Clinical trial NCT03020082
Conditions: Chronic Hepatitis C
Keywords: Danoprevir non-cirrhotic Chinese HCV G1 SVR12
Sponsor: Ascletis Pharmaceuticals Co., Ltd.
Start date: 2016-06-01; Completion date: 2017-05-01
Enrollment: 141 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of Ritonavir-boosted ASC08 (Danoprevir) in Combination with Peg-IFN and RBV in Treatment-Naive Non-Cirrhotic Patients Who Have Chronic Hepatitis Genotype 1.

Detailed description:

Arms: arm 1: Participants will receive Ritonavir- boosted Danoprevir 100mg/100mg BID in combination with subcutaneous injection of weekly peginterferon alfa-2a at 180 mcg and RBV administered orally 500mg (5 tablets)( body weight \<75Kg) BID, 600mg (6 tablets) BID body weight ≥75Kg for 12 weeks.
Interventions: intervention 1: Danoprevir intervention 2: Ritonavir intervention 3: peginterferon alfa-2a intervention 4: RBV
Intervention descriptions: intervention 1: Danoprevir (DNV)administered orally 100mg BID for 12 weeks; intervention 2: Ritonavir administered orally 100mg BID for 12 weeks; intervention 3: PEG-IFN abdominal or thigh subcutaneous injection, 180μg, once a week for 12 weeks; intervention 4: RBV administered orally 500mg (5 tablets)( body weight \<75Kg) BID, 600mg (6 tablets) BID body weight ≥75Kg, for 12 weeks.

Protocol documents:
Prot_001.pdf: 
Number：NCT03020082                             ID：ASC-DNVr-II/III-CTP-02 
 
A Multi-centered, Open Label, Phase III Study on 
Efficacy, Safety of Ritonavir-boosted ASC08 
(Danoprevir) in Combination With Peg-IFN and RBV 
in Treatment-Naive Non-Cirrhotic Patients Who 
Have Chronic Hepatitis Genotype 1 
 
 
Clinical Trial Protocol 
 
 
Principal Investigator: Prof. Wei Lai 
Leading site of clinical trial: Peking University People's Hospital 
 
Institution in charge of statistics: Peking University Clinical Research Institute 
 
Contract Research Organization: Shanghai Tigermed Consulting Co., Ltd. 
 
Sponsor: Ascletis Pharmaceuticals Co., Ltd. 
 
Study protocol version No.: 3.0 
Established: January 16, 2017 
 
 
 
 


Number：NCT03020082                             ID：ASC-DNVr-II/III-CTP-02 
I 
 
 
Confidentiality Statement 
The information contained in this trial protocol is confidential, and any 
information supplemented to this protocol is also confidential and is the property of 
the Ascletis Pharmaceuticals Co., Ltd.. The purpose of providing relevant information 
in this trial protocol is to use this information for an upcoming clinical trial funded by 
the Ascletis Pharmaceuticals Co., Ltd., which is hereby provided to investigators 
participating in this clinical trial in a confidential manner. The investigator may 
disclose the contents of the protocol to other participants of the clinical trial or the 
management personnel of the clinical trial institution and the Ethics Committee of the 
investigator with the same objective and subject to the following conditions: All the 
information should be used only when the Ascletis Pharmaceuticals Co., Ltd. 
authorizes the clinical study described in this protocol, and the contents of this 
protocol cannot be used for other clinical trials. Except for the information that shall 
be introduced to the subject in obtaining the informed consent, no information of this 
protocol shall be disclosed to any other individual or group without the prior written 
permission of the Ascletis Pharmaceuticals Co., Ltd.. 
 
 
 
 
 
 
 
 
 
 


