekly 
No. of Drug bags 
Received / Visit 
1 
1 
 
 


 
   
                   
 
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3.5.4.3 Labeling 
The drug bag of investigational drug will be clearly labeled as following:  
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-1008-001 
Drug Appearance: Brown capsule 
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: UCSF Medical Center 
 
"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    
計劃書編號: BLI-1008-001 
藥物外觀: 棕色膠囊 
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: 加州大學舊金山分校醫學中心 
 
"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 
   
 
Protocol Number: BLI-1008-001 
Protocol Version: 2.0  
Date: 2020/06/30 
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-1008-001 
Drug Appearance: Brown capsule 
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: UCSF Medical Center 
 
"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    
計劃書編號: BLI-1008-001 
藥物外觀: 棕色膠囊 
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: 加州大學舊金山分校醫學中心 
 
"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 
   
 
Protocol Number: BLI-1008-001 
Protocol Version: 2.0  
Date: 2020/06/30 
Confidential 
BioLite, Inc. 
萊特先進生醫股份有限公司 
3.5.5 Study Drug Storage 
Investigational drugs will be stored in a locked cabinet at room temperature 
(15~25°C) in Department of Pharmacy, UCSF Medical Center. 
  
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 
   
 
Protocol Number: BLI-1008-001 
Protocol Version: 2.0  
Date: 2020/06/30 
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 are as follows.  
4.1 Inclusion Criteria 
1. 
Aged 18-70 years 
2. 
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 
3. 
Subjects must be able to understand and willing to sign informed consent 
4. 
Able to discontinue the use of any psychotropic medications for the treatment of 
ADHD symptoms at screening 
5. 
Meet strict operational criteria for adult ADHD according to the Diagnostic and 
Statistical Manual of Mental Disorders, 5th Edition (DSM-5) 
6. 
A total score of 20 or higher on the 12-item ADHD index of Conners' Adult Attention-
Deficit/Hyperactivity Disorder Rating Scale-Self Report: Short Version (CAARS-S:S) 
at screening 
7. 
Have a moderate or severe symptom of ADHD with score of 4 or higher in Clinical 
Global Impression-ADHD-Severity (CGI-ADHD-S) at screening 
 
4.2 Exclusion Criteria 
1. 
Have any clinically significant concurrent medical condition (endocrine, renal, 
respiratory, 
cardiovascular, 
hematological, 
immunological, 
cerebrovascular, 
neurological, anorexia, obesity or malignancy) that has become unstable and may 
interfere with the interpretation of safety and efficacy evaluations 
2. 
Have any clinically significant abnormal laboratory, vital sign, physical examination, 
or electrocardiogram (ECG) findings at screening that, in the opinion of the 
investigator, may interfere with the interpretation of safety or efficacy evaluations 
3. 
Have known serological evidence of human immunodeficiency virus (HIV) antibody 
4. 
Are pregnant as confirmed by a positive pregnancy test at screening 
5. 
Have QTc values >450 msec at screening using Fridericia's QTc formula 
6. 
Have current of bipolar and psychotic disorders 
 
 


 
   
                   
 
Protocol 
   
 
Protocol Number: BLI-1008-001 
Protocol Version: 2.0  
Date: 2020/06/30 
Confidential 
BioLite, Inc. 
萊特先進生醫股份有限公司 
7. 
Have a current major depression disorder, obsessive-compulsive disorder, post-
traumatic stress disorder, generalized anxiety disorder, panic disorder and eating 
disorder (also if treated but not currently symptomatic) 
NOTE: Comorbid diagnoses identified during screening and baseline are acceptable 
provided that ADHD is the primary diagnosis and the comorbid diagnoses will not 
confound study data or impair subject’s ability to participate (per the Investigator’s 
judgement and documented in source note). 
8. 
Have any history of a significant suicide attempt, or possess a current risk of 
attempting suicide, in the investigator's opinion, based on clinical interview and 
responses provided on the Columbia-Suicide Severity Rating Scale (C-SSRS). 
9. 
Have a history of jailing or imprisonment in the past 6 months due to worsening of 
symptoms of ADHD. 
 
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 this 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 
   
 
Protocol Number: BLI-1008-001 
Protocol Version: 2.0  
Date: 2020/06/30 
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 
eight 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 sixth, seventh and eighth digits: the patient number will be 
consecutive numbers commencing with “001”. At screening visit, 
these should be blank. 
The third, fourth and fifth digits: the screening number will be consecutive 
numbers commencing with “001”. 
The second digit: the site number; UCSF Medical Center will be assigned to 
“1”. 
The first digit: the part number; Part I will be assigned to “1”, Part II will be 
assigned to “2”. 


