Clinical trial NCT03974516
Conditions: Chemotherapy-induced Myelosuppression
Sponsor: i Cure Biotech Co., Ltd.
Start date: 2020-08-10; Completion date: 2022-03-11
Enrollment: 13 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This study will be performed in healthy volunteers in a conventional 3+3 dose-escalation design.

Detailed description:
Four cohorts (dose level A, B, C, and D) of up to 6 evaluable volunteers per cohort are planned to be sequentially accrued to receive Careseng 1370 1, 2, and 3 sachets per day, 4,000 mg/sachet before meal (starting from 1 sachet). At least 5 days of staggering and with the investigator's judgement of no safety concern will be required to administer the next volunteer for the first three volunteers of each cohort. The staggering time is counted from Day 1 of one volunteer to Day 1 of the next volunteer.

Careseng 1370 should be taken around 1 hour before meal. No volunteer is allowed to be assigned to more than 1 dose level. All dose escalation/de-escalation decisions will be made by the Data and Safety Monitoring Board (DSMB).

Arms: arm 1: Level A (1 sachet): 1 sachet before breakfast. Careseng 1370 granule 4,000 mg sachet consisted of 652 mg (16.3%, w/w) DS-1370 drug substance powder (dry extracts of Panax notoginseng stems and leaves) arm 2: Level B (2 sachets): 1 sachet before breakfast, 1 sachet before lunch. Careseng 1370 granule 4,000 mg sachet consisted of 652 mg (16.3%, w/w) DS-1370 drug substance powder (dry extracts of Panax notoginseng stems and leaves) arm 3: Level C (3 sachets): 1 sachet before breakfast, 2 sachets before lunch. Careseng 1370 granule 4,000 mg sachet consisted of 652 mg (16.3%, w/w) DS-1370 drug substance powder (dry extracts of Panax notoginseng stems and leaves) arm 4: Level D (1 sachet)(modified cohort): 1 sachet before breakfast on 1st, 3rd and 5th days.

Careseng 1370 granule 4,000 mg sachet consisted of 652 mg (16.3%, w/w) DS-1370 drug substance powder (dry extracts of Panax notoginseng stems and leaves)
Interventions: intervention 1: Careseng 1370
Intervention descriptions: intervention 1: Careseng 1370 should be taken around 1 hour before meal.

Protocol documents:
Prot_000.pdf: 
Study Protocol
Confidential
 
Careseng 1370 for Healthy Volunteers 
Version: 5.0 
(Protocol Number: Careseng 1370-01)
Date: 18Sep2020
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Study Protocol
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Careseng 1370 for Healthy Volunteers 
Version: 5.0 
(Protocol Number: Careseng 1370-01)
Date: 18Sep2020
 
 
 
 
 
 
 
 
 
 
SIGNATURE PAGE 
 
 
 
 
 
 
 
 
 
 
 
Signature: _____________________________ Date: _________________ (dd-mmm-yyyy) 
 
 


Study Protocol
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Version: 5.0 
(Protocol Number: Careseng 1370-01)
Date: 18Sep2020
 
 
 
 
 
 
 
 
 
 
PROTOCOL APPROVAL PAGE 
 
 
 
  
 
 
 
 
 
 
 
Protocol Title: A Phase I Dose-Escalation Study in Healthy Volunteers to Evaluate the Safety and 
Tolerability Profiles of Careseng 1370 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Version: 5.0 
(Protocol Number: Careseng 1370-01)
Date: 18Sep2020
 
 
 
 
 
 
 
 
 
 
LIST OF ABBREVIATIONS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-GT
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Study Protocol
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Careseng 1370 for Healthy Volunteers 
Version: 5.0 
(Protocol Number: Careseng 1370-01)
Date: 18Sep2020
 
 
 
 
 
 
 
 
 
 
TABLE OF CONTENTS 
SIGNATURE PAGE ................................................................................................................ 2
PROTOCOL APPROVAL PAGE .......................................................................................... 3
LIST OF ABBREVIATIONS .................................................................................................. 4
TABLE OF CONTENTS ......................................................................................................... 5
PROTOCOL SUMMARY ....................................................................................................... 7
SCHEDULE OF ASSESSMENTS ........................................................................................ 16
1.
BACKGROUND AND RATIONALE ........................................................................ 19
1.1
GENERAL INTRODUCTION ........................................................................................................................ 19
1.2
RATIONALE AND JUSTIFICATION FOR THE STUDY .................................................................................... 21
1.3
POTENTIAL RISKS AND BENEFITS ............................................................................................................ 22
2.
OBJECTIVES AND ENDPOINTS............................................................................. 23
2.1
OBJECTIVES ............................................................................................................................................. 23
2.2
ENDPOINTS .............................................................................................................................................. 23
3.
STUDY POPULATION ............................................................................................... 25
3.1
VOLUNTEERS ENROLLMENT .................................................................................................................... 25
3.2
INCLUSION CRITERIA ............................................................................................................................... 25
3.3
EXCLUSION CRITERIA .............................................................................................................................. 25
3.4
WITHDRAWAL CRITERIA ......................................................................................................................... 27
3.5
CONCOMITANT THERAPY ........................................................................................................................ 27
4.
STUDY DESIGN .......................................................................................................... 29
4.1
RANDOMIZATION AND BLINDING ............................................................................................................ 30
4.2
TERMINATION OF STUDY ......................................................................................................................... 30
4.3
DOSE DELAY AND DISCONTINUATION RULES ......................................................................................... 30
5.
TRIAL MATERIALS .................................................................................................. 32
5.1
TRIAL PRODUCT ...................................................................................................................................... 32
5.2
DOSAGE AND ADMINISTRATION .............................................................................................................. 32
5.3
STORAGE AND DRUG ACCOUNTABILITY .................................................................................................. 33
5.4
PACKAGING/LABELING ........................................................................................................................... 33
5.5
IP RETRIEVAL AND/OR DESTRUCTION ..................................................................................................... 33
5.6
DOSE DISPENSING AND ASSESSMENT OF COMPLIANCE ........................................................................... 33
6.
STUDY MEASUREMENTS ....................................................................................... 34


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6.1
ELIGIBILITY ............................................................................................................................................. 34
6.2
MEDICAL HISTORY .................................................................................................................................. 34
6.3
MEDICATION HISTORY ............................................................................................................................ 35
6.4
DEMOGRAPHICS, PHYSICAL EXAMINATION, VITAL SIGNS, HEIGHT, AND BODY WEIGHT ....................... 35
6.5
LABORATORY EXAMINATION AND PK SAMPLING.................................................................................... 35
6.6
DOSING, DISPENSE AND RETRIEVE CARESENG 1370 ............................................................................... 36
6.7
12-LEAD EKG AND CHEST X-RAY .......................................................................................................... 36
6.8
DISPENSE AND RETRIEVE DIARY ............................................................................................................. 36
6.9
PREGNANCY TEST ................................................................................................................................... 36
7.
STUDY SCHEDULE ................................................................................................... 36
8.
ADVERSE EVENTS .................................................................................................... 43
8.1
DEFINITIONS ............................................................................................................................................ 43
8.2
AE/SAE INTENSITY AND RELATIONSHIP ASSIGNMENT ........................................................................... 44
8.3
COLLECTING, RECORDING AND REPORTING OF ADVERSE EVENTS .......................................................... 46
9.
DATA ANALYSIS ....................................................................................................... 48
9.1
DATA QUALITY ASSURANCE ................................................................................................................... 48
9.2
CLINICAL DATA MANAGEMENT .............................................................................................................. 48
10.
SAMPLE SIZE AND STATISTICAL METHODS .................................................. 49
10.1
DETERMINATION OF SAMPLE SIZE ...................................................................................................... 49
10.2
STATISTICAL AND ANALYTICAL PLANS .............................................................................................. 49
11.
ETHICAL CONSIDERATIONS ................................................................................ 51
11.1
INFORMED CONSENT........................................................................................................................... 51
11.2
IRB AND REGULATORY REVIEW......................................................................................................... 51
11.3
CONFIDENTIALITY OF DATA AND VOLUNTEER RECORDS ................................................................... 51
11.4
CONFLICT OF INTEREST POLICY .......................................................................................................... 52
12.
PUBLICATIONS ......................................................................................................... 53
13.
RETENTION OF TRIAL DOCUMENTS ................................................................. 54
14.
PROTOCOL AMENDMENT HISTORY ................................................................. 55
15.
REFERENCES ............................................................................................................. 57
16.
APPENDIX ................................................................................................................... 58
 
 


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Version: 5.0 
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PROTOCOL SUMMARY 
 
 
 
 
 
 
 
 
 
Phase I 
 
XXXXXXXXXXXXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Primary objective 
The primary study objective is to explore the safety and tolerability 
profiles of Careseng 1370 as single agent based on dose limiting 
toxicity (DLT) observed in healthy volunteers. The results will be 
employed for future study to determine the maximal tolerated dose 
(MTD) of Careseng 1370 to treat chemotherapy-induced 
myelosuppression in advanced non-small cell lung cancer (NSCLC) 
patients.  
DLT is defined as any  Grade 2 adverse event from Day 1 to Day 10 
(DLT observation period), causally at least possibly related to Careseng 
1370 administration as judged by the investigator. The grading system 
applied in this study is Guidance for Industry: Toxicity Grading Scale 
for Healthy Adult and Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials 12 (Appendix 1), issued by United States Food 
and Drug Administration in September 2007. The definition of Grade 5 
(death) was added to this grading system as it was not defined in the 
guidance (Section 8.2 and Appendix 1). 
Secondary objective 
The secondary study objective is to evaluate the pharmacokinetic 
profiles of marker ingredient in Careseng 1370, 20(S)-protopanaxadiol 
(PPD), and its metabolites in healthy volunteers. 


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. One cohort (level D, modified cohort) of up to 6 
evaluable volunteers per cohort will be planned to be accrued to receive 
1 sachet of Careseng 1370 every other day (level D) when the dose de-
escalates from level A. 
 
 
 
 
 
 
 
 
 


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No volunteer is allowed to be assigned to more than 1 dose level. All 
decisions for dose escalation/de-escalation will be made by the DSMB.
 
 
 
 
 
 
 


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- Dose level A: Careseng 1370 1 sachet before breakfast for 
consecutive 5 days  
- Dose level B: Careseng 1370 1 sachet before breakfast and 1 sachet 
before lunch for consecutive 5 days 
- Dose level C: Careseng 1370 1 sachet before breakfast and 2 sachets 
before lunch for consecutive 5 days 
- Dose level D (modified cohort): Careseng 1370 1 sachet before 
breakfast on 1st, 3rd and 5th days 
The duration of dosing time between breakfast and lunch from Day 2 to 
Day 5 should be as close to those for Day 1. Volunteers should take 
Careseng 1370 for lunch (if there is one) at 4 hours (  10 minutes) after 
taking Careseng 1370 for breakfast on that day. 
 
 
 
 
 
 
 
 
 
- 
Day -1: registration of hospitalization in the evening 
 


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- 
Day 1: approximately 24 hours of hospitalization (pre-dose PK 
blood sampling and dosing at site for breakfast and lunch) 
- 
Day 2: discharge from hospitalization (pre-dose PK blood 
sampling and dosing (if scheduled) at site for breakfast and at 
home for lunch) 
- 
Day 3 pre-dose PK blood sampling and dosing at site for breakfast 
and at home for lunch 
- 
Day 4: pre-dose PK blood sampling and dosing (if scheduled) at 
site for breakfast and at home for lunch. Registration for 
hospitalization after planned dosing (if scheduled) on Day 4 
 
 
 
 
- 
Day 5: hospitalization (pre-dose PK blood sampling, dosing at site 
for breakfast and lunch, and post-dose PK blood sampling (level A
and D: 0.5, 1, 2, 4, 6, 12 hours after dosing on Day 5; level B and 
C: 0.5, 1, 2, 4, 4.5, 5, 6, 7, 8, 9, 10, 12, 16 hours after the 1st dose 
on Day 5)) 
 
- 
Day 6: post-dose PK blood sampling for 24 hours, discharge from 
hospitalization 
- 
Day 7: post-dose PK blood sampling for 48 hours 
- 
Day 8: post-dose PK blood sampling for 72 hours 
- 
Day 12 (±2) 


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Study Protocol
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(Protocol Number: Careseng 1370-01)
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5. Female volunteer of childbearing potential who:  
 
 
 
 
 
 
 
6. Male volunteer with female spouse/partners who are of childbearing 
potential refuses to adopt at least two forms of birth control (at least 
one of which must be a barrier method) from Screening visit until 
Final visit 
 
 
 
 
 
 


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3. Any pathological event, clinical adverse event, or any change in the 
volunteer
participation in the study may be harmful to the volunteer
. 
 