Number：NCT03020082                             ID：ASC-DNVr-II/III-CTP-02 
II 
CONTENTS 
List of Abbreviations ......................................................................................................................... 1 
Protocol Synopsis .............................................................................................................................. 4 
1. research background ................................................................................................................... 12 
1.1 Clinical Need for Hepatitis C Treatment ............................................................................... 12 
1.2 Nonclinical Studies ............................................................................................................... 13 
1.3 Clinical Studies ..................................................................................................................... 16 
2. test purpose ................................................................................................................................. 20 
3. trial design ................................................................................................................................... 20 
3.1 Rationality ............................................................................................................................. 20 
3.2 Multicenter ............................................................................................................................ 30 
3.3 Number of cases .................................................................................................................... 30 
3.4 Study procedures ................................................................................................................... 31 
4. subjects ........................................................................................................................................ 31 
4.1 Inclusion Criteria ................................................................................................................... 31 
4.2 Exclusion criteria .................................................................................................................. 32 
4.3 Drop-out cases....................................................................................................................... 35 
4.4 Excluded cases ...................................................................................................................... 35 
4.5 Terminating the trial .............................................................................................................. 36 
4.6 Subject Management ............................................................................................................. 36 
5. investigational drugs ................................................................................................................... 38 
5.1 Drug Name and Strength ....................................................................................................... 38 
5.2 Concomitant Medications and Diet ....................................................................................... 38 
5.3 Drug Labeling ....................................................................................................................... 39 
5.4 Drug Storage ......................................................................................................................... 40 
5.5 Drug Dispensing and Recovery ............................................................................................ 40 
6. treatment regimen ....................................................................................................................... 40 
6.1 Dosage and Administration ................................................................................................... 40 
6.2 Dose Modifications ............................................................................................................... 41 
7. clinical observation items ............................................................................................................ 42 
7.1 Screening Period ................................................................................................................... 43 
7.2 Baseline ................................................................................................................................. 44 
7.3 Treatment Period ................................................................................................................... 44 
7.4 Post-Treatment Follow-up Period ......................................................................................... 45 
8. efficacy evaluation ...................................................................................................................... 45 
8.1 Primary evaluation indicators ............................................................................................... 45 
8.2 Secondary evaluation indicators ........................................................................................... 45 
9. safety evaluation ......................................................................................................................... 46 
9.1 Safety indicators .................................................................................................................... 46 
9.2 Adverse Events ...................................................................................................................... 46 
9.3 Non-Serious Adverse Events of Special Interest ................................................................... 49 
9.4 Serious Adverse Events ......................................................................................................... 50 
9.5 Handling of Adverse Events .................................................................................................. 51 


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10. data management and statistical analysis .................................................................................. 52 
10.1 Data Safety Monitoring Committee .................................................................................... 52 
10.2 Data Management ............................................................................................................... 52 
10.3 Statistical Analysis .............................................................................................................. 52 
11. risk control of clinical study ...................................................................................................... 55 
11.1 Main risks ............................................................................................................................ 55 
11.2 Risk control measures for clinical study ............................................................................. 55 
12. quality control and quality assurance of clinical trials .............................................................. 58 
12.1 Clinical Trial Site and Study Personnel............................................................................... 58 
12.2 Clinical Monitoring ............................................................................................................. 58 
12.3 Clinical Audits ..................................................................................................................... 58 
13. Ethics ......................................................................................................................................... 58 
13.1 Ethics Committee ................................................................................................................ 59 
13.2 Guidance on GCP ................................................................................................................ 59 
13.3 Informed Consent Form ...................................................................................................... 59 
13.4 Confidentiality of Subject Information ............................................................................... 59 
14. trial management ....................................................................................................................... 59 
14.1 Ethics Management ............................................................................................................. 59 
14.2 Training ............................................................................................................................... 60 
14.3 Protocol Deviations and Violations ..................................................................................... 60 
14.4 Data Tracking and Verification ........................................................................................... 61 
14.5 Replacement of Study Sites ................................................................................................ 62 
14.6 Study Termination and Closure ........................................................................................... 62 
15. Data storage and information use .............................................................................................. 62 
15.1 Storage of Materials ............................................................................................................ 62 
15.2 Use of Information .............................................................................................................. 63 
Main responsibilities assumed by all parties ................................................................................... 64 
16.1 Principal Investigator Responsibilities ................................................................................ 64 
16.2 Main Responsibilities of Sponsor ....................................................................................... 65 
17. Expected progress of the trial .................................................................................................... 66 
18. References ................................................................................................................................. 66 
Appendix 1 Liver Biopsy Scores .................................................................................................... 68 
Appendix 2 Dose Modification Principles ...................................................................................... 69 
Appendix 3 NCI CTCAE (v4.03) ................................................................................................... 71 
Appendix 4 Test Flow ..................................................................................................................... 80 
 
 
 
 
 
 


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List of Abbreviations 
Abbreviation 
Chinese name 
Abbreviation 
Chinese name 
AE 
Adverse events 
EO 
Acidophil 
AFP 
Alpha-fetoprotein 
EPO 
Erythropoietin 
ALB 
Albumin 
ERY 
Urine red blood cell 
ALT 
Alanine aminotransferase 
FAS 
Full Analysis Dataset 
ALP 
Alkaline phosphatase 
FBG 
Fasting plasma glucose 
AMA 
Antimitochondrial 
antibody 
FDA 
Food and Drug 
Administration 
ANA 
Antinuclear antibody 
Fg 
Fibrinogen 
ANC 
Absolute neutrophil count 
GCP 
Good Clinical Practice 
APTT 
Activated partial 
thromboplastin time 
G-CSF 
Granulocyte colony 
stimulating factor 
ASC08/r 
Ritonavir-fortified ASC08 
GI 
Gastrointestinal 
AST 
Aspartate aminotransferase 
GLU 
Glucose 
BASO 
Basophils 
Γ-GT 
Gamma-glutamyltransferase 
BMI 
Body mass index 
HB 
Hemoglobin 
BUN 
Urea nitrogen 
HbA1c 
Glycosylated hemoglobin 
CFDA 
China Food and Drug 
Administration 
HCV 
Hepatitis C Virus 
CHC 
Chronic hepatitis C 
HDL-c 
High density lipoprotein 
cholesterol 
CK 
Creatine kinase 
INR 
International normalized 
ratio 
Cr 
Creatinine 
LDH 
Lactate dehydrogenase 