 
   
                   
 
Protocol 
   
 
Protocol Number: BLI-1008-001 
Protocol Version: 2.0  
Date: 2020/06/30 
Confidential 
BioLite, Inc. 
萊特先進生醫股份有限公司 
4.5 Early Withdrawal of Subjects 
Subjects will be withdrawn from this trial if they meet one of the following withdrawal 
criteria: 
˙ Subjects wish to withdraw. (Subjects are not obligated to give reasons for 
discontinuation from this trial.) 
˙ Subjects can’t obey the regulation of the study. 
˙ Investigator considers that withdrawal from study is the best interest of a subject. 
˙ The subject is pregnant during the trial. 
Subjects withdrawn from the study due to adverse event(s) must be followed until the 
events are recovered, recovered with residual effects, death, or lost to follow-up. 
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.  
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 Study, six eligible subjects will receive a low-dose treatment with 1 PDC-1421 
Capsule thrice daily for 28 days (4 weeks) and be assessed once a week (Visit 2, 3, 4, 5, 
and 6). After passing a dose-up checkpoint for the safety of individual subjects, these 
subjects will then receive a high-dose treatment with 2 PDC-1421 Capsules thrice daily for 
another 28 days (4 weeks). Subjects will be assessed every two weeks (Visit 6, 7 and 8) in 
high-dose treatment. After the end of part I Study, subjects will be requested to return for 
a follow-up visit (Visit 9) two weeks later after the last dose. 
During the COVID-19 public health emergency, the assessments of CAARS, CGI, 
ADHDRS, C-SSRS, AE evaluation, Concomitant Medication, Physical examination can 
be conducted by telephone, video, or email, but those remote assessments should be 


 
   
                   
 
Protocol 
   
 
Protocol Number: BLI-1008-001 
Protocol Version: 2.0  
Date: 2020/06/30 
Confidential 
BioLite, Inc. 
萊特先進生醫股份有限公司 
documented. 
Table 15. Part I-schedule of assessments 
*On ±2 days.  
 
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 and laboratory 
examination at screening are outlined below: 
˙ Informed consent 
˙ Subject information, including date of birth, gender, body height and weight 
˙ Medical history (within six month), including any clinically significant psychiatric, 
neurological, gastrointestinal, renal, hepatic, cardiovascular, respiratory, metabolic, 
Procedure table: BLI-1008-001 protocol 
*Week 
-2 
0 
1 
2 
3 
4 
 6 
 8 
 10 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
DSM-V 
√ 
 
 
 
 
 
 
 
 
CAARS-S:S 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
CGI-ADHD-S 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
CGI-ADHD-I 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
ADHD-RS-IV 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
C-SSRS 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
AE/SAE evaluation 
 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Concomitant 
Medication 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
Physical 
examination 
√ 
 
 
√ 
 
Vital sign 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
ECG 
√ 
 
 
√ 
 
Hematology 
√ 
√ 
 
√ 
 
√ 
√ 
√ 
 
Blood Chemistry 
√ 
√ 
 
√ 
 
√ 
√ 
√ 
 
Blood drawing 
(venipuncture) 
√ 
√ 
 
√ 
 
√ 
√ 
√ 
 
Pregnancy test 
√ 
 
 
 
 
 
 
 
√ 


 
   
                   
 
Protocol 
   
 
Protocol Number: BLI-1008-001 
Protocol Version: 2.0  
Date: 2020/06/30 
Confidential 
BioLite, Inc. 
萊特先進生醫股份有限公司 
endocrine, hematological or other major disorders 
˙ 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-5, CAARS-S:S , CGI-ADHD-S , ADHD-RS-IV , C-SSRS  
˙ Concomitant medication evaluation 
˙ Eligibility evaluation: laboratory data, other tests and evaluation results shall be 
obtained at Screening to determine the appropriateness of subject enrolled in this 
study 
 