 
 


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(for data change from the baseline) 
 
 


Study Protocol
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(Protocol Number: Careseng 1370-01) 
Date: 18Sep2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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(Protocol Number: Careseng 1370-01) 
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* 
-
1st dose of that day (level A-D), or the timing for examinations scheduled on that day (2nd and 4th days of level D). 
1. 
Screening visit can be on the same day as Day -1 if healthy volunteers meet the entry criteria at Screening visit. The eligibility checked on Day 1 will be based on the results of 
body weights, physical exam, vital signs, and 12-lead EKG of Day 1 as well as other information collected during Screening visit. 
2. 
Healthy volunteers should come fasted for these measurements prior to Careseng 1370 administration (pre-dose measurement, Day 1 to Day 5), and prior to breakfast 
(Screening, Day 6, Day 12, and Day 22). 
3. 
Healthy volunteers should come fasted for laboratory examinations at all scheduled time points, except 8 hours post-first dose on Day 1, and 4 hours post-dose on Day 5.  
Laboratory examination to be measured in this study will consist of the following: 
- 
Hematology: hemoglobin, hematocrit (Hct), RBC, WBC (with differential), absolute neutrophil count (ANC), lymphocyte count, platelets, international normalized ratio 
(INR) of prothrombin time, activated partial thromboplastin time (APTT). 
- 
Biochemistry: AST, ALT, albumin, alkaline phosphatase (ALP), total bilirubin, creatinine, blood urea nitrogen (BUN), c-reactive protein, total protein, gamma glutamyl 
transferase ( -GT), blood glucose, uric acid, total cholesterol, triglycerides, sodium, potassium, calcium, magnesium, phosphorus, amylase, lipase 
- 
Urinalysis: pH, protein, RBC, WBC, casts 
- 
Immunology: CD3, CD4, CD8, CD19, CD16 and CD56 (presented as CD3+, CD3+/CD4+, CD3+/CD8+, CD19+, CD16+/CD56+, and CD4/CD8 ratio, for Screening 
visit, Day 2, Day 6 and Day 22) 
4. 
Time window of ±20 minutes is allowed.  
5. 
The time point for pre-dose PK blood sampling is prior to the first dose of that day. Time points for pre-dose PK blood sampling on Day 2 to Day 5 should be as close as that on 
Day 1. 
6. 
Time points for post-dose PK blood sampling after dosing on Day 5 for level A and D are as follows: 0.5 hour (± 5 minutes), 1 hour (± 5 minutes), 2 hours (± 5 minutes), 4 
hours (± 5 minutes), 6 hours (± 5 minutes), 12 hour (± 20 minutes), 24 (± 2) hours, 48 (± 2) hours, and 72 (± 2) hours.  
7. 
Time points for post-dose PK blood sampling after the first dose on Day 5 for level B and C are as follows: 0.5 hour (± 5 minutes), 1 hour (± 5 minutes), 2 hours (± 5 minutes), 
4 hours (± 5 minutes), 4.5 hours (± 5 minutes), 5 hours (± 5 minutes), 6 hours (± 5 minutes), 7 hours (± 5 minutes), 8 hours (± 5 minutes), 9 hours (± 5 minutes), 10 hours (± 5 
minutes), 12 hour (± 20 minutes), 16 hour (± 20 minutes), 24 (± 2) hours, 48 (± 2) hours, and 72 (± 2) hours.  
8. The dosing times for breakfast and for lunch from Day 2 to Day 5 should be as close to those for Day 1. Volunteers should take Careseng 1370 for lunch (if there is one) at 4 
hours (  10 minutes) after taking Careseng 1370 for breakfast on that day. Volunteers will take the Careseng 1370 for administration for lunch at home on Days 2, 3, and 4 
(except level A and D). Volunteers of level D will receive 1 sachet of Careseng 1370 every other day. Volunteers need to bring used and unused Careseng 1370 back at the next 
visit. The information to be collected in diary should contain at least the number of sachets taken together with respective dosing time for each day.  
9. 
If possible, and after the withdrawal is consented or Careseng 1370 is discontinued, volunteers will be assessed using the procedures planned for the Final visit within 3 days. 


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10. 
on. 
11. Adverse events will be collected from informed consent is signed. 
12. 12-lead EKG will be performed before and about 1 hour after Careseng 1370 administration for breakfast. Volunteers of level D will receive 12-lead EKG one time at scheduled 
visits when there is no scheduled dosing on that day. 
13. 12-lead EKG, Chest X-Ray and laboratory test performed within 14 days are acceptable. 
14. Subjects are required to return to the site for hospitalization on Day 4 after planned dosing on that day. This implementation aims to perform the planned procedures at the 
similar timing as those on Day 1. 


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1. 
BACKGROUND AND RATIONALE 
1.1 
 
Panax notoginseng (Burk.) F.H. Chen (Panax notoginseng) is a species of the genus 
Panax, family Araliaceae. Three species in this genus (Panax ginseng C.A. Meyer, 
Panax quinquefolius L. and Panax notoginseng (Burk.) F.H. Chen) are highly 
regarded as medicinal plants in China and the USA (Wen and Zimmer, 1996).1 Panax 
notoginseng belongs to the same genus as Korean ginseng (Panax ginseng Meyer) and 
American ginseng (Panax quinquefolius L.), and their main components are similar 
(Li et al., 2014).2 The root of Panax notoginseng, known as Sanqi or Tianqi in East 
Asian countries, is one of the primary herbs in traditional Chinese medicine. Sanqi, 
which has been widely used as a tonic and haemostatic drug for more than 400 years, 
still has an important place in today's regional market. With the increasing study of 
Chinese material medica, substantial efforts have been made to research the 
phytochemistry and pharmacological effects of Panax notoginseng and over 200 
compounds have been isolated from Panax notoginseng, and a variety of 
pharmacological effects have been found. 
Typical botanical characteristics of Panax notoginseng include growing to a height of 
30 60 cm, dark green leaves branching from a stem and a cluster of red berries in the 
middle. The stems are upright, simple, erect and unbranched (Guo et al., 2010).3 The 
main root is conical or cylindrical and ranges in length from 1 to 6 cm. The main root 
is taupe or drab yellow on the surface, with several wrinkles and root marks. 
Generally, Panax notoginseng is removed from the soil and dried before it blooms in 
autumn. It can be ground singly into powder that is swallowed or combined with other 
herbs (Committee for the Pharmacopoeia of China, 2010).4 The distribution of Panax 
notoginseng is very narrow due to its sensitivity to sunlight. After a long period of 
evolution, it grows primarily in the Wenshan mountain area of Yunnan province. It 
has a narrow habitat located around N 23.5° and E 104° that ranges in altitude from 
1200 to 2000 m. A large percentage of the raw materials in China is produced here 
(Guo et al., 2010).3 
As for Ethnopharmacology, the root of Panax notoginseng has played an 
indispensable role in Chinese healthcare for a long time. It is the main ingredient in 
Yun Nan Bai Yao (
), a famous haemostatic herbal remedy that is used to 
stop bleeding, decrease inflammation and relieve pain (Sun et al., 2010).5 Panax 
notoginseng is also one of the sources of cardiotonic pill that has been used in China, 
Korean and Russia for the treatment of cardiovascular diseases, such as occlusive 
vasculitis, coronary diseases, atherosclerosis, and cerebral infarction (Zhao et al., 
2006).6 The initial description of this plant can be traced back to the Compendium of 


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Material Medica (
), written by Shi Zhen Li. In this classic book, Panax 
notoginseng was recorded to have the actions to stop bleeding, remove blood stasis, 
alleviate pain, and it could be applied to treat bleeding caused by swords or axes, as 
well as hemoptysis, hematemesis, epistaxis and blood dysentery. Then the subsequent 
book Supplements for Compendium of Material Medica(
), written 
by Xue Min Zhao, described the function of Sanqi as similar to that of Panax ginseng 
C. A. Meyer. The difference is that Panax ginseng C.A. Meyer is good for tonifying qi 
(
), while Panax notoginseng is especially helpful for nourishing the blood. It is 
in Compendium of Material Medica(
) and many material medical 
books, and just can be found in few books, like New Compilation of Material Medica 
(
) and Chinese Medicine Dictionary (
). In the 
Chinese pharmacopoeia, the properties of this herb are described as warm in nature, 
sweet and slightly bitter in taste. It is attributive to the liver and spleen meridians, it 
has the actions to dissipate blood stasis, stop bleeding, promote blood circulation and 
alleviate pain, so it can be applied in haemoptysis, hematemesis, rhinorrhagia, 
haemafecia, metrorrhagia and metrostaxis, traumatic bleeding and pain caused by 
traumatic injury (Committee for the Pharmacopoeia of China, 2010).4 
Because of its defined clinical effects, some formulas were created by ancient doctors. 
Nowadays, many prescriptions are in clinical use. There are nearly 60 kinds of 
Chinese patent medicines in the Chinese pharmacopoeia, and the forms including 
capsules, granules, tablets, pills, dripping pills, powders, etc., in which capsules and 
tablets are the most used forms (Shi et al., 2012).7 Although Panax notoginseng have 
been used massively, there are over 1500 t of stems and leaves of Panax notoginseng 
were turned out every year, but less than 5% stems and leaves is to be used only. 
The stems of Panax notoginseng and the leaves of Panax notoginseng demonstrate a 
certainty of clinical application of anti-tumor activity (Jiang et al., 2014).8 The 
compositions and contents of saponins isolated from the leaves of Panax notoginseng 
are significantly different from the underground parts in that the leaves and stems of 
Panax notoginseng, mainly contain plentiful PPD-type saponins, such as ginsenosides 
Rb3, Rb1, Rc, and notoginsenoside Fc (Wang et al., 2016).9 Furthermore, chemical 
profile indicates the leaves of Panax notoginseng contain the marker saponins F2, 
20(R)-Rg3, 20(S)-Rg3, and Rh2 (Wang et al., 2016),9 and these compounds illustrate 
anti-proliferation effect on human colorectal cancer cells (Wang et al., 2007).10  
In a myelosuppression attenuation study using DS1370 (same as drug substance DS-
1370 used in this study), dry extracts of Panax notoginseng powder, 30 mice were 
divided into 5 groups, which were control group, docetaxel (Doc) + cisplatin (CP) 


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group, Doc + CP + DS1370 (1,072 mg/kg) group, Doc + CP + DS1370 (536 mg/kg) 
group, Doc + CP + DS1370 (268 mg/kg) group. Each groups included 6 mice. Doc (12 
mg/kg) was injected to mice via intraperitoneal injection on Day 0, then, CP (12 
mg/kg) was injected to mice via intraperitoneal injection 6 hours later, and sample 
DS1370 was administered by oral gavage from Day 1 to Day 5. The study results 
indicate sample DS1370 can attenuate the myelosuppression that caused by cisplatin 
and docetaxel injection. According to the results of peripheral blood cells count and 
bone marrow hematopoiesis ability, the effective doses of DS1370 are 536 mg/kg and 
1072 mg/kg. Additionally, the dosages of DS1370 at 268, 536, and 1072 mg/kg are 
considered to be safe with employed chemotherapy as these dosages after 
chemotherapy did not cause further body weight reduction or tumor suppression on 
mice.11 
1.2 
 
1.2.1 Rationale for the Study Purpose 
 
1.2.2 Rationale for Doses Selected 


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1.2.3 Rationale for Study Population 
Healthy volunteers are recruited to explore the safety and tolerability profiles 
of Careseng 1370 for safety concern and as reference to determine 
recommended dose for cancer subjects receiving chemotherapy in the future. 
1.2.4 Rationale for Study Design 
Single arm, dose escalation of Careseng 1370 with traditional 3+3 paradigm 
will be employed to achieve the purpose of this study  
1.3 
 
There will be no potential benefits for healthy volunteers to participate in this study.  
Potential risks of Careseng 1370 are based on the toxicology findings in Sprague-
Dawley (SD) rats. Possible influence on coagulation prolonged prothrombin time (PT) 
and activated partial thromboplastin time (APTT) was noted in both sexes of rats 
receiving mid- (1,350 mg/kg/day) and high-dose (2,700 mg/kg/day) for 13 weeks. But 
the prolonged PT and APTT were not seen at the end of recovery period in 2,700 
mg/kg recovery animals. It was also noted that the mean body weights of mid- and 
high-dose male rats were 9.3% and 13.8% lower than that of the controls, respectively. 
Final mean body weight of high-dose recovery male rats was 11.8% lower than that of 
the controls. Final mean body weight gains of mid- and high-dose male rats were 
15.7% and 23.2% lower than that of the controls. Final mean body weight gains of 
high-dose recovery males was 19.2% lower than that of the controls. Therefore, body 
weight loss and bleeding prolonged are possible risks that subjects in this study may 
experience. 