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ECRF 
Electronic Case Report Form 
LDL-c 
Low-density lipoprotein 
cholesterol 
CTCAE 
Common Terminology 
Criteria for Adverse Events 
LEU 
Urine leukocyte 
DAA 
Direct antiviral drugs 
LLN 
Lower limit of normal 
DBIL 
Direct bilirubin 
LLOQ 
Lower limit of quantitation 
DC 
Differential leukocyte count 
LYMPH 
Lymphocyte 
DMC 
Data Safety Monitoring 
Board 
MONO 
Monocyte 
ECG 
Electrocardiogram 
NCI 
National Cancer Institute 
EMA 
European Medicines Agency 
NEUT 
Neutrophils 
Abbreviation 
Chinese name 
Abbreviation 
Chinese name 
NS 
Non-structural 
RVR 
Rapid virological response 
OATP 
Organic anion-
transporting polypeptide 
SAE 
Serious adverse event 
PEG-IFNα 
Pegylated interferon alfa 
SMA 
Anti-smooth muscle 
antibody 
PK 
Pharmacokinetics 
SS 
Safety data set 
PLT 
Platelets 
SVR 
Sustained virologic response 
PPS 
Per-Protocol Set 
TBIL 
Total bilirubin 
P/R 
PEG-IFNα/RBV 
TC 
Total cholesterol 
PRO 
Urine protein 
TG 
Triglyceride 
PT 
Prothrombin time 
TP 
Total protein 
RBC 
Red blood cell 
TPO 
Thrombopoietin 


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RBV 
Ribavirin 
TSH 
Thyroid-stimulating 
hormone 
Ret 
Reticulocyte 
UA 
Uric acid 
RGT 
Response-guided therapy 
ULN 
Upper limit of normal 
RTV 
Ritonavir 
WBC 
Leucocyte 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol Synopsis 
Test name 
A Multi-centered, Open Label, Phase III Study on Efficacy, 
Safety of Ritonavir-boosted ASC08 (Danoprevir) in Combination 
With Peg-IFN and RBV in Treatment-Naive Non-Cirrhotic Patients 
Who Have Chronic Hepatitis Genotype 1 
Sponsor 
Ascletis Pharmaceuticals Co., Ltd. 
Leading 
site 
of 
clinical trial 
Peking University People's Hospital 
Statistical unit 
Peking University Clinical Research Institute 
Contract 
Research 
Organization 
Shanghai Tigermed Consulting Co., Ltd 
Test objective 
Primary objective 
(1) To evaluate the rate of subjects achieving SVR12 after 12 
weeks of ASC08/r in combination with PEG-IFNα and RBV in 
treatment-naive non-cirrhotic subjects with chronic hepatitis C 
genotype 1 virus infection. 
(2) To evaluate the safety of ASC08/r combined with PEG-IFN
α and RBV in treatment-naive non-cirrhotic subjects with chronic 
hepatitis C genotype 1 virus infection. 
Secondary objectives 
(1) To evaluate the proportion of subjects achieving RVR4, 
SVR4, and SVR24; 
(2) To evaluate changes in virological response rates over time; 
(3) To evaluate the kinetics of viral load changes; 
(4) To evaluate the recurrence rate after combination therapy; 
(5) To evaluate the resistance characteristics of the virus to 


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ASC08. 
Test design 
Multi-center, open single-arm clinical study. 
Investigational 
drug 
Investigational drug: ASC08 tablets, 100 mg/tablet. 
Intensive drug: ritonavir tablets, 100 mg/tablet. 
Concomitant 
drugs 
Peginterferon alfa-2a Injection, 180 μg/0.5 mL; 
Ribavirin Tablets, 100 mg/tablet. 
Number of cases 
A total of 127 subjects were included. All included subjects 
entered the ASC08/r treatment group. 
Test Flow 
The subjects should receive the screening examination 
within 28 days before the start of drug treatment, and eligible 
subjects should be enrolled in this clinical study for treatment. 
During the treatment phase, subjects received a 12-week 
combination of ASC08/r + PEG-IFNα + RBV. 
All subjects were followed post-treatment for 24 weeks after 
the end of combination therapy. After treatment, the follow-up 
will be completed, and the subjects will be withdrawn from the 
study. 
Subject 
Selection 
Criteria 
Inclusion criteria 
(1) Aged 18 years and above, male or female; 
(2) Establish the diagnosis of CHC must meet one of the 
following conditions: (1) hepatitis C virus infection ≥ 6 months (6 
months ago anti-HCV antibody positive, or HCV RNA positive); (2). 
Liver tissue biopsy within 1 year before inclusion consistent with 
CHC pathological features. 
(3) Anti-HCV positive. 
(4) Serum HCV RNA ≥ 1.0 × 104 IU/mL; 
(5) HCV genotyping is genotype 1. 