5.2.2. Part I Study. - Treatment Period (Visit 2~8) and Follow-up  
(Visit 9) 
Subjects who meet the eligibility criteria will be enrolled and take test drug at this 
period. Six eligible subjects will take 1 capsule of PDC-1421 Capsule thrice daily for four 
weeks. They will receive a drug bag and be instructed to take 1 PDC-1421 Capsule thrice 
daily after meals. Weekly visits (Visit 2, 3, 4 and 5) will be requested during this 28-day 
treatment period. At Visit 6, all subjects will be evaluated with safety assessments and to 
be decided whether they will enter the high-dose treatment by the investigator. In the high-
dose treatment, subjects will receive a drug bag and be instructed to take 2 PDC-1421 
Capsule thrice daily after meals for 4 weeks. Biweekly visits (Visit 6, 7 and 8) will be 
requested during this 28-day treatment period. After two weeks of the last dose 
administration, subjects are assessed for a follow-up. Then, a checkpoint will be conducted. 
If subjects have no drug-related SAE, the schedule can be conducted to the part II. 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 (only at Visit 
8). 
˙ Vital sign: heart rate, blood pressure, body temperature 


 
   
                   
 
Protocol 
   
 
Protocol Number: BLI-1008-001 
Protocol Version: 2.0  
Date: 2020/06/30 
Confidential 
BioLite, Inc. 
萊特先進生醫股份有限公司 
˙ ECG (Only at Visit 8).  
˙ Hematology: RBC, WBC, platelets, hematocrit, hemoglobin, prothrombin time (PT), 
partial thromboplastin time (aPTT) (Only at Visit 2,4,6,7 and 8). 
˙ Blood chemistry: AST, ALT, LDH, total bilirubin, BUN, serum creatinine, free 
thyroxine (FT4), TSH, sodium, calcium, potassium, LDL, HDL, triglyceride, 
cholesterol (Only at Visit 2,4,6,7, and 8). 
˙ CAARS-S:S , CGI-ADHD-S , CGI-ADHD-I , ADHD-RS-IV , C-SSRS and 
concomitant medication evaluation. 
˙ AE/SAE evaluation (Subjects will not need to be assessed for AE/SAE at visit 2.) 
˙ Drug accountability 
 
Follow-up visit will be performed at visit 9 after two weeks of the last dose 
administration. The test items are outlined in the following: 
˙ 
C-SSRS.  
˙ 
AE/SAE evaluation 
˙ 
Pregnancy test 
 
5.3 Other Medication During the Study 
To avoid conflict or unknown effects with the study drug, subjects are prohibited from 
taking any anti-ADHD medication 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 and are currently taking  Zolpidem, 
Zopiclone or Zaleplon (sedative-hypnotics), they will be queried whether they can comply 
with the discontinuation: 
1. Subjects who indicate that they can discontinue will be washed out for 1 week, 
and then allowed to begin study protocol; 
2. Subjects who indicate that they are unable to discontinue will be allowed to enroll 
if they are able to agree that their use will be consistent and will not change for 
the duration of the study. (The maximum daily dose in Zolpidem, Zopiclone and 
Zaleplon are 10 mg, 7.5 mg and 10 mg respectively.) 
 


 
   
                   
 
Protocol 
   
 
Protocol Number: BLI-1008-001 
Protocol Version: 2.0  
Date: 2020/06/30 
Confidential 
BioLite, Inc. 
萊特先進生醫股份有限公司 
6. Efficacy Assessments 
6.1 Specification of the efficacy parameters 
Efficacy parameters are outlined as follows:  
˙ ADHD-RS-IV 
˙ Clinical Global Impression 
˙ CAARS-S:S 
 
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 study, 
efficacy assessments are conducted from screening stage to the last visit. The rating scales 
are as follows: 
 
˙ ADHD-RS-IV 
The ADHD-RS-IV with Adult Prompts is an 18-item scale base on the DSM-IV-
TR’ criteria for ADHD that provides a rating of the severity of symptoms15. The adult 
prompts serve a guide to explore more fully the extent and severity of ADHD 
symptoms and create a framework to ascertain impairment. The odd-numbered 9 
items assess inattentive symptoms and the even-numbered 9 items assess hyperactive-
impulsive symptoms. Scoring is based on a 4-point, yielding a possible total score of 
0–54. Likert-type severity scale: 0 = Never or Rarely, 1 = Sometimes, 2 = Often, 3 = 
Very Often. Clinicians should score the highest score that is generated for the prompts 
for each item. 
 
For inattention (IA) subscale raw score: Add the odd-numbered 9 items 
For hyperactivity-impulsivity (HI) subscale raw score: Add the even-numbered 9 
items 
To obtain the total raw score: Add the IA and HI subscale raw scores. 