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2. 
OBJECTIVES AND ENDPOINTS  
2.1 
 
Primary objective: 
The primary study objective is to explore the safety and tolerability profiles of 
Careseng 1370 as single agent based on DLT observed in healthy volunteers. The 
results will be employed for future study to determine the MTD of Careseng 1370 to 
treat chemotherapy-induced myelosuppression in advanced non-small cell lung cancer 
(NSCLC) patients. 
DLT is defined as any  Grade 2 adverse event from Day 1 to Day 10 (DLT 
observation period), causally at least possibly related to Careseng 1370 administration 
as judged by the investigator. The grading system applied in this study is Guidance 
for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled 
12 (Appendix 1), issued by United 
States Food and Drug Administration in September 2007. The definition of Grade 5 
(death) was added to this grading system as it was not defined in the guidance (Section 
8.2 and Appendix 1). 
Secondary objective: 
The secondary study objective is to evaluate the pharmacokinetic (PK) profiles of 
marker ingredient in Careseng 1370, 20(S)-protopanaxadiol (PPD), and its metabolites 
in healthy volunteers. 
2.2 
 
2.2.1. Primary endpoints 
 
2.2.2. Secondary endpoints 
1. Changes from baseline to applicable post-dosing visits in vital signs, 
physical examination, body weight, EKG and laboratory examination 
results. Baseline will be the value of measurement closest to and before start 
of IP administration. 
2. Pharmacokinetic parameters of marker ingredient in Careseng 1370, 20(S)-
protopanaxadiol (PPD) and its metabolites 
2.2.3. Exploratory endpoints 


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3. 
STUDY POPULATION 
3.1 
 
In design of traditional 3+3 paradigm with four candidate dose levels, the number of 
evaluable healthy volunteers will be up to 24. 
Note: A volunteer is considered evaluable if he/she  
1. receives any Careseng 1370, and 
2. experiences DLT OR completes DLT observation period with at least 80% of study drug compliance 
and has exposed to Careseng 1370 for at least 4 days (level A, B, and C), OR completes DLT 
observation period with 100% of study drug compliance (level D). 
3.2 
 
A healthy volunteer is eligible for the study if all of the followings apply: 
1. 
Adult aged between 20-40 years old (inclusive)  
2. 
Physically and mentally healthy volunteer as confirmed by an interview, medical 
history, clinical examination, chest X-rays, and electrocardiogram. Volunteer 
with non-clinically significant signs or symptoms may be eligible at 
 
3. 
Body Mass Index (BMI) between 18.5 and 24, inclusive (BMI will be calculated 
as weight in kilogram [kg]/(height in meters)2 [m2]) 
4. 
Clinically normal hematology, biochemistry and urinalysis determinations based 
. Volunteer with non-clinically significant signs or 
symptoms 
 
5. 
Volunteer is willing and able to comply with study procedures and sign informed 
consent prior to initiation of any study-mandated procedures. 
3.3 
 
 
1. 
Volunteer who has a history or evidence of a medical condition that would 
expose them to a risk of a significant adverse event or interfere with the 
assessments of safety or pharmacodynamics variables during the course of the 
trial, including but not limited to hepatic, renal, respiratory, cardiovascular, 
endocrine, immune, neurological, musculoskeletal or hematological disease as 
determined by the clinical judgment of the investigator 


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2. 
Volunteer has received any other investigational agent within 4 weeks prior to the 
first dose of study drug 
3. 
Volunteer has taken or potentially takes any herbal 
medication/supplements/medicinal food, prescription medication and/or over-the-
counter medication within 2 weeks prior to the first dose of study drug  
4. 
Volunteer has consumed alcohol, caffeine, grapefruit juice, nicotine, phosphorous 
supplement, calcium supplement, or food rich in calcium within 24 hours prior to 
the first dose of study drug 
5. 
Female volunteer of childbearing potential who:  
- is lactating; or 
- has positive pregnancy test result at eligibility checking; or 
- refuses to adopt at least two forms of birth control (at least one of which must 
be a barrier method) from Screening visit to Final visit.  
 
 
 
 
6. 
Male volunteer with female spouse/partners who are of childbearing potential 
refuses to adopt at least two forms of birth control (at least one of which must be 
a barrier method) from Screening visit until Final visit 
7. 
Known or suspected allergy or hypersensitivity to any ingredients of study 
product 
8. 
With history of stroke, myocardial infarction, or Coronary Artery Bypass Graft 
(CABG) surgery within the last 6 months prior to the screening visit 
9. 
With history of cardiac failure (New York Heart Association class 2 or above), 
unstable angina, or life-threatening arrhythmia within the last 6 months prior to 
the screening visit 
10. With blood pressures as systolic blood pressure < 90 mmHg or > 170 mmHg or 
diastolic blood pressure < 50 mmHg or > 120 mmHg at eligibility checking  
11. History of psychiatric disorder 
12. History of left ventricular outflow obstruction, such as aortic stenosis and 
hypertrophic cardiomyopathy 


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13. With a history of human immunodeficiency virus (HIV) infection or hepatitis B 
or C infection 
14. Plan to receive surgery from Screening visit until Final visit 
15. Known or suspected hypersensitivity to any component of Careseng 1370, 
including components in plants of genus Panax, Tween 80, Kolliphor® P188, 
Fujicalin, and ginseng flavor 
3.4 
 
Healthy volunteers may be withdrawn from the trial due to any of the following 
conditions: 
1. 
Volunteer decides to withdraw his/her informed consent. 
2. 
Volunteer experiences intolerable symptoms. 
3. 
Any pathological event, clinical adverse event, or any change in the volunteer
status giving indication to the investigator that further participation in the study 
may be harmful to the volunteer
. 
4. 
Volunteer becomes pregnant from Screening visit until Final visit. 
Volunteer
serum or urine pregnancy test 
at Screening visit and Final visit and any time if investigator or volunteer 
suspects the volunteer is pregnant. 
5. 
Volunteer develops DLT. 
6. 
Volunteer is lost to follow-up or dies. 
7. 
Volunteer misses dosing and fails to reach 80% of study drug compliance, does 
not keep appointments, or otherwise does not adhere to protocol requirements. 
The reasons for withdrawal must be recorded in the electronic Case Report Form 
(eCRF) and in the volunteer
participants withdrawn from the study will be requested as possible to return for 
assessments scheduled at Final visit. If a volunteer is withdrawn due to an AE, every 
effort will be made to follow the event until the AE resolved or stabilized at a level 
acceptable to the investigator. 
3.5 
 
All medications, supplements, and herbal medicinal food taken by the study volunteer 
beginning four weeks prior to the Screening visit up to Final visit will be recorded on 
the appropriate page of the eCRF. This record will include the name of the medication, 


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frequency, unit dose, dates of the drug was started and stopped, and the indication for 
the use of the drug. 
Prohibited therapies include the following: 
1. 
Other investigational drugs within 4 weeks prior to Day 1 until Final visit 
2. 
Other herbal medications/supplements/medicinal food within 2 weeks prior to 
Day 1 until Day 15 
3. 
Prescription medication and/or over-the-counter medication within 2 weeks prior 
to Day 1 until Day 15 
4. 
Alcohol, caffeine, grapefruit juice, nicotine, calcium or phosphorous supplement 
within 24 hours prior to Day 1 until Day 7 
5. 
Food rich in calcium within 24 hours prior to Day 1 until Day 7, including dairy 
food, soymilk, tofu, black bean, clams, sardines, squid, cauliflower, kale, 
cabbage, Chinese mustard, basil, black sesame, seaweed, black jelly ear, calcium-
fortified food, etc. A calcium-restricted diet plan designed for 4 different dose 
cohorts (Dose level A: 1,730 mg calcium/day; Dose level B: 960 mg 
calcium/day; Dose level C: 200 mg calcium/day, Dose level D: 1,730 mg 
calcium/day) will be provided to volunteers as a dietary guideline during this 
period of time 
6. 
Any type of surgery from Screening visit until Final visit. 
Additionally, volunteers will be advised to avoid ingesting excessive amount of food 
very rich in phosphorous during the dosing period, including yolk, animal organs, 
dried meat, dried seafood, grains, beans, nuts, royal jelly, coke, beer, yakult, chips, 
powder of milk, yeast, tea, or cocoa, etc. 
 
 


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4. 
STUDY DESIGN 
. One cohort (level D, modified cohort) of up to 6 
evaluable volunteers per cohort will be planned to be accrued to receive 1 sachet of 
Careseng 1370 every other day (level D) when the dose de-escalates from level A. 
 
- 
Level A (1 sachet): 1 sachet before breakfast 
- 
Level B (2 sachets): 1 sachet before breakfast, 1 sachet before lunch 
- 
Level C (3 sachets): 1 sachet before breakfast, 2 sachets before lunch 
 
 
 
 
 
 


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4.1 
 
 
4.2 
 
 
 
4.3 
 
 


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5. 
TRIAL MATERIALS 
5.1 
 
 
 
 
 
 
 
- DS-1370 drug substance (dry extracts of Panax notoginseng 
powder): 652 mg (16.3%) 
- Excipients as below: 
- Tween 80: 326 mg (8.15%)  
- Kolliphor® P188: 326 mg (8.15%) 
- Fujicalin: 2,608 mg (65.2%) 
- Ginseng flavor: 88 mg (2.2%) 
 
5.2 
 
 
- 
Dose level A: Careseng 1370 1 sachet before breakfast for consecutive 5 days  
- 
Dose level B: Careseng 1370 1 sachet before breakfast and 1 sachet before lunch 
for consecutive 5 days  
- 
Dose level C: Careseng 1370 1 sachet before breakfast and 2 sachets before lunch 
for consecutive 5 days  
- 
Dose level D (modified chort): Careseng 1370 1 sachet before breakfast on 1st, 3rd 
and 5th days 
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5.3 
 
The IP shipping is to be arranged by the sponsor/designee to the study site and to be 
handled by the investigator/designee or the designated pharmacist for management 
and dispensation. Careseng 1370 sachets should be stored at controlled temperature of 
15 (59°F) to 30°C (86°F). Long-term exposure to bright light should be avoided. All 
of the used and unused Careseng 1370 sachets will be returned from the clinical site to 
the sponsor unless prohibited by site policy. Each batch shipped, used, and returned 
from/to the sponsor to/from the clinical site will be recorded according to date to keep 
track of the Careseng 1370 sachets with precise details. 
5.4 
 
All medication used in this study will be prepared, packaged, and labeled under the 
responsibility of a qualified person at sponsor with Standard Operating Procedures 
(SOPs) of sponsor, Good Manufacturing Practice (GMP) guidelines, ICH GCP 
guidelines, and applicable local laws/regulations. Careseng 1370 sachets will be 
packaged in aluminum foil/bags. All aluminum foil/bags for packaging study 
medication will be labeled 
--Limited by United States law to 
regulatory requirements in the local language.  
5.5 
 
Used and unused study drug should be returned to the sponsor for destruction unless 
prohibited by site policy. In this instance, study drug may be destroyed at the study 
center according to standard institutional procedures after verification for drug 
accountability has been conducted by the study monitor, Sponsor or representative. 
Should this occur, a copy of the standard institutional procedure for destroying 
investigational drugs will be provided to the Sponsor. Upon destruction, a copy of the 
certificate of destruction must be provided for the Sponsor files and site drug 
accountability records. 
5.6 
 
Volunteer
compliance will be assessed by the following formula: 
# of sachets of study drug actually administered 
× 100%
Total # of sachets of study drug assigned at that level 
 
 
 


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6. 
STUDY MEASUREMENTS 
6.1 
 
Eligibility should be thoroughly checked by the investigators at Screening visit and 
Day 1 visit.  
If a volunteer is a screen failure, a minimal set of screen failure information is required 
to ensure transparent reporting of screen failure subjects, to meet the regulatory 
authority requirement and to respond to queries from regulatory authorities and 
IRBs/IECs. Minimal information includes demographics, screen failure details, 
concomitant medication, and any serious adverse event. 
Re-screening for 
eligibility will be allowed if the volunteer is willing to 
participate in the study and one of the following conditions meets: 
- 
If a volunteer consents to participate and meets the eligibility criteria but a delay 
occurs in starting to participate in due to certain change in situation such that 
some measurement relevant to eligibility became invalid owing to the delay 
- 
If the cause of screen failure has now resolved or adequately treated such that 
volunteer
conditions have now stabilized 
- 
If there is an alternative manner to indicate that the volunteer may be suitable. 
In these situations, 
- 
A new eCRF will be used 
- 
A new Screening number will be assigned to the person 
- 
The person will be marked as having been re-screened on both the eCRF and the 
source document. 
- 
The old eCRF will be completed as fully as possible following eCRF completion 
guide and data on the old eCRF is not copied to the new eCRF. 
- 
The volunteer needs to sign a new ICF as part of the screening procedure. 
It is not appropriate to re-screen a volunteer if he/she has previously failed to meet the 
eligibility criteria and no further changes or treatments have been able to indicate that 
the volunteer may be suitable. 
Volunteer may be re-tested/measured for procedures relevant to causes of screen 
failure if investigator considers such causes can be resolved soon. 
6.2 
 
General medical history within 6 months should be recorded at Screening visit. 
Histories of psychiatric disorder, left ventricular outflow obstruction, HIV infection or 
hepatitis B or C, and major surgery will be recorded on a lifetime basis. 