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(6) Patients who have not received any interferon and/or other 
DAA treatment (regardless of the length of time); 
(7) Patients with non-cirrhosis; Non-cirrhosis is defined as: (1) 
Fibroscan value ≤ 9.6kPa during screening, or liver biopsy within 
1 year before inclusion confirmed as non-cirrhosis (Metavir score ≤ 
3 points); (2). 9.6 &lt; Fibroscan value ≤ 12.9 during screening, 
must be confirmed as non-cirrhotic by liver biopsy. 
(8) Patients who voluntarily sign the informed consent form; 
Exclusion Criteria 
(1) Patients with Fibroscan &gt; 12.9kPa, or patients with liver 
cirrhosis by histopathological examination; 
(2) Patients with previous or existing evidence of chronic liver 
disease caused by non-HCV (such as hemochromatosis, 
autoimmune liver disease, Wilson's disease, α1 antitrypsin 
deficiency, alcoholic liver disease, chronic drug-induced liver 
disease, etc.); 
(3) Patients with a history of hepatocellular carcinoma, or patients 
with suspected hepatocellular carcinoma before screening or 
screening, or patients with suspected hepatocellular carcinoma on 
color Doppler ultrasonography at screening, or AFP &gt; 50 ng/mL; 
(4) Anti-HAV (IgM), HBsAg, anti-HEV (IgM), anti-HIV one of the 
positive; 
(5) BMI &lt; 18 or ≥ 30 kg/m2; 
(6) ANC &lt; 1.5 × 109/L, PLT &lt; 100 × 109/L, HB &lt; 110 
g/L (female) or &lt; 120 g/L (male); INR &gt; 1.5; ALP ≥ 1.5 
times ULN; ALT or AST ≥ 5 times ULN; TBIL ≥ 2 times ULN 
(DBIL ≥ 35% TBIL); Cr ≥ 1.5 times ULN; TSH &gt; ULN or 
TSH &lt; LLN; 
(7) Patients who have or have had neurological and/or psychiatric 
psychiatric disorders, have poor self-control, and cannot express 


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their wishes with certainty; 
(8) Patients with obvious cardiovascular dysfunction, such as heart 
function grade III or above or score &lt; 50%; or patients with 
severe cardiovascular disease (such as ventricular tachyarrhythmia, 
myocardial infarction, angina pectoris, coronary artery disease or 
other serious cardiovascular disease); or patients with existing 
uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg 
and/or diastolic blood pressure ≥ 100 mmHg); or patients with 
obvious clinical abnormal ECG results; 
(9) Patients with severe acute or chronic respiratory or severe 
urinary system diseases; 
(10) Have received solid organ transplantation or corneal 
transplantation or bone marrow transplantation, or plan to receive 
organ transplantation during this clinical study; 
(11) Patients with autoimmune diseases (such as dermatomyositis, 
immune (congenital) thrombocytopenic purpura, inflammatory 
bowel disease, interstitial lung disease, interstitial nephritis, 
polymyositis, psoriasis, rheumatoid arthritis, sarcoidosis, systemic 
lupus erythematosus, etc.) (ANA &gt; 1:80 and/or AMA positive 
and/or SMA positive); 
(12) Patients with uncontrolled diabetes (HbA1c &gt; 7.0%) or 
thyroid disease (such as hypothyroidism, hyperthyroidism) and 
other endocrine system diseases, or fundus examination suggests 
the presence of clinically significant retinal diseases (such as retinal 
hemorrhage, cotton wool exudation spots, papilledema, optic 
neuropathy, retinal artery or vein occlusion, etc.); 
(13) Patients with severe hematologic diseases or at increased risk 
of anemia (e.g., thalassemia, sickle cell anemia, spherocytosis, 
history of gastrointestinal bleeding); 
(14) Patients with or suspected malignant tumors; 
(15) Patients with gastrointestinal disorders or postoperative 
diseases that may interfere with the absorption of investigational 
drugs or severe digestive system diseases that may interfere with 