 
   
                   
 
Protocol 
   
 
Protocol Number: BLI-1008-001 
Protocol Version: 2.0  
Date: 2020/06/30 
Confidential 
BioLite, Inc. 
萊特先進生醫股份有限公司 
 
 
˙ Clinical Global Impression 
At the baseline visit, clinicians completed the CGI-S and were asked to evaluate 
the severity of subjects’ illness with respect to ADHD symptoms based on the 
clinician’s experience with this particular population. Possible scores ranged from 1 
(normal, not ill at all) to 7 (among the most extremely ill subjects). At all subsequent 
study visits, clinicians used the CGI-I to rate the subjects’ total improvement based on 
comparison with their baseline assessment from 1 (very much improved) to 7 (very 
much worse). 
 
˙ CAARS-S:S 
Conners' Adult Attention-Deficit/Hyperactivity Disorder Rating Scale-Self 
Report: Short Version (Conners et al., 1998; CAARS-S:S). This consists of 26 items 
rated from 0 ‘not at all, never’ to 3 ‘very much, very frequently.’ Four subscales each 
composed of 5 items (A: inattention/memory problems; B: hyperactivity/restlessness; 
C: impulsivity/emotional lability; and D: problems with self-concept) as well as a 12-
item ADHD index can be computed14. The CAARS-S:S was administered by 
computer-assisted personal interview (CAPI) prior to the first treatment session. 


 
   
                   
 
Protocol 
   
 
Protocol Number: BLI-1008-001 
Protocol Version: 2.0  
Date: 2020/06/30 
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, 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, 
death, lost to follow-up) and severity. Common Terminology Criteria for Adverse Events 
v4.03 (CTCAE Table 16) is a descriptive terminology and the grading (severity) scale is 
provided for each AE term.  
 


 
   
                   
 
Protocol 
   
 
Protocol Number: BLI-1008-001 
Protocol Version: 2.0  
Date: 2020/06/30 
Confidential 
BioLite, Inc. 
萊特先進生醫股份有限公司 
Table 16. 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 
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. 
 


 
   
                   
 
Protocol 
   
 
Protocol Number: BLI-1008-001 
Protocol Version: 2.0  
Date: 2020/06/30 
Confidential 
BioLite, Inc. 
萊特先進生醫股份有限公司 
7.6 SAE Report Procedure 
7.6.1 Expedited Reporting of SAEs 
Since the clinical study is to be carried out in U.S., when expedited SAEs meet the 
informed criteria according to the relevant regulations, they will be reported to the Food 
and Drug Administration (FDA), U.S. by the Sponsor. Written reports should be made on 
the ADR Reporting Form on Med watch 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.  
 
Principal investigator: Dr. Keith McBurnett 
Phone: +1-415-476-7892 
Address: 401 Parnassus Ave., Langley Porter Building, San Francisco, California, USA    
 
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 
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 seven calendar days following the 
telephone/fax report to sponsor. 


 
   
                   
 
Protocol 
   
 
Protocol Number: BLI-1008-001 
Protocol Version: 2.0  
Date: 2020/06/30 
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 study, six subjects each will be evaluated for safety and efficacy assessments 
at 1 and then 2 capsules TID dose for total 56 days (28 days at each dose). 
 
8.2 Statistical Method 
Simple descriptive statistics with 95% confidence interval will be performed with data 
collected in this study wherever applicable. All data shall be tabulated and presented in the 
study report. The safety and efficacy data will be analyzed using the non-parametric 
method wherever appropriate. 
 
The purpose for Part I is exploratory in safety and the formal statistical analysis will 
not be needed. The descriptive statistics will be provided. Safety endpoints will be listed 
and summarized as appropriate: median and range for continuous data; frequencies, total 
numbers and percentages for categorical data. 
 
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. An intent-to-treat (ITT) 
basis will be defined as the data are analyzed on patients who take at least one dose of study 
medication and have any post-baseline measurements collected. The safety measures are 
conducted on the patients who take at least one dose of study medication. The data are 
analyzed utilizing the last observation carried forward (LOCF) technique to impute the 
missing data. 
 
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. All adverse events 


 
   
                   
 
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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).  


 
   
                   
 
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Protocol Number: BLI-1008-001 
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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. 
During the COVID-19 public health emergency, the monitoring can be performed remotely, 
but it should be documented. 
 
9.2 Sponsor Auditing 
Prior to locking the database of safety, the representative of Sponsor’s quality 
assurance department may 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-1008-001 
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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 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 wait 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 /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 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 


 
   
                   
 
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Protocol Number: BLI-1008-001 
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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 the UCSF Medical Center 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. 