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6.3 
 
Previous medications should only be recorded up to 4 weeks before Screening visit.  
6.4 
 
Demographics including gender, date of birth, and race will be collected at Screening 
visit.  
Physical examination conducted in this study will include the following items: general 
appearance, skin, eyes, ears, nose, throat, head and neck, heart, chest and lungs, 
abdomen, extremities, lymph nodes, musculoskeletal, neurological, and other. 
Vital signs measurement will consist of systolic/diastolic blood pressure, respiratory 
rate, pulse rate or heart rate, and body temperature. Respiratory rate, pulse rate or heart 
rate and blood pressure (systolic/diastolic) will be obtained after the volunteer has 
been at rest for at least 5 minutes in a sitting position. 
Height will be recorded only at Screening visit. Body weight will be recorded at all 
scheduled visits except visit 8 and 9. 
Healthy volunteers should come fasted, specific for pre-dose measurement of physical 
examination, vital signs, and body weight prior to Careseng 1370 administration 
during dosing period (Day 1 to Day 5). 
6.5 
 
Laboratory examination to be measured in this study will consist of the following: 
Hematology: hemoglobin, hematocrit (Hct), RBC, WBC (with differential), absolute 
neutrophil count (ANC), lymphocyte count, platelets, international normalized ratio 
(INR) of prothrombin time (PT), activated partial thromboplastin time (APTT). 
Immunology: CD3, CD4, CD8, CD19, CD16 and CD56 assessments, presented as 
CD3+, CD3+/CD4+, CD3+/CD8+, CD19+, CD16+/CD56+, and CD4/CD8 ratio. 
Biochemistry: AST, ALT, albumin, alkaline phosphatase (ALP), total bilirubin, 
creatinine, blood urea nitrogen (BUN), c-reactive protein, total protein, gamma 
glutamyl transferase ( -GT), blood glucose, uric acid, total cholesterol, triglycerides, 
sodium, potassium, calcium, magnesium, phosphorus, amylase, lipase. 
Urinalysis: pH, protein, RBC, WBC, casts. 
Healthy volunteers should come fasted for laboratory examinations at all scheduled 
time points, except 8 hours post-first dose on Day 1, and 4 hours post-dose on Day 5.  


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pre-dose PK blood sampling means blood collection for PK prior 
to the first dose of that day (level A-D), or at scheduled visits without dosing of that 
day (level D). 
post-
 PK blood sampling after the 1st 
dose on Day 5. PK blood samplings at scheduled time points will be collected and 
examined for the concentration of 20(S)-protopanaxadiol (PPD) and its metabolites, 
and analyzed for PK parameters. 
6.6 
 
Careseng 1370 will be dosed at site and dispensed for taking at home following the 
table below. Used and unused IP will be returned at the next scheduled visits.  
 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Breakfast 
Site 
Site# 
Site 
Site# 
Site 
Lunch* 
Site 
Home 
Home 
Home 
Site 
#Not required for level D; *Not required for level A and D 
Volunteers should take Careseng 1370 for lunch (if there is one) at 4 hours (  10 
minutes) after taking Careseng 1370 for breakfast on that day. The definition of 
second dosing somewhere else before lunch except level A and D (off-site dosing). 
6.7 
 
12-Lead EKG measurement will at least include rhythm, ventricular rate, PR interval, 
QRS duration, QT and QTc intervals. Healthy volunteers should come fasted, specific 
for pre-dose measurement of 12-Lead EKG prior to Careseng 1370 administration 
during dosing period (Day 1 to Day 5). 
Chest X-Ray will only be performed at Screening visit and 
discretion for unscheduled visit if necessary. 
6.8 
 
The information to be collected in diary should contain at least number of sachets 
taken at home of Day 2 to Day 4 and each dosing time. 
6.9 
 
 
7. 
STUDY SCHEDULE 


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The schedule of assessment is tabulated in front of the protocol main text. The 
assessments or procedures to be performed at each study visit are listed below. The 
results of protocol specific assessments and procedures will be recorded in the source 
documents for all study volunteers and on the appropriate page of the eCRF. 
Unscheduled visit will be arranged when investigator considers necessary. 
 1
 
 
 Obtain informed consent form 
 Assign volunteer identifier 
 Obtain medical history 
 Collect volunteer demographics data 
 Record medication history (including concomitant medications) 
 Measure height  
 Measure body weight 
 Perform physical examination  
 Assess vital signs 
 Conduct 12-lead EKG (test performed within 14 days are acceptable) 
 Perform pregnancy (urine or serum test for female volunteers of childbearing 
potential)  
 Conduct laboratory tests (with immunology test) (test performed within 14 days are 
acceptable) (fasting) 
 Conduct chest X-ray (test performed within 14 days are acceptable) 
 Assess the volunteer
inclusion/exclusion criteria) 
 Record adverse events  
 Dispense diary 
 
 
 


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 Measure body weight 
 Perform physical examination 
 Assess vital signs 
 Conduct 12-lead EKG 
 Pre-dose PK blood sampling 
 Diary return and dispensing 
 
inclusion/exclusion criteria) 
 
 Dosing before breakfast at site 
 Perform physical examination (8 hours post-first dose, ±20 minutes are allowed) 
 Assess vital signs (1, 4 and 8 hours post-first dose, ±20 minutes are allowed) 
 Conduct 12-lead EKG (1, 4, 8, and 12 hours post-first dose, ±20 minutes are 
allowed) 
 Conduct laboratory tests (excluding immunology test, only for 8 hours post-first 
dose, ±20 minutes are allowed) 
 Dosing before lunch at site (not applicable for Dose level A and D) 
 Record adverse events 
 Record concomitant medications 
 
1st Discharge (Day 2; Visit 3) 
 
 Measure body weight  
 Perform physical examination  
 Assess vital signs 
 Conduct 12-lead EKG  
 Conduct laboratory tests (with immunology test) together with pre-dose PK blood 
sampling  
 
 Dosing (if scheduled) before breakfast at study site 


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 Conduct 12-lead EKG about 1 hour after IP administration (except level D) 
 Record adverse events 
 Record concomitant medications 
 Drug (except level A and D) dispensing, and diary return and dispensing 
 
 
 
 Measure body weight  
 Perform physical examination  
 Assess vital signs  
 Conduct 12-lead EKG  
 Conduct laboratory tests (except immunology test) together with PK blood 
sampling  
 Drug (except level A and D) and diary return 
During the treatment 
 Dosing (if scheduled) for breakfast at site 
Post-dose 
 Conduct 12-lead EKG about 1 hour after IP administration (except level D on Day 
4) 
 Record adverse events 
 Record concomitant medications 
 Drug (except level A and D) and diary dispensing 
 
 
 
 
 
 
 
 Measure body weight 
 Perform physical examination 
 Assess vital signs 


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 Conduct 12-lead EKG 
 Conduct laboratory tests (except immunology test) together with PK blood 
sampling 
 Drug (except level A and D) return, and diary return and dispensing 
 
 Dosing before breakfast at site (last dose for level A and D) 
 Dosing before lunch at site (not applicable for Dose level A and D; last dose for 
level B and C) 
 
 Dose level A and D: post-dose PK blood sampling at 0.5 hour (± 5 minutes), 1 hour 
(± 5 minutes), 2 hours (± 5 minutes), 4 hours (± 5 minutes), 6 hours (± 5 minutes), 
12 hours (± 20 minutes), 24 (± 2) hours (at Visit 7), 48 (± 2) hours (at Visit 8), and 
72 (± 2) hours (at Visit 9) 
 Dose level B and C: post-dose PK blood sampling at 0.5 hour (± 5 minutes), 1 hour 
(± 5 minutes), 2 hours (± 5 minutes), 4 hours (± 5 minutes), 4.5 hours (± 5 
minutes), 5 hours (± 5 minutes), 6 hours (± 5 minutes), 7 hours (± 5 minutes), 8 
hours (± 5 minutes), 9 hours (± 5 minutes), 10 hours (± 5 minutes), 12 hours (± 20 
minutes), 16 hours (± 20 minutes), 24 (± 2) hours (at Visit 7), 48 (± 2) hours (at 
Visit 8), and 72 (± 2) hours (at Visit 9) 
 Conduct laboratory tests (except immunology test) (only for 4 hours post-dose, ±20 
minutes are allowed) 
 Perform physical examination (only for 4 hours post-dose, ±20 minutes are 
allowed) 
 Assess vital signs (only for 4 hours post-dose, ±20 minutes are allowed) 
 Conduct 12-lead EKG (only for 1, 4, 8, and 12 hours post-dose, ±20 minutes are 
allowed) 
 Record adverse events 
 Record concomitant medications 
 
 
 Measure body weight 
 Perform physical examination  
 Assess vital signs 
 Conduct 12-lead EKG 
 Conduct laboratory tests (with immunology test) together with PK blood sampling 
for 24 (± 2) hours post-dose (fasting) 
 Record adverse events 


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 Record concomitant medications 
 Diary return and dispensing 
 
 
 PK blood sampling for 48 (± 2) hours post-dose 
 Diary return 
 Record adverse events 
 Record concomitant medications 
 
 
 PK blood sampling for 72 (± 2) hours post-dose 
 Record adverse events 
 Record concomitant medications 
 
 
 Measure body weight 
 Perform physical examination 
 Assess vital signs 
 Conduct 12-lead EKG 
 Conduct laboratory tests (except immunology test) (fasting) 
 Record adverse events 
 Record concomitant medications 
 
 
 Measure body weight 
 Perform physical examination 
 Assess vital signs 
 Conduct 12-lead EKG 
 Perform pregnancy test for female volunteers of childbearing potential 
 Conduct laboratory tests (with immunology test) (fasting) 
 Record adverse events 
 Record concomitant medications 
 
 


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 except the following:  
 Record adverse events 
 Record concomitant medications 


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8. 
ADVERSE EVENTS 
8.1 
 
- 
Adverse Event (AE): 
An AE is any untoward medical occurrence in a volunteer or clinical investigation 
participant administered a study medication and that does not necessarily have a 
causal relationship with this treatment. An AE can therefore be any unfavorable 
and unintended sign, symptom, or disease temporally associated with the use of a 
study medication, whether or not related to the study medication. Laboratory 
abnormalities should not be recorded as AEs unless determined to be clinically 
significant by the Investigator. 
- 
Expected AE: 
Expected AE is defined as any event, the specificity or severity of which is 
consistent with the current investigator brochure or other technique documents.  
- 
Unexpected AE: 
Unexpected AE is defined as any event, the specificity or severity of which is not 
consistent with the current investigator brochure or other technique documents. 
"Unexpected", as used in this definition, refers to an adverse drug experience that 
has not been previously observed (e.g., included in the investigator brochure) 
rather than from the perspective of such experience not being anticipated from the 
pharmacological properties of the pharmaceutical product. 
- 
Serious Adverse Event (SAE): 
Serious Adverse Event (SAE): A Serious Adverse Event is defined as an AE 
meeting one of the following conditions: 
 
 
 
 
 
 
 
 
 
 


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8.2 
 
- 
AE/SAE Intensity 
The investigator must rate the intensity for all AEs that occur during the study, 
12 
(Appendix 1), issued by United States Food and Drug Administration in 
September 2007. The definition of Grade 5 (death) was added to this grading 
system as it was not defined in the guidance. 
The toxicity grade of adverse events will be rated according to the following 
definition by the investigator when AEs are not listed in the US FDA Guidance 
(Appendix 1) applied in this study:  
 Grade 1 (Mild): 
No interference with activity 
 Grade 2 (Moderate): 
Some interference with activity not requiring medical intervention 
 Grade 3 (Severe): 
Prevents daily activity and requires medical intervention 
 Grade 4 (Life threatening): 
Emergency room visit or hospitalization 
 
Grade 5 (Death) 
Note: The definitions of Grade 1 to G
for Healthy Adult and Adolescent 
12 
issued by United States Food and Drug Administration in September 2007 (Appendix 1). The 
definition of Grade 5 (death) was added to this grading system as it was not defined in the guidance 
(Section 8.2 and Appendix 1). 
- 
AE/SAE Relationship Assessment 
The investigator will be asked to assess all AEs with respect to their causal 
relationship to the study drug according to the following classification:  


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Definitely Related 
There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal 
laboratory test result, occurs in a plausible time relationship to study 
agent/intervention administration and cannot be explained by concurrent 
disease or other drugs or chemicals. The response to withdrawal of the study 
agent/intervention (dechallenge) should be clinically plausible. The event must 
be pharmacologically or phenomenologically definitive, with use of a 
satisfactory rechallenge procedure if necessary. 
 