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the absorption of investigational drugs; 
(16) Patients who are receiving or plan to receive hormone 
replacement therapy during clinical studies; 
(17) Patients who need to take the following drugs during clinical 
study: (1) liver enzyme CYP3A4 inducers (such as rifampicin, 
rifampicin, phenobarbital, phenytoin, carbamazepine) and CYP3A 
inhibitors (such as ketoconazole, voriconazole); (2). OATP 
inhibitors (e.g., cyclosporine, rifampicin) or substrates (e.g., 
rosuvastatin); III. Drugs with a narrow therapeutic window and 
extensively metabolized by CYP3A and/or substrates for p-
glycoprotein transporters (e.g., alfuzosin, astemizole, terfenadine, 
dihydroergotamine, ergometrine, ergotamine, methylergometrine, 
cisapride, pimozide, midazolam, triazolam, atorvastatin, lovastatin, 
simvastatin, fluticasone propionate); IV. Hormonal contraceptives; 
V. Probenecid and bile acid-binding resins; VI. Immunosuppressive 
drugs; VII. Have cytotoxic effects or chemotherapeutic agents; VIII. 
Antiarrhythmic drugs (e.g., amiodarone, bepristone, flecainide, 
propafenone, quinidine); IX. Corticosteroids (other than topical 
hydrocortisone and dexamethasone); X. PDE5 inhibitors (sildenafil, 
tadalafil, vardenafil). The above list of drugs does not contain all 
drugs that are contraindicated for concomitant use with ritonavir. 
For a complete list of contraindicated drugs, refer to the Ritonavir 
Tablets package insert. 
(18) Blood donation or blood loss more than 400 mL within 2 
months before inclusion; or received G-CSF, EPO, TPO within 6 
months before inclusion, or received blood transfusion within 6 
months before inclusion, or received other treatments with 
improved hematological parameters within 6 months before 
inclusion; 
(19) Allergic to test drugs (including RTV, PEG-IFN α, RBV), or 
have a history of multiple drug allergies, or have a history of 
specific reactions; 
(20) Women of childbearing age (18 years to 1 year after 


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menopause) who are pregnant, lactating and take effective 
contraceptive measures and maintain until at least 6 months after 
stopping the experimental drug treatment; 
(21) Male patients with female partners of childbearing potential 
who take effective contraceptive measures and maintain them for at 
least 6 months after stopping the treatment with the investigational 
drug; 
(22) Patients with a history of alcoholism, drug abuse or drug abuse 
within 6 months before enrollment that affects the evaluation of the 
test results; 
(23) Patients who participated in other clinical studies and received 
study drug treatment within 3 months before inclusion; 
(24) In addition to the above, patients who are not suitable for this 
clinical trial as judged by the investigator. 
Dosing Regimen 
(1) ASC08 Tablets 
Oral; 100 mg (1 tablet) twice daily for 12 weeks. 
(2) RTV 
Oral; 100 mg (1 tablet) twice daily for 12 weeks. 
(3) PEG-IFNα 
Subcutaneous injection in the abdomen or thigh; 180 μg (1 vial) once 
weekly for 12 weeks. 
(4) RBV 
Oral; weight &lt; 75 kg, 500 mg (5 tablets) twice daily, weight ≥ 75 
kg, 600 mg (6 tablets) twice daily; for 12 weeks. 
Clinical 
observation items 
Screening Period 
(1) Vital signs and physical examination. 
(2) BMI determination. 
(3) Laboratory tests: 
I. Blood routine examination; 
Urinalysis; 


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III. blood biochemical tests; 
IV. blood electrolyte examination; 
V. Coagulation test; 
VI. thyroid function tests. 
(4) HbA1c. 
(5) Immunological examination. 
(6) AFP. 
(7) Color Doppler ultrasound. 
(8) HAV, HBV, HEV and HIV detection. 
(9) Fundus examination. 
(10) Pregnancy test. 
(11) Electrocardiography. 
(12) IL28B and HCV genotyping assays. 
(13) HCV detection. 
(14) HCV RNA detection. 
(15) Examination for cirrhosis. 
(16) Drug resistance monitoring. 
Baseline 
(1) Vital signs and physical examination. 
(2) Laboratory tests. 
(3) HCV RNA detection. 
(4) Pregnancy test. 
(5) Electrocardiography. 