 
   
                   
 
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Protocol Number: BLI-1008-001 
Protocol Version: 2.0  
Date: 2020/06/30 
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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 (not applicable for 
eCRF) 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 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 agrees 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 


 
   
                   
 
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Protocol Number: BLI-1008-001 
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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 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. 
 


 
   
                   
 
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Protocol Number: BLI-1008-001 
Protocol Version: 2.0  
Date: 2020/06/30 
Confidential 
BioLite, Inc. 
萊特先進生醫股份有限公司 
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 need 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. 
 
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 FDA and IRB. 
() 
Copies of FDA and IRB approval letter for this study. 
() 
Curricula Vitae of Investigator and sub-investigator. 
() 
Other documentation of IRB complied with FDA regulations. 
() 
Copy of Informed Consent Form approved by both FDA and IRB. 


 
   
                   
 
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Protocol Number: BLI-1008-001 
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() 
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. 


 
   
                   
 
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Protocol Number: BLI-1008-001 
Protocol Version: 2.0  
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BioLite, Inc. 
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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. 
Wong DT, Threlkeld PG, Best KL, Bymaster FP. A new inhibitor of norepinephrine 
uptake devoid of affinity for receptors in rat brain. J Pharmacol Exp Ther. 1982 
Jul;222(1):61-5. 
3. 
Bolden-Watson C, and Richelson E. Blockade by newly-developed antidepressants of 
biogenic amine uptake into rat brain synaptosomes. Life Sci. 1993;52(12):1023-9. 
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. 
Pliszka SR, McCracken JT, Maas JW.  Catecholamines in attention-deficit 
hyperactivity disorder: current perspectives. J Am Acad Child Adolesc Psychiatry. 
1996 Mar;35(3):264-72.  
6. 
Arnsten AF, Steere JC, Hunt RD. The contribution of alpha 2-noradrenergic 
mechanisms of prefrontal cortical cognitive function. Potential significance for 
attention-deficit hyperactivity disorder. Arch Gen Psychiatry. 1996 May;53(5):448-
55. 
7. 
Biederman J, and Spencer T. Attention-deficit/hyperactivity disorder (ADHD) as a 
noradrenergic disorder. Biol Psychiatry. 1999 Nov 1;46(9):1234-42. 
8. 
Zhou J. Norepinephrine transporter inhibitors and their therapeutic potential. Drugs 
Future. 2004; 29(12): 1235-44. 
9. 
Davids E, Zhang K, Tarazi FI, Baldessarini RJ. Animal models of attention-deficit 
hyperactivity disorder. Brain Res Brain Res Rev. 2003 Apr;42(1):1-21.  
10. Prediger RD, Pamplona FA, Fernandes D, Takahashi RN. Caffeine improves spatial 
learning deficits in an animal model of attention deficit hyperactivity disorder (ADHD) 


 
   
                   
 
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Protocol Number: BLI-1008-001 
Protocol Version: 2.0  
Date: 2020/06/30 
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-- the spontaneously hypertensive rat (SHR). Int J Neuropsychopharmacol. 2005 
Dec;8(4):583-94. Epub 2005 May 9. 
11. Allen AJ, Kurlan RM, Gilbert DL, Coffey BJ, Linder SL, et al. Atomoxetine treatment 
in children and adolescents with ADHD and comorbid tic disorders. Neurology. 2005 
Dec 27;65(12):1941-9. 
12. Wilens TE, Haight BR, Horrigan JP, Hudziak JJ, Rosenthal NE, et al. Bupropion XL 
in adults with attention-deficit/hyperactivity disorder: a randomized, placebo-
controlled study. Biol Psychiatry. 2005 Apr 1;57(7):793-801. 
13. Spencer TJ, Adler LA, McGough JJ, Muniz R, Jiang H, Pestreich L. Efficacy and 
safety of dexmethylphenidate extended-release capsules in adults with attention-
deficit/hyperactivity disorder. Biol Psychiatry. 2007 Jun 15;61(12):1380-7. Epub 
2006 Nov 29.  
14. Conners, C. K., Erhardt, D., Sparrow, E. (1999). Conners’ Adult ADHD Rating Scales 
(CAARS) Technical Manual. Toronto, ON: Multi-Health Systems. 
15. George J. DuPaul, Thomas J. Power, Arthur D. (1998). ADHD Rating Scale-IV: 
Checklists, Norms, and Clinical Interpretation.  

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