Probably Related 
There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The clinical event, including an abnormal laboratory test 
result, occurs within a reasonable time sequence to administration of the study 
agent/intervention, is unlikely to be attributed to concurrent disease or other 
drugs or chemicals, and follows a clinically reasonable response on withdrawal 
(dechallenge). Rechallenge information is not required to fulfill this definition.  
 
Possibly Related 
There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). 
However, the influence of other factors may have contributed to the event 
(e.g., the volunteer
be flagged as requiring more information and later be upgraded to probable or 
certain as appropriate. 
 
Unlikely 
A clinical event, including an abnormal laboratory test result, whose temporal 
relationship to study agent/intervention administration makes a causal 
relationship improbable (e.g., the event did not occur within a reasonable time 
after administration of the trial medication) and in which other drugs or 
chemicals or underlying disease provides plausible explanations (e.g., the 
volunteer
 
 
Not related 
The AE is completely independent of study agent/intervention administration, 
and/or evidence exists that the event is definitely related to another etiology. 
There must be an alternative, definitive etiology documented by the clinician 
Expected Events Related to Disease Process: Provide explicit definitions of the 


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type(s), grade(s), and duration(s) of adverse event(s) that will be considered 
disease related. 
8.3 
 
8.3.1 
 
 
8.3.2 
 
 
 
Social reasons in absence of an adverse event 
 
Surgery or procedure planned before entry into the study (must be 
documented in the eCRF) 
 
 


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Confidential
 
Careseng 1370 for Healthy Volunteers 
Version: 5.0 
 
(Protocol Number: Careseng 1370-01) 
Date: 18Sep2020 
 
 
 
 
 
 
 
 
 
 
9. 
DATA ANALYSIS 
9.1 
 
Electronic CRFs will be provided for the recording and collection of volunteer data. 
All eCRFs will be completed following e
visit. Corrections to data on the eCRFs will be documented or traced. The investigator 
will review eCRFs to indicate that, to his/her knowledge, they are complete and 
accurate. If further changes are made after this, the investigator will need to again sign 
the investigator signature page. Designated source documents will be signed and dated 
by the appropriate study personnel. 
9.2 
 
The investigator must agree to complete and maintain source documents and eCRFs 
for each volunteer participating in the study or by his/her designees. 
The sponsor/CRO will be responsible for the processing and quality control of the 
operating procedures (SOPs) for clinical studies. 
The handling of data, including data quality control, will comply with regulatory 
Ps as well as provisions of the study-specific 
data management plan. 
 
 


Study Protocol
Confidential
 
Careseng 1370 for Healthy Volunteers 
Version: 5.0 
 
(Protocol Number: Careseng 1370-01) 
Date: 18Sep2020 
 
 
 
 
 
 
 
 
 
 
10. 
SAMPLE SIZE AND STATISTICAL METHODS 
10.1 
 
Planned 4 cohorts of up to 6 evaluable healthy volunteers in design of traditional 3+3 
paradigm with three candidate dose levels, the number of evaluable healthy volunteers 
will be up to 24. Around 29 eligible healthy volunteers will be recruited to complete 
up to 24 evaluable healthy volunteers. 
Note: A volunteer is considered evaluable if he/she  
1. receives any Careseng 1370, and  
2. experiences DLT OR completes DLT observation period with at least 80% of study drug compliance 
and has exposed to Careseng 1370 for at least 4 days (level A, B and C), OR completes DLT 
observation period with 100% of study drug compliance (level D). 
10.2 
 
10.2.1 Analysis Population 
 
 
 
 
10.2.2 Statistical analysis 
by dose level
(for data change 
from baseline)
 
Safety Analyses 


Study Protocol
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Careseng 1370 for Healthy Volunteers 
Version: 5.0 
 
(Protocol Number: Careseng 1370-01) 
Date: 18Sep2020 
 
 
 
 
 
 
 
 
 
 
 
10.2.3 Interim Analyses 
 
10.2.4 
 
 


Study Protocol
Confidential
 
Careseng 1370 for Healthy Volunteers 
Version: 5.0 
 
(Protocol Number: Careseng 1370-01) 
Date: 18Sep2020 
 
 
 
 
 
 
 
 
 
 
11. 
ETHICAL CONSIDERATIONS 
11.1 
 
Extensive discussion of risks and possible benefits of this therapy will be provided to 
the participants and their families.  
Consent forms will be IRB approved and the participant will be asked to read and 
review the document. Upon reviewing the document, the investigator will explain the 
research study to the participant and answer any questions that may arise. The 
participants will sign the informed consent document prior to any procedures being 
done specifically for the study. The participants should have sufficient opportunity to 
discuss the study and process the information in the consent process prior to agreeing 
to participate. The participants may withdraw consent at any time throughout the 
course of the trial. A copy of the informed consent document will be given to the 
participants for their records. The rights and welfare of the participants will be 
protected by emphasizing to them that the quality of their medical care will not be 
adversely affected if they decline to participate in this study. 
11.2 
 
This protocol and the associated informed consent documents must be submitted to the 
IRB and health authority for review and approval. The study will not be initiated until 
the IRB and health authority provide written approval of the aforementioned 
documents and until approval documents have been obtained by the Principal 
Investigator and sponsor or CRO.  
No changes from the final approved protocol will be initiated without the health 
 written 
amendment, except when necessary to eliminate immediate hazards to the study 
participants or when the change involves only logistics or administration. Any 
significant deviation from the protocol when no approved amendment exists will be 
regarded as a protocol violation, and will be addressed as such during the reporting of 
the study. 
11.3 
 
Include procedures for maintaining participant confidentiality, any special data 
security requirements, and record reten
 


Study Protocol
Confidential
 
Careseng 1370 for Healthy Volunteers 
Version: 5.0 
 
(Protocol Number: Careseng 1370-01) 
Date: 18Sep2020 
 
 
 
 
 
 
 
 
 
 
Participant confidentiality is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s) and their agents. This confidentiality is extended to 
cover testing of biological samples and genetic tests in addition to the clinical 
information relating to participating volunteers. 
The study protocol, documentation, data and all other information generated will be 
held in strict confidence. No information concerning the study or the data will be 
released to any unauthorized third party, without prior written approval of the sponsor. 
The study monitor or other authorized representatives of the sponsor may inspect all 
documents and records required to be maintained by the Investigator, including but 
not limited to, medical records (office, clinic or hospital) and pharmacy records for the 
participants in this study. The clinical study site will permit access to such records. 
The information provided by sponsor in this protocol and the associated Clinical 
Investigator's Brochure and the data generated by this clinical study are to be 
considered as confidential property of sponsor. 
11.4 
 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of 
persons who have a role in the design, conduct, analysis, publication, or any aspect of 
this trial will be disclosed and managed. Furthermore, persons who have a perceived 
conflict of interest will be required to have such conflicts managed in a way that is 
appropriate to their participation in the design and conduct of this trial. 


Study Protocol
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Careseng 1370 for Healthy Volunteers 
Version: 5.0 
 
(Protocol Number: Careseng 1370-01) 
Date: 18Sep2020 
 
 
 
 
 
 
 
 
 
 
12. 
PUBLICATIONS 
The data and information associated with this study may be used by sponsor now and 
in the future for the purposes of presentation, publication at discretion of sponsor or 
for submission to regulatory authority. In addition, relative to the release of any 
proprietary information, sponsor reserves the right of prior review of any publication 
or presentation of data from this study. 
In signing this protocol, the investigator agrees to the release of the data from this 
study and acknowledges the above publication policy. 
 


Study Protocol
Confidential
 
Careseng 1370 for Healthy Volunteers 
Version: 5.0 
 
(Protocol Number: Careseng 1370-01) 
Date: 18Sep2020 
 
 
 
 
 
 
 
 
 
 
13. 
RETENTION OF TRIAL DOCUMENTS 
Records for all participants, including CRFs, all source documentation (containing 
evidence to study eligibility, history and physical findings, laboratory data, results of 
consultations, etc.) as well as IRB records and other regulatory documentation should 
be retained by the PI in a secure storage facility. The records should be accessible for 
inspection and copying by authorized authorities.  
All study documentation at the clinical site and sponsor records will be archived in 
accordance with International Council for Harmonisation (ICH) Good Clinical 
Operation Procedures (SOP)s. Study records should not be destroyed without prior 
written agreement between sponsor or CRO and the study investigator. 
 
 


Study Protocol
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Careseng 1370 for Healthy Volunteers 
Version: 5.0 
 
(Protocol Number: Careseng 1370-01) 
Date: 18Sep2020 
 
 
 
 
 
 
 
 
 
 
14. 
PROTOCOL AMENDMENT HISTORY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Study Protocol
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Careseng 1370 for Healthy Volunteers 
Version: 5.0 
 
(Protocol Number: Careseng 1370-01) 
Date: 18Sep2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Study Protocol
Confidential
 
Careseng 1370 for Healthy Volunteers 
Version: 5.0 
 
(Protocol Number: Careseng 1370-01) 
Date: 18Sep2020 
 
 
 
 
 
 
 
 
 
 
15. 
REFERENCES 
1. 
Wen J., Zimmer E.A., Phylogeny and biogeography of Panax L. (the Ginseng genus, 
Araliaceae): inferences from its sequences of nuclear ribosomal DNA Mol. 
Phylogenetics Evol. 1996;167-177 
2. 
Li D., Cao J., Bi X., Xia X., Li W., Zhao Y., New dammarane-type triterpenoids from 
the leaves of Panax notoginseng and their protein tyrosine phosphatase 1B inhibitory 
activity J Ginseng Res. 2014 Jan; 38(1): 28 33. 
3. 
Guo H.B., Cui X.M., An N., Cai G.P., Sanchi ginseng (Panax notoginseng (Burk.) F.H. 
Chen) in China: distribution, cultivation and variations Genet. Resour. Crop Evol., 
2010;57, 453-460. 
4. 
Committee for the pharmacopoeia of China Pharmacopoeia of China, Part I, China 
Medical Science And Technology Press., Beijing (2010). 
5. 
Sun S., Wang C.Z., Tong R., Li X.L., Fishbein A., Wang Q., He T.C., Du W., Yuan 
C.S., Effects of steaming the root of Panax notoginseng on chemical composition and 
anticancer activities Food Chem., 2010;118:307-314. 
6. 
Zhao G.R., Xiang Z.J., Ye T.X., Yuan Y.J.,.Guo Z.X Antioxidant activities of Salvia 
miltiorrhiza and Panax notoginseng Food Chem., 2006:99; 767-774. 
7. 
Shi, J.P., Lu, J.Z., Liu, R.X., Guo, J.W., Deng, Z.J., Li, L.M.,. Analysis on dosage form 
and technology of Chinese patent medicine containing Panax notoginseng in Chinese 
pharmacopoeia (2010 edition). Pharmacy Today 2012; 22:392 394. 
8. 
Jiang B.H., Zhao Y. Q., Sun J.J., Zhao Y., Hu X.M., Liu L. Enzymatic transformation of 
Panax notoginseng stem and leaves for preparation anti-tumor activity constituents 
BTAIJ, 10(5), 2014;1066-1073. 
9. 
Wang R.F., Li J. Hu H.J., Li J. Yang Y.B., Yang L., Wang Z.T. Chemical transformation 
and target preparation of saponins in stems and leaves of Panax notoginseng. J Ginseng 
Res (2016) 1-7. 
10. 
Wang C.Z., Luo X.J., Zhang B., Song W.X., Ni M., Mehendale S., Xie J.T., Aung H.H., 
He T.C., Yuan C.S., Notoginseng enhances anti-cancer effect of 5-fluorouracil on human 
colorectal cancer cells. Cancer Chemother Pharmacol. 2007;60(1):69-79. 
11. 
Study Report. Drug Development of DS1370 on Myelosuppression Attenuation that 
Induced by Chemotherapy II. Institute of Pharmaceutics, Natural Resource 
Development, Development Center for Biotechnology, Taiwan. Study 
No.:CBC0606102; Report Date: Oct 31, 2017. 
12. 
Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials. United States Department of 
Health and Human Services, Food and Drug Administration, Center for Biologics 
Evaluation and Research. September 2007. (Appendix 1) 
 


Study Protocol
Confidential
 
Careseng 1370 for Healthy Volunteers 
Version: 5.0 
 
(Protocol Number: Careseng 1370-01) 
Date: 18Sep2020 
 
 
 
 
 
 
 
 
 
 
16. 
APPENDIX   
 
 
 
 

SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol version: 5.0, 18SEP2020 
Sponsor: XXXXXXXXXXXXXXX. 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
Statistical Analysis Plan:  Mock-up Tables and Figures ............................................................................................... 1
Table of Contents .............................................................................................................................................................. 2
1
Statistical Changes from Study Protocol ............................................................................................................... 3
1.1
Visit Adjustment ............................................................................................................................................ 3
1.2
Analysis Populations ...................................................................................................................................... 3
1.3
Treatment Compliance .................................................................................................................................. 3
1.4
Pharmacokinetic Analysis ............................................................................................................................. 3
3
Protocol Versions and Protocol Amendments ...................................................................................................... 4
4
Mock-up Tables and Figures .................................................................................................................................. 5
Instructions and Abbreviations: ...................................................................................................................................... 6
14
TABLES and FIGURES ......................................................................................................................................... 8
14.1
DEMOGRAPHIC DATA AND BASELINE CHARACTERISTICS ....................................................... 8
 .......................................................................... 
 ...................................... 
 ............................................................................................................................... 
 .............................................. 
 ................................................................ 
 ...................................................................... 
14.2
EFFICACY DATA ...................................................................................................................................... 11
14.3
SAFETY DATA ........................................................................................................................................... 12
 ........................................................... 
 ............................................................................................... 
 ............................................................................................. 
 .................................................................................................. 
 .............................................................................................. 
 ........................................................................................................................... 
 ............................................................................................................... 
 ...................................................................................................... 
 