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(6) Drug resistance monitoring. 
Treatment period 
(1) Vital signs and physical examination. 
(2) Laboratory tests. 
(3) HCV RNA detection. 
(4) Pregnancy test. 
(5) Electrocardiography. 
(6) Drug resistance monitoring. 
Post-Treatment Follow-up Period 
Vital signs and physical examination, laboratory tests, HCV 
RNA testing, pregnancy test, electrocardiogram, and drug resistance 
monitoring were completed at each follow-up visit. 
Efficacy evaluation 
indicators 
Main evaluation indicators 
Rate of subjects achieving SVR12. 
Secondary evaluation indicators 
(1) Rate of subjects achieving RVR4. 
(2) Rate of subjects achieving SVR4. 
(3) Rate of subjects achieving SVR24. 
(4) Virological response rate at different visit times. 
(5) HCV RNA over time. 
(6) Recurrence rate. 
(7) Changes in viral resistance. 
Safety 
evaluation 
indicators 
(1) Adverse events observed by the investigator and reported by 
the subject during the study; 
(2) Clinically significant changes in vital signs before and after 


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treatment; 
(3) Clinically significant changes in laboratory values before and 
after treatment; 
(4) Changes in electrocardiogram before and after treatment. 
Statistical Analysis 
Measurement data will be described and mean, standard 
deviation, median, minimum and maximum will be calculated. 
Enumeration data were described using the number and percentage 
of cases in each category. 
All statistical tests were performed using the test, and a P value 
of less than 0.05 was considered to indicate a statistically significant 
difference. 
Estimated 
duration of trial 
The entire trial is expected to be completed within 15 months. 
 
 
 
 
1. research background 
1.1 Clinical Need for Hepatitis C Treatment 
The World Health Organization estimates that more than 170 million people 
(about 3% of the global population) are infected with hepatitis C virus (HCV) 
worldwide. HCV infection can not only lead to chronic hepatitis C (CHC), but also 
progress to cirrhosis, hepatocellular carcinoma and liver failure, ultimately leading to 
death. According to the annual incidence data published by the National Health and 
Family Planning Commission, the annual number of reported hepatitis C cases in 
China has exceeded 200,000 since 2012. Studies have shown that the viral gene 
infected by most CHC patients in China is type 1 (GT1). Hepatitis C has a low public 
awareness and is the notifiable disease with the highest missed diagnosis rate in 
China, with a missed diagnosis rate of 52%. The incidence of hepatitis C in China is 
very high, and the number of deaths has exceeded that of AIDS, avian influenza and a 


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variety of other infectious diseases, but hepatitis C has not received public attention, 
and only 2% of hepatitis C patients receive standardized treatment. 
At present, the main regimen for the treatment of CHC in China is pegylated 
interferon α (PEG-IFNα) combined with ribavirin (RBV), that is, P/R regimen. 
The course of treatment (48 weeks) with this P/R regimen for HCV GT1 infection 
was very significant, and the patient's tolerance was poor. In 2011, the Food and Drug 
Administration (FDA) approved two first-generation direct-acting antiviral drugs 
(DAAs) — boceprevir and telaprevir, both small molecule drugs that are new 
protease inhibitor drugs. Boceprevir and telaprevir are clinically used in combination 
with PEG-IFNα and RBV for the treatment of HCV GT1 infection. This therapy 
improves the proportion of treatment-naive and treatment-experienced patients 
achieving sustained virological response (SVR), but there are still conditions with 
long course of treatment, adverse drug reactions and no significant improvement in 
patient tolerance. In November and December 2013, the US FDA successively 
approved two second-generation DAA new drugs that can be used to treat HCV GT1 
infection — Simeprevir (protease inhibitor) and Sofosbuvir (polymerase inhibitor). 
Simeprevir and Sofosbuvir in combination with PEG-IFNα and RBV were applied 
to clinically treat treatment-naïve and treatment-experienced patients with CHC 
genotype 1, with further improvements in efficacy, course of treatment, and safety. 
However, to date, no new DAA drugs have been marketed in China. 
ASC08 tablet (Danoprevir tablet, DNV) belongs to the protease inhibitors in the 
second-generation DAA. ASC08 is a macrocyclic peptidomimetic compound that 
competitively inhibits the activity of HCV nonstructural (NS) protein gene 3/4 A 
protease, which plays a key role in HCV polypeptide post-translational modification 
and viral replication. The results showed that low-dose ASC08 (ASC08/r) fortified 
with low-dose ritonavir (RTV) had the characteristics of high antiviral activity, strong 
specificity, good pharmacokinetics (PK) and sustained virological response (SVR) 
and high safety. 
1.2 Nonclinical Studies 
1.2.1 Nonclinical Pharmacodynamics 
ASC08 is a potent and specific inhibitor that selectively inhibits HCV NS3/4A 
protease activity in HCV replicons and has a synergistic effect with PEG-IFNα and 
other direct antiviral drugs. ASC08 has unique in vitro kinetic properties and binds to 