 
 
 
 
 
 
 
 
 
 
 
 
1 Statistical Changes from Study Protocol  
 
 
 
1.1 Visit Adjustment 
 
1.2 Analysis Populations 
 
 
 
 
 
 
 
 
 
 
1.3 Treatment Compliance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.4 Pharmacokinetic Analysis 
 
 
 
2 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
3 Protocol Versions and Protocol Amendments 
 
Summary of important statistical-related changes for protocol version V4.0 
Additional time points for PK blood sampling for Dose level B and C 
 
Summary of important statistical-related changes for protocol version V5.0 
Addition of 1 lower dose cohort (level D), and the corresponding information 
 


 
 
 
 
 
 
 
 
 
 
 
 
4 Mock-up Tables and Figures 
The Mock-up 
 and 
 is planned according to ICH E3, in which relevant 
CSR section is 14. The words shadowed below are to be adjusted or repeated upon real data, or 
just for notification.  
 
Columns {Label, Dose Level} will be included in the table with the analyzed population 
specified. In the mock table below, only the Label with one dose level column were presented 
to show the descriptive/inferential statistics to be displayed in the final tabulation. 
 


 
 
 
 
 
 
 
 
 
 
 
 
Instructions and Abbreviations:
(1) Site ID C :  
 
 
 
 
 
(2) Dose Level: 
- A (1 sachet/day): Careseng 1370 1 sachet before breakfast for consecutive 5 days  
- B (2 sachets/day): Careseng 1370 1 sachet before breakfast and 1 sachet before lunch for consecutive 5 days 
- C (3 sachets/day): Careseng 1370 1 sachet before breakfast and 2 sachets before lunch for consecutive 5 days 
- D (1 sachet/day): Careseng 1370 1 sachet before breakfast on 1st, 3rd and 5th days (modified cohort) 
 
(3) Population 
 
 
- 
 
 Maximum Tolerated Dose
 
- 
 
- 
 
 
(4) For Visit Name (in Tables and Figures) and Visit Code (in Subject Data Listing): 
isit No. 
Visit Description 
Visit Day
Visit Name 
Visit Code 
1 
 
 
 
V01 
2 
 
 
 
V02D01 
3 
 
 
 
V03D02 
4 
 
 
 
V04D03 
5 
Visit 5: Day 4 
 
 
V05D04 
6 
Visit 6 Hospitalization: Day 4 to Day 5  
 
Visit 6 (Day 5) 
V06D05 
7 
Visit 7 Discharge: Day 6 
(24 2 hrs post-last dose) 
 
Visit 7 (Day 6) 
V07D06 
8 
Visit 8 Follow-up Visit: Day 7  
(48 2 hrs post-last dose)  
 
Visit 8 (Day 7) 
V08D07 
9 
Visit 9 Follow-up Visit: Day 8  
(72 2 hrs post-last dose)  
 
Visit 9 (Day 8) 
V09D08 
10 
Visit 10 Follow-up Visit: Day 12±2  
 
Visit 10 (Day 12) 
V10D12 
11 
Visit 11 Final Visit 
(Day 22±2, within 3 days after withdrawal) 
 
Visit 11 (Day 22) 
V11D22 
- 
Unscheduled Visit 
- 
 
.
 
 
(5) 
 
 
 
 
<To be added upon real data in final tabulation> 
 
(6) For clinical relevance 
 
 
LLN: lower limit of normal range 
ULN: upper limit of normal range 
 
(7) For Transition of Clinical Relevance 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
(8) Abbreviations of statistics 
N: number of non-missing values 
Missing: number of missing values  
Mean: mean of values 
SD: standard deviation of values 
Q1: 25% quartile of values 
Q3: 75% quartile of values 
Median: median of values 
IQR: inter-quartile-range (IQR=Q3-Q1) 
Min: minimum of values 
Max: maximum of values 
CI: confidence interval 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
14 
 
 
 
 
 
 
 
 
 
14.1 
 
14.1.1 
 
Population: All Screened Subjects / Eligible Subjects 
Characteristics 
Study Site 
 
 
 
 
.All Screened Subjects 
 
 
n 
XXX 
 
Eligible Subjects 
XXX (XXX.X%) 
 
Screening Failures 
<Screen Failure Reason 1> 
<Screen Failure Reason 2> 
<Screen Failure Reason 3> 
 
XXX (XXX.X%) 
XXX (XXX.X%) 
XXX (XXX.X%) 
XXX (XXX.X%) 
XXX (XXX.X%) 
 
 
 
 
.Population of Eligible Subjects 
 
 
n 
XXX 
 
ITT 
XXX (XXX.X%) 
 
MTD-Evaluable 
Non-MTD-Evaluable 
XXX (XXX.X%) 
XXX (XXX.X%) 
 
<Reason 1>  
<Reason 2> 
... 
XXX (XXX.X%) 
XXX (XXX.X%) 
XXX (XXX.X%) 
 
Non-ITT 
XXX (XXX.X%) 
 
 
 
 
.Dose Level of Eligible Subjects 
 
 
n 
XXX 
 
A (1 sachet/day) 
XXX (XXX.X%) 
 
B (2 sachets/day) 
XXX (XXX.X%) 
 
C (3 sachets/day) 
XXX (XXX.X%) 
 
D (1 sachet/day) 
XXX (XXX.X%) 
 
 
 
 
. Protocol Deviation of Eligible Subjects 
 
 
n 
XXX 
 
Major Protocol Deviation  
XXX (XXX.X%) 
 
<Protocol Deviation 1>  
<Protocol Deviation 2> 
... 
XXX (XXX.X%) 
XXX (XXX.X%) 
 
Minor Protocol Deviation  
XXX (XXX.X%) 
 
<Protocol Deviation 1>  
<Protocol Deviation 2> 
... 
XXX (XXX.X%) 
XXX (XXX.X%) 
... 
 
 
 
 
ITT: Intent-to-Treat population, MTD-Evaluable: Maximum Tolerated Dose-Evaluable Population (subset of 
ITT) 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
14.1.2 
 
Population: Intent-to-Treat Population 
Characteristics 
Dose Level 
 
. Study Termination  
 
 
n 
XXX 
 
Study Completed 
XXX (XXX.X%) 
 
Study Not Completed 
Withdrew consent 
Protocol issue  
 
XXX (XXX.X%) 
XXX (XXX.X%) 
XXX (XXX.X%) 
XXX (XXX.X%) 
 
 
 
 
. Study Duration [days] 
 
 
n (Missing)  
Mean (SD) 
Median (IQR) 
Q1~Q3 
Min~Max 
XXX 
XXX (XXX) 
XXX (XXX) 
XXX~XXX 
XXX~XXX 
 
 
 
 
.Population 
 
 
n 
XXX 
 
MTD-Evaluable
Non-MTD-Evaluable 
XXX (XXX.X%)
XXX (XXX.X%) 
<Reason 1>  
<Reason 2> 
... 
XXX (XXX.X%) 
XXX (XXX.X%) 
XXX (XXX.X%) 
 
 
 
 
.Protocol Deviation 
 
 
n 
XXX 
 
Major Protocol Deviation  
XXX (XXX.X%) 
 
<Protocol Deviation 1>  
<Protocol Deviation 2> 
... 
XXX (XXX.X%) 
XXX (XXX.X%) 
 
Minor Protocol Deviation  
XXX (XXX.X%) 
 
<Protocol Deviation 1>  
<Protocol Deviation 2> 
... 
XXX (XXX.X%) 
XXX (XXX.X%) 
... 
 
 
 
 
. Study Visits Completed, Adjusted Visits Completed 
 
 
N 
XXX 
 
Visit 1 (Screening)
Visit 2 (Day 1) 
Visit 3 (Day 2) 
Visit 4 (Day 3) 
Visit 5 (Day 4) 
Visit 6 (Day 5) 
Visit 7 (Day 6) 
Visit 8 (Day 7) 
Visit 9 (Day 8) 
Visit 10 (Day 12) 
Visit 11 (Day 22) 
XXX (XXX.X%)
XXX (XXX.X%) 
XXX (XXX.X%) 
XXX (XXX.X%) 
XXX (XXX.X%) 
XXX (XXX.X%) 
XXX (XXX.X%) 
XXX (XXX.X%) 
XXX (XXX.X%) 
XXX (XXX.X%) 
XXX (XXX.X%) 
 
 
 
 
Study Duration [days] = Date of Termination - Visit 1, or alternatively as the last visit date - Visit 1
Adjusted Visits Completed: Visits except visit 8 and visit 9 not in its visit window are shifted to corresponding 
scheduled visits 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
14.1.3 
 
Population: Intent-to-Treat Population 
Characteristics 
Dose Level 
 
. Study Sites 
 
 
n (Missing)  
XXX (XXX) 
 
Site 1: TMUH 
XXX (XXX.X%) 
 
 
 
 
. Variable, including Age [Y/O], Baseline Body Weight [kg], Height 
[cm], BMI [kg/m^2] 
 
 
n (Missing)  
Mean (SD) 
Median (IQR) 
Q1~Q3 
Min~Max 
XXX (XXX) 
XXX (XXX) 
XXX (XXX) 
XXX~XXX 
XXX~XXX 
 
 
 
 
. Gender 
 
 
n (Missing)  
XXX (XXX) 
 
Male  
Female 
XXX (XXX.X%) 
XXX (XXX.X%) 
 
 
 
 
. Race (multiple selection) 
 
 
n (Missing)  
XXX (XXX) 
 
Black or African American 
American Indian or Alaska Native 
Asian 
Native Hawaiian or Other Pacific Islander 
White 
Not Reported 
Unknown 
XXX (XXX.X%) 
XXX (XXX.X%) 
XXX (XXX.X%) 
XXX (XXX.X%) 
XXX (XXX.X%) 
XXX (XXX.X%) 
XXX (XXX.X%) 
 
 
 
 
Age [Y/O] = int((date of informed consent  date of birth)/365.25) 
BMI [kg/m^2]= Weight [kg] / (Height [cm])^2 * 10000 
Baseline is Visit 2 or alternatively as Visit 1 if Visit 2 data is not available 
 
14.1.4 
 
Population: Intent-to-Treat Population  
Characteristics 
Dose Level 
 
.General Medical History 
 
 
n 
XXX 
 
At least one below 
XXX (XXX.X%) 
 
<Body System 1> 
<Body System 2> 
<Body System 3> 
<Body System 4> 
 
XXX (XXX.X%) 
XXX (XXX.X%) 
XXX (XXX.X%) 
XXX (XXX.X%) 
 
 
 
 
 
. Current Condition 
 
 
n 
XXX 
 
At least one below 
XXX (XXX.X%) 
 
<Body System 1> 
<Body System 2> 
<Body System 3> 
<Body System 4> 
 
XXX (XXX.X%) 
XXX (XXX.X%) 
XXX (XXX.X%) 
XXX (XXX.X%) 
 
 
 
 
 
. Chest X-Ray 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
Characteristics 
Dose Level 
 
n (Missing)  
Normal 
NCS 
CS (Medical History) 
CS (Adverse Event) 
Not Interpretable 
XXX (XXX) 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
 