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NS3/4A in two steps to form a stable complex. The low dissociation rate of this 
complex significantly improved the inhibitory activity of ASC08. 
ASC08 had a potent effect on HCV NS3/4A proteases isolated from HCV 
genotypes 1 to 6 in the sub- to nanomolar order. In transient replicon analysis, ASC08 
was less active than the Con1 reference against one genotype 2b isolate (&gt; 2000-
fold) and four genotype 3a isolates (372- to 3666-fold) containing NS3 protease from 
clinical isolates, but remained potent against two genotype 4a isolates (less than 2-fold 
EC50 transfer). 
In vitro, increased concentrations of ASC08 led to variants in HCV genotype 1b 
replicon with reduced susceptibility to ASC08: substitution of amino acid D168 in 
NS3 confers in vitro resistance to ASC08. At high concentrations, other substitutions 
were also observed, mostly at F43S, A156S, and A156V. The sensitivity of HCV 
replicons with other substitutions to ASC08 was significantly lower than that of 
replicons with only D168 substitution. Varying degrees of cross-resistance are also 
observed between different amino acid substitutions, resulting in reduced sensitivity 
to ASC08, or to other HCV protease inhibitors under investigation. 
1.2.2 Non-clinical kinetics 
PK assessment of oral or intravenous administration of ASC08 in rats and 
cynomolgus monkeys showed low (rat) to medium/high (monkey) total clearance, 
moderate volume of distribution, high protein binding (protein), and high liver-to-
plasma ratio, and no gender differences in PK parameters. 
After oral administration of 14C-ASC08 to rats, the highest level of radioactivity 
was observed in the liver. Elimination of radioactivity was rapid (primarily in bile) 
with only a few tissues containing quantifiable levels at 24 hours. 
ASC08 has low permeability and can bleed through P-glycoprotein, non-breast 
cancer resistance protein. It is also a substrate of organic anion transporting 
polypeptide (OATP) 1B1 and OATP1B3. 
In vitro, the ASC08 metabolite was similar across species. ASC08 is primarily 
metabolized by CYP3A4, and RTV improves pharmacokinetics primarily by 
inhibiting the formation of ASC08 metabolites. A number of hydroxyl metabolites are 
present in low amounts in human plasma. Co-administration of RTV can reduce its 
content below the detection limit. The human mass balance test confirmed that 
ASC08 was the predominant form present in plasma. When co-administered with 


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RTV, individual metabolite production in plasma did not exceed 10% of the total 
dose. 
In vitro, ASC08 was a weak inhibitor of CYP2C8, 2C9, and 3A4, and human 
multidrug resistance protein 1; it was a strong inhibitor of OATP1B1, OATP1B3, and 
UDP glucuronosyltransferase-1A1. ASC08 did not induce CYP1A2, 2B6, 2C9, or 
3A4 activity. ASC08 did not induce mRNA expression in the inducers of human 
multidrug resistance protein 1, rat multidrug resistance protein, or human hepatocyte 
UDP glucuronosyltransferase-1A1. 
1.2.3 Toxicology 
ASC08 was tolerated up to 2000 mg/kg (oral administration) in rats and 600 
mg/kg (oral administration) and 60 mg/kg (intravenous administration) in monkeys in 
a topical study. 
In the repeated-dose study, rats administered ASC08600 mg/kg/day died, and 
monkeys administered ASC08600 mg/kg/day showed persistent vomiting or/and 
diarrhea. Pregnant Animals: Rats given 800 mg/kg/day and rabbits (including non-
pregnant) given greater than 200 mg/kg/day developed toxic effects. 
After repeated dosing, the only clinically relevant local irritant toxicities 
observed in monkeys and rats were gastrointestinal (GI) side effects. Four monkeys 
were euthanized after gastrointestinal adverse reactions such as persistent vomiting 
or/and diarrhea occurred at doses greater than 300 mg/kg/day for 8 consecutive days. 
In monkeys, dose-limiting but reversible GI-related adverse effects were observed at 
doses greater than 200 mg/kg/day and included: periodic loose or soft stools and/or 
vomiting, decreased food consumption, decreased body weight with dehydration, and 
changes in serum electrolyte parameters. The GI adverse effects observed in monkeys 
at doses less than 150 mg/kg/day generally did not affect the overall clinical condition 
of this animal; chronic lesions occurred only in the study at 600 mg/kg/day for 6 
months with incomplete recovery after a 5-week recovery period. GI-related findings 
were likely due to local irritation of the dose and were not related to systemic 
exposure. The No observed adverse effect level (NOAEL) of GI adverse reactions 
after 6-month administration was 200 mg/kg/day in rats and 60 mg/kg/day in 
monkeys. The NOAEL for systemic effects from chronic gavage administration was 
150 mg/kg/day in the monkey toxicity study regardless of local GI irritation due to 
gavage administration.  