 
 
 
visit 2 
 
14.1.5 
 
 
Population: Intent-to-Treat Population 
Characteristics 
Dose Level 
 
. Prohibited Medications, Treatments, Procedures  
. Prohibited Foods 
n (Missing)  
XXX (XXX) 
 
At least one below 
XXX (XXX.X%) 
 
<Category 1> 
<Category 2> 
<Category 3> 
<Category 4> 
 
XXX (XXX.X%) 
XXX (XXX.X%) 
XXX (XXX.X%) 
XXX (XXX.X%) 
 
 
 
14.1.6 
 
Population: Intent-to-Treat Population 
Characteristics 
Dose Level 
 
Total IP Administration [sachets],  
Treatment Duration [days]  
Treatment Compliance [%],  
Mean Daily Dose [sachet/day]  
 
 
n (Missing)  
Mean (SD)    
Median (IQR) 
Q1~Q3        
Min~Max      
 
XXX 
XXX (XXX) 
XXX (XXX) 
XXX~XXX 
XXX~XXX 
 
. Treatment Compliance 
 
 
n (Missing)  
XXX (XXX) 
 
<60% 
60 ~ <80% 
80 ~ <100% 
100 ~ <120% 
0% 
XXX (XXX.X%) 
XXX (XXX.X%) 
XXX (XXX.X%) 
XXX (XXX.X%) 
XXX (XXX.X%) 
 
 Treatment Duration [days] = the last dosing date - the first dosing date + 1. 
 Treatment Compliance [%] = Total IP Administration [sachets] / Dose Level [sachet/day] / Treatment 
Duration [days] * 100% 
 Mean Daily Dose [sachet/day] = Total IP Administration [sachets] / Treatment Duration [days] 
14.2 
 
N/A 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
14.3 
 
 
 
Adjusted Visit 
Laboratory 
Assessment  
Physical 
Examination 
Body Weight 
Vital Signs 
12-Lead 
Electrocardiogram 
Baseline 
N 
Baseline is Visit 1 
(Screening), no need 
to present statistics 
for Baseline 
additionally 
N. 
Y 
Baseline is Day 
1 , or 
alternatively as 
Visit 1 if Day 1 
data are not 
available. 
Y 
Baseline is Day 1 
Pre-dose, or 
alternatively as Visit 
1 if Day 1 Pre-dose 
data are not 
available. 
Y 
Baseline is Day 1 Pre-
dose, or alternatively as 
Visit 1 if Day 1 Pre-dose 
data are not available. 
Visit 1 
(Screening) 
Y 
Y 
Y 
Y 
Y 
Visit 2 (Day 1) 
Y 
(8 hours post-first 
dose) 
Y 
(Pre-dose),  
(8 hours post-
first dose) 
Y 
  
Y 
(Pre-dose),  
(1 hour post-first 
dose),  
(4 hours post-first 
dose), 
(8 hours post-first 
dose) 
Y 
(Pre-dose),  
(1 hour post-first dose),  
(4 hours post-first dose), 
(8 hours post-first dose), 
(12 hours post-first dose)
Visit 3 (Day 2) 
Y 
Y 
Y 
Y 
Y 
(Pre-dose),  
(1 hour post-first dosing 
post-first dosing ) 
Visit 4 (Day 3) 
Y 
Y 
Y 
Y 
Y 
(Pre-dose),  
(1 hour post-first 
dosing ) 
Visit 5 (Day 4) 
Y 
Y 
Y 
Y 
Y 
(Pre-dose),  
(1 hour post-first 
dosing ) 
Visit 6 (Day 5) 
Y 
(Pre-dose),  
(4 hours post dosing)
Y 
(Pre-dose),  
(4 hours post 
dosing) 
Y 
Y 
(Pre-dose),  
(4 hours post dosing) 
Y 
(Pre-dose),  
(1 hour post-first dose),  
(4 hours post-first dose), 
(8 hours post-first dose), 
(12 hours post-first dose)
Visit 7 (Day 6) 
Y 
Y 
Y 
Y 
Y 
Visit 8 (Day 7) 
N 
N 
N 
N 
N 
Visit 9 (Day 8) 
N 
N 
N 
N 
N 
Visit 10 (Day 12) 
Y  
Y 
Y 
Y 
Y  
Visit 11 (Day 22) 
Y 
Y 
Y 
Y 
Y 
Y denotes that the Visit is performed in the corresponding tables. 
N denotes that the Visit is not performed in the corresponding tables. 
3, 7, 11 only for immunology 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
14.3.1 
 
For 14.3.1.4, population will include ITT and MTD-Evaluable population. 
14.3.1.1 
 
Population: Intent-to-Treat Population / MTD-Evaluable Population 
Characteristics [Event#:Subj#] 
Treatment 
 
Repeat Population: Intent-to-Treat Population, MTD-Evaluable Population 
n 
XXX 
 
Subjects with AE 
Subjects with Treatment-Related AE 
Subjects with DLT 
 
Treatment-Related AE 
Subjects with AE Leading to Action Taken 
Subjects with AE Leading to Drug withdrawn 
Subjects with SAE 
Subjects with Death SAE 
Subjects with SUSAR 
Subjects with Death SUSAR 
XXX : XXX (XXX.X%) 
XXX : XXX (XXX.X%) 
XXX : XXX (XXX.X%) 
XXX : XXX (XXX.X%) 
XXX : XXX (XXX.X%) 
XXX : XXX (XXX.X%) 
XXX : XXX (XXX.X%) 
XXX : XXX (XXX.X%) 
XXX : XXX (XXX.X%) 
XXX : XXX (XXX.X%) 
XXX : XXX (XXX.X%) 
 
 
 
 
Subject with multiple events are counted as one incidence. 
Treatment-Related is defined as Definitely Related, Probable Related, or Possibly Related 
 
 
Repeat Population only when the two populations are not identical 
14.3.1.2 
 
14.3.1.3 
 
14.3.1.4 
 
[For 14.3.1.2-3] Population: Intent-to-Treat Population 
[For 14.3.1.4] Population: Intent-to-Treat Population / MTD-Evaluable Population 
Characteristics [Event#:Subj#] 
Dose Level 
 
Repeat Population: Intent-to-Treat Population, MTD-Evaluable Population (Applied for 
14.3.1.4) 
 
. By MedDRA SOC and Preferred Term 
 
 
n 
XXX 
 
At least one below  
 
<MedDRA Body System 1> 
<MedDRA Preferred Term 1> 
<MedDRA Preferred Term 2> 
<MedDRA Preferred Term 3> 
 
 
<MedDRA Body System 2> 
<MedDRA Preferred Term 1> 
<MedDRA Preferred Term 2> 
<MedDRA Preferred Term 3> 
 
XXX : XXX (XXX.X%) 
 
XXX : XXX (XXX.X%) 
XXX : XXX (XXX.X%) 
XXX : XXX (XXX.X%) 
XXX : XXX (XXX.X%) 
XXX : XXX (XXX.X%) 
 
XXX : XXX (XXX.X%) 
XXX : XXX (XXX.X%) 
XXX : XXX (XXX.X%) 
XXX : XXX (XXX.X%) 
 
For each MedDRA (version 23.0) SOC or Preferred Term, Subject with multiple events are counted as one 
incidence. 
[For 14.3.1.3] Treatment-Related is defined as Definitely Related, Probable Related, or Possibly Related 
 
 
Repeat Population only when the two populations are not identical 
Sorted in descending order of Subject No, Event No. of Total column by MedDRA Body System first, and then MedDRA 
Preferred Term. 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
14.3.1.5 
 
14.3.1.6 
 
Population: Intent-to-Treat Population 
Characteristics [Event#:Subj#] 
Dose Level 
 
. By Severity Grade, MedDRA SOC and Preferred Term 
 
 
n 
XXX 
 
At least one below 
 
Grade 4, Grade 5 
<MedDRA Body System 1> 
<MedDRA Preferred Term 1> 
<MedDRA Preferred Term 2> 
 <MedDRA Preferred Term 3> 
 
 
<MedDRA Body System 2> 
<MedDRA Preferred Term 1> 
<MedDRA Preferred Term 2> 
 <MedDRA Preferred Term 3> 
 
XXX : XXX (XXX.X%) 
 
XXX : XXX (XXX.X%) 
XXX : XXX (XXX.X%) 
XXX : XXX (XXX.X%) 
XXX : XXX (XXX.X%) 
XXX : XXX (XXX.X%) 
XXX : XXX (XXX.X%) 
 
XXX : XXX (XXX.X%) 
XXX : XXX (XXX.X%) 
XXX : XXX (XXX.X%) 
XXX : XXX (XXX.X%) 
 
[For 14.3.1.6] Treatment Related is defined as Definitely Related, Probable Related, or Possibly Related 
 
 Notes: 
Sorted in descending order of Subject No, Event No. of Total column by MedDRA Body System first, and then MedDRA 
Preferred Term for each Grade Level 
 
14.3.1.7 
 
Population: Intent-to-Treat Population 
Characteristics [Event#:Subj#] 
Dose Level 
 
. By Action Taken, MedDRA SOC and Preferred Term 
 
 
n 
XXX 
 
At least one below 
 
Drug interrupted, Drug withdrawn 
<MedDRA Body System 1> 
<MedDRA Preferred Term 1> 
<MedDRA Preferred Term 2> 
 <MedDRA Preferred Term 3> 
 
<MedDRA Body System 2> 
<MedDRA Preferred Term 1> 
<MedDRA Preferred Term 2> 
 <MedDRA Preferred Term 3> 
 
XXX : XXX (XXX.X%) 
 
XXX : XXX (XXX.X%) 
XXX : XXX (XXX.X%) 
XXX : XXX (XXX.X%) 
XXX : XXX (XXX.X%) 
XXX : XXX (XXX.X%) 
 
XXX : XXX (XXX.X%) 
XXX : XXX (XXX.X%) 
XXX : XXX (XXX.X%) 
XXX : XXX (XXX.X%) 
 
 
 
 
 
 
 Notes: 
Sorted in descending order of Subject No, Event No. of Total column by Action Taken first, then MedDRA Body System, 
and then MedDRA Preferred Term 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
14.3.1.8 
 
14.3.1.9 
 
 
Population: Intent-to-Treat Population 
Characteristics [Event#:Subj#] 
Dose Level 
 
. By SAE Criteria, MedDRA SOC and Preferred Term 
 
 
n 
XXX 
 
At least one below 
 
<SAE Criterion> 
<MedDRA Body System 1> 
<MedDRA Preferred Term 1> 
<MedDRA Preferred Term 2> 
 <MedDRA Preferred Term 3> 
 
<MedDRA Body System 2> 
<MedDRA Preferred Term 1> 
<MedDRA Preferred Term 2> 
 <MedDRA Preferred Term 3> 
 
XXX : XXX (XXX.X%) 
 
XXX : XXX (XXX.X%) 
 
XXX : XXX (XXX.X%) 
XXX : XXX (XXX.X%) 
XXX : XXX (XXX.X%) 
XXX : XXX (XXX.X%) 
 
XXX : XXX (XXX.X%) 
XXX : XXX (XXX.X%) 
XXX : XXX (XXX.X%) 
XXX : XXX (XXX.X%) 
 
 
 
 
SAE Criteria 'F/L/H' and 'F/L' will be counted as 'F' only, and 'L/H' as 'L', where F=Fatal (Death), L=Life 
threatening, H=Require hospitalization or prolongation of existing hospitalization. 
 
Program
 Notes: 
 
Sorted in descending order of Subject No, Event No. of Total column by SAE Criterion, MedDRA Body System, and 
MedDRA Preferred Term 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
14.3.2 
 
14.3.2.1 
 
14.3.2.2 
 
14.3.2.3 
 
14.3.2.4 
 
14.3.3 
 
14.3.3.1 
 
14.3.3.2 
 
14.3.3.3 
 
14.3.3.4 
 
14.3.4 
 
14.3.4.1 
 
14.3.4.2 
 
14.3.4.3 
 
14.3.4.4 
 
14.3.4.5 
 
for analysis. 
 
14.3.5 
 
14.3.5.1 
 
14.3.5.2 
 
14.3.5.3 
 
14.3.5.4 
 
14.3.5.5 
 
14.3.5.6 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
<For continuous Laboratory Examination > 
Population: Intent-to-Treat Population 
Characteristics 
Dose Level 
 
 
. (Adjusted) Visits, see visit table below 14.3 
 
 
 
n (Missing)  
Mean (SD) 
Median (IQR) 
Q1~Q3 
Min~Max  
XXX (XXX) 
XXX (XXX) 
XXX (XXX) 
XXX~XXX 
XXX~XXX 
 
 
 
n (Missing)  
Normal 
NCS 
CS (Medical History) 
CS (Adverse Event) 
XXX (XXX) 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%  
XXX (XX.X%) 
 
 
. (Adjusted) Visits - Baseline, see visit table below 14.3 
n (Missing)  
Mean (SD) 
Median (IQR) 
Q1~Q3 
Min~Max  
 
95% CI (WI) 
XXX (XXX) 
XXX (XXX) 
XXX (XXX) 
XXX~XXX 
XXX~XXX 
 
XXX~XXXwt 
 
 
 
. Baseline to (Adjusted) Visits, see visit table below 14.3 
n (Missing)  
Relieved 
Unchanged 
Worsened (Medical History) 
Worsened (Adverse Event) 
XXX (XXX) 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
 
 
 
 
For CI (WI, within group), t denotes by using one sample t-test, w denotes CI of median (determined by 
Shapiro-Wilk normality test) 
 
Refer to [Instructions and Abbreviations] of title pages for Transition of Clinical Relevance 
 
 
(Screening). 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
<For categorical urinalysis data> 
Population: Intent-to-Treat Population 
Characteristics 
Dose Level 
 
. (Adjusted) Visits, see visit table below 14.3 
 
 
 
n (Missing)  
<Value 1> 
<Value 2> 
<Value 3> 
XXX (XXX) 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
 
 
n (Missing)  
Normal 
NCS 
CS (Medical History) 
CS (Adverse Event) 
 
XXX (XXX) 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%  
XXX (XX.X%) 
 
 
 
 
Baseline to (Adjusted) Visits, see visit table below 14.3 
 
 
n (Missing)  
<Value 1> 
<Value 2> 
<Value 3> 
XXX (XXX) 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
 
 
 
 
Baseline to (Adjusted) Visits, see visit table below 14.3 
 
 
n (Missing)  
Relieved 
Unchanged 
Worsened (Medical History) 
Worsened (Adverse Event) 
XXX (XXX) 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
 
 
 
Refer to [Instructions and Abbreviations] of title pages for Transition of Clinical Relevance 
 
 
 
 
  


 
 
 
 
 
 
 
 
 
 
 
 
14.3.6 
 
14.3.6.1 
 
Population: Intent-to-Treat Population  
Characteristics 
Dose Level 
 
. (Adjusted) Visits, see visit table below 14.3 
n (Missing)  
XXX (XXX) 
 
At least one below 
XXX (XXX.X%) 
 
<Body System 1> 
CS (Medical History) 
CS (Adverse Event) 
 
<Body System 2> 
CS (Medical History) 
CS (Adverse Event) 
 
<Body System 3> 
CS (Medical History) 
CS (Adverse Event) 
 
XXX (XXX.X%) 
XXX (XXX.X%) 
XXX (XXX.X%) 
 
XXX (XXX.X%) 
XXX (XXX.X%) 
XXX (XXX.X%) 
 
XXX (XXX.X%) 
XXX (XXX.X%) 
XXX (XXX.X%) 
 
 
 
 
 
 
14.3.7 
 
14.3.7.1 
 
14.3.7.2 
 
14.3.7.3 
 
14.3.7.4 
 
14.3.7.5 
 
14.3.7.6 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
14.3.8 
 
14.3.8.1 
Population: Intent-to-Treat Population 
Characteristics 
Dose Level 
 
. (Adjusted) Visits, see visit table below 14.3 
 
 
n (Missing) 
Normal 
NCS 
CS (Medical History) 
CS (Adverse Event) 
XXX (XXX) 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
 
 
 
 
. Baseline to (Adjusted) Visits, see visit table below 14.3 
 
 
n (Missing)  
Relieved 
Unchanged 
Worsened (Medical History) 
Worsened (Adverse Event) 
XXX (XXX) 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
 
 
 
 
 Baseline is Visit 2 (Day 1, Pre-dose) or alternatively as Visit 1 (Screening) if Visit 2 (Day 1, Pre-dose) 
data are not available. 
 Refer to [Instructions and Abbreviations] of title pages for Transition of Clinical Relevance 
14.3.8.2 
Population: Intent-to-Treat Population 
Characteristics 
Dose Level 
 
. (Adjusted) Visits, see visit table below 14.3 
 
 
n (Missing)  
Normal 
Abnormal 
XXX (XXX) 
XXX (XX.X%) 
XXX (XX.X%) 
 
 
 
 
. Baseline to (Adjusted) Visits, see visit table below 14.3 
 
 
n (Missing)  
Normal to Abnormal 
No Change 
Abnormal to Normal 
XXX (XXX) 
XXX (XX.X%) 
XXX (XX.X%) 
XXX (XX.X%) 
 
 
 
 
 Baseline is Visit 2 (Day 1, Pre-dose) or alternatively as Visit 1 (Screening) if Visit 2 (Day 1, Pre-dose) 
data are not available. 
14.3.8.3 
 
14.3.8.4 
 
14.3.8.5 
 
14.3.8.6 
 
14.3.8.7 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol version: 5.0, 18SEP2020 
Sponsor: XXXXXXXXXXXXXXXXX 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
The Mock-up Subject Data Listings  is planned according to ICH E3, in which relevant CSR 
section is 16.2. The words shadowed below are for notifications, or to be revised, or 
variables/format/footnotes to be included.  
 
All listing will be sorted by (1) Eligibility {Eligible subjects by dose level, Screen failures} (2) 
Subject ID (3) Visit No. (4) Item No.  
 
Instructions and Abbreviations:  
(1) 
C S S -D R R
C S S
 
 
 
 
Site ID C  
1 = 
 
Screening number S C S S  
Assigned sequentially from S C 01 for each site 
Dose Level D 
A = Careseng 1370 1 sachet before breakfast for consecutive 5 days 
B = Careseng 1370 1 sachet before breakfast and 1 sachet before 
lunch for consecutive 5 days 
C = Careseng 1370 1 sachet before breakfast and 2 sachets before 
lunch for consecutive 5 days 
Subject Number D R R : 
Assigned sequentially from D 01 for dose level D  for each site 
 
(2) 
 
D denotes dose level 
 
: 
 
 
B: Careseng 1370 1 sachet before breakfast and 1 sachet before lunch for consecutive 5 days 
 
C: Careseng 1370 1 sachet before breakfast and 2 sachets before lunch for consecutive 5 days 
 
D (1 sachet/day) (modified cohort): Careseng 1370 1 sachet before breakfast on 1st, 3rd and 5th days 
 
P denotes population 
 
 
I: intent-to-treat (ITT) population 
 
 
 
 Volunteers receive any Careseng 1370 
  
M: Maximum Tolerated Dose (MTD)-Evaluable Population, satisfying 
 
 
1. A subset of ITT population 
 
2. 
 
A denotes age in Y/O 
 
 
Age = int((date of informed consent  date of birth)/365.25) 
G denotes gender 
 
 
M: male 
 
 
F: female 
 
(3) 
YYYY-MM-DD 
 
(4) 
 
isit No. 
Visit Description 
Visit Day 
Visit Name 
Visit Code 
1 
 
 
 
V01 
2 
 
 
 
V02D01 
3 
 
 
 
V03D02 
4 
 
 
 
V04D03 
5 
Visit 5: Day 4 
 
 
V05D04 
6 
Visit 6 Hospitalization: Day 4 to Day 5  
 
Visit 6 (Day 5) 
V06D05 
7 
Visit 7 Discharge: Day 6 
(24±2 hrs post-last dose) 
 
Visit 7 (Day 6) 
V07D06 


 
 
 
 
 
 
 
 
 
 
 
 
isit No. 
Visit Description 
Visit Day 
Visit Name 
Visit Code 
8 
Visit 8 Follow-up Visit: Day 7  
(48±2 hrs post-last dose)  
 
Visit 8 (Day 7) 
V08D07 
9 
Visit 9 Follow-up Visit: Day 8  
(72±2 hrs post-last dose)  
 
Visit 9 (Day 8) 
V09D08 
10 
Visit 10 Follow-up Visit: Day 12±2  
 
Visit 10 (Day 12) 
V10D12 
11 
Visit 11 Final Visit 
(Day 22±2, within 3 days after withdrawal) 
 
Visit 11 (Day 22) 
V11D22 
- 
Unscheduled Visit 
- 
 
.
 
 
(5) 
For the visit/assessment days and hour (like AE Onset Day), they were derived by formula below  
Day/Hour = [visit/assessment date/time  the first treatment date/time + 1]
/time  
Day/Hour = [visit/assessment date/time  the first treatment date/time]
/time  
 
Duration in days/hours = [end date/time  onset date/time] if end date/time is inactive 
 
(6) Full term 
 
 
 
 
<To be added upon real data in final tabulation> 
 
(7) 
for
 
 Hematology 
 
 
 
 
 
Hemoglobin 
 
 
Hematocrit (Hct) 
 
 
RBC 
 
 
WBC 
 
 
Neutrophils 
 
 
Lymphocytes 
 
 
Monocytes 
 
 
Eosinophils 
 
 
Basophils 
NEUT 
 
Absolute neutrophil Count (ANC) 
LYM 
Lymphocytes 
Lymphocyte Count 
PLAT 
Platelets 
Platelet 
INR 
Prothrombin Intl. 
Normalized Ratio 
International normalized ratio (INR) 
APTT 
Activated Partial 
Thromboplastin Time 
Activated partial thromboplastin 
time (APTT) 
 
 
 
 
 
 
 
AST, SGOT 
 
 
ALT, SGPT 
 
 
Albumin 
 
 
Alkaline Phosphatase (ALP) 
 
 
Total bilirubin 
 
Creatinine 
Creatinine 
UREAN 
Urea Nitrogen 
Blood urea nitrogen (BUN) 
CRP 
C Reactive Protein 
C-reaction protein (CRP) 
 
 
Total protein 
 
 
Gamma-glutamyl transferase (
-
GT) 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Glucose 
Blood Glucose 
URATE 
Urate 
Uric Acid 
 
 
Total Cholesterol 
 
 
Triglyceride (TG) 
 
 
Sodium (Na) 
 
 
Potassium (K) 
 
 
Calcium (Ca) 
 
 
Magnesium 
 
 
Phosphorus 
 
 
Amylase 
LIPASET 
 
Lipase 
 
 
 
 
 
 
pH 
pH 
PROT 
Protein 
Protein 
RBC 
Erythrocytes 
RBC 
WBC 
Leukocytes 
WBC 
 
 
Casts 
 
 
 
 
 
 
 
CD3+ 
 
 
CD3+/CD4+ 
 
 
CD3+/CD8+ 
 
 
CD19+ 
 
 
CD16+/CD56+ 
 
 
CD4/CD8 Ratio 
 
(8) 
Serial
 
 
 
 
 
 
 
 
 
 
(9) 
For clinical relevance,  
 
 
 
 
 
(10) 
General abbreviations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
16.2 
 
16.2.1 
 
16.2.1.1 
 
 
16.2.1.2 
 
 
 
 
 
 
16.2.1.3 
 
 
16.2.1.4 
 
 
16.2.1.5 
 
 
16.2.1.6 
 
 
16.2.2 
 
16.2.2.1 
 
 
16.2.2.2 
 
 
 
 
16.2.2.3 
 
 
16.2.3 
 
16.2.3.1 
 
16.2.3.2 
 
 
16.2.4 
 
16.2.4.1 
 
 
16.2.4.2 
 
 
 
16.2.4.3 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
16.2.5 
 
 
16.2.5.1 
 
16.2.5.2 
 
 
16.2.6 
 
16.2.6.1 
 
 
 
16.2.6.2 
 
 
16.2.7 
 
16.2.7.1 
 
16.2.7.2 
 
 
 
 
 
 
 
 
 
 
16.2.7.3 
 
 
16.2.7.4 
 
16.2.7.5 
 
16.2.7.6 
 
16.2.7.7 
 
16.2.7.8 
 
16.2.7.9 
 
(Unexpected Treatment Related SAE) 
 
16.2.8 
 
16.2.8.1 
 
16.2.8.2 
 
16.2.8.3 
 
16.2.8.4 
 
16.2.8.5 
 
16.2.8.6 
 


 
 
 
 
 
 
 
 
 
 
 
 
16.2.8.7 
 
 
 
16.2.9 
 
16.2.9.1 
 
16.2.9.2 
 
16.2.9.3 
 
16.2.9.4 
 
 
16.2.9.5 
 
 
16.2.10 
 
 
V02D01 Pre-Dose 
V06D05 Pre-Dose 
V07D06 24h 
V03D02 Pre-Dose 
V06D05 0.5h 
V08D07 48h 
V04D03 Pre-Dose 
V06D05 1h 
V09D08 72h 
V05D04 Pre-Dose 
V06D05 2h 
 
 
V06D05 4h 
 
 
V06D05 6h 
 
 
V06D05 12h 
 
 
16.2.10.1 
 
 
16.2.11 
 
16.2.11.1