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In safety pharmacology studies, ASC08 was administered at doses up to 600 
mg/kg and had no significant effect on cardiovascular function in vitro, nor on 
cardiovascular or pulmonary function in monkeys in vivo. Doses of up to 600 mg/kg 
in rats had no significant effect on neurobehavioral function, doses of up to 60 mg/kg 
had no significant effect on GI motility (decreased GI motility at 200 and 600 mg/kg), 
and doses of up to 200 mg/kg had no significant effect on renal function (slight 
changes in urine parameters at 600 mg/kg). 
ASC08 was not mutagenic or teratogenic in in vitro and in vivo assays. In 
reproductive toxicity studies, there were no ASC08-related effects on embryo-fetal 
development in rats (300 mg/kg/day) or rabbits (120 mg/kg/day), and no ASC08-
related effects on fertility parameters in rats (300 and 800 mg/kg/day in females and 
males, respectively). 
1.3 Clinical Studies 
1.3.1 Clinical kinetics 
The PK of ASC08 co-administered with low-dose RTV (ASC08/r) has been 
evaluated in healthy adult volunteers and patients with CHC. 
RTV showed significant "intensified" PK of ASC08 in healthy volunteers. In 
healthy Caucasian volunteers, administration of RTV 100 mg and ASC08 100 mg 
significantly increased AUC0- ∞, Cmax, and C12h of ASC08 by approximately 5.5-
fold, 3.25-fold, and 42-fold, respectively, compared with administration of ASC08 
100 mg. In healthy Chinese volunteers, AUC0- ∞, Cmax, and C12h of ASC08 were 
also significantly increased by approximately 6.6-fold, 3.6-fold, and 56-fold, 
respectively, when administered with RTV 100 mg and ASC08 100 mg compared 
with ASC08 100 mg at steady state; AUC0- ∞ and Cmax of ASC08 were also 
significantly increased by approximately 7.3-fold and 5.6-fold, respectively, when 
administered with multiple doses of RTV 100 mg and ASC08 100 mg at steady state. 
Multiple oral doses of ASC08/r (100 mg capsule formulation) 100/100 mg q12h, 
200/100 mg q24h, and 200/100 mg q12h in patients with CHC genotype 1, combined 
with PEG-IFNα/RBV for 15 days (NP22660, groups 1-3). After oral administration of 
ASC08/r with food, the Tmax of ASC08 was in the range of 1.0 h and 3.0 h. During 
the initial 2 days, ASC08 concentrations increased and then decreased gradually until 
steady state was reached by day 6 – 10 of dosing. The AUC value of ASC08 on Day 
14 was less than 30% to 40% of that on Day 1. Similar to the results in healthy 


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volunteers, the exposure-dose relationship of ASC08 in ASC08/r was greater than 
linear increase at 100/100 mg and 200/100 mg. Doubling the dose of ASC08 
administered (100/100 mg q12h and 200/100 mg q12h) resulted in an approximately 
4-5-fold increase in exposure. 
When ASC08 was administered as a 100 mg film-coated tablet with RTV, a 
high- or low-fat meal had no effect on ASC08 AUC0- ∞ or C12, but Cmax was 
decreased by nearly 40% and Tmax was delayed by nearly 1 to 2 hours. RTV showed 
dose- and time-dependent inhibition/induction of CYP3A and P-gp, but inhibition was 
more common. Dose-dependent inhibition of CYP2D6 was also observed. RTV is 
known to induce CYP1A2, 2B6, 2C9, 2C19, and UGT. 
The results of the human mass balance test showed that the majority of the 
radioactive dose was present in the feces when 100 mg of 14C-ASC08 was 
administered in combination with 100 mg of RTV. The oxidative metabolites in feces 
were approximately 25% and 2% of the total radioactivity in subjects administered 
100 mg 14C-ASC08 and in combination with 100 mg RTV, respectively. 
Two clinical trials were conducted with CHC patients as subjects: NV22776 
(DAUPHINE) in Caucasian subjects and YV28218 (DAPSANG) in Taiwanese 
subjects to observe the PK difference of ASC08/r between Taiwanese and Caucasian 
subjects. The results of the trial showed that plasma exposure was 66% higher in 
Taiwanese subjects than in Caucasian subjects at similar doses. In the clinical PK trial 
NP25297 in healthy Japanese subjects, the in vivo exposure at the 100 mg/100 mg 
ASC08/r dose group was 58% higher than in healthy Caucasian subjects at the same 
dose. 
In a clinical study of NP27946 (RUSHMORE) in Caucasian subjects, the in vivo 
exposure in subjects with cirrhosis was approximately 3-fold higher at the 100 
mg/100 mg ASC08/r dose compared to non-cirrhotic subjects. In the clinical study of 
YV28218 (DAPSANG) in Taiwanese subjects, the in vivo exposure in subjects with 
cirrhosis was approximately 2-fold higher than that in subjects without cirrhosis at the 
equivalent dose. 
1.3.2 Clinical Efficacy 
Two major clinical studies of ASC08/r in the treatment of HCV-infected patients 
are: DAUPHINE and DAPSANG. 


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DAUPHINE is a completed Phase 2b study in Caucasian subjects with CHC. 
This study compared three different ASC08/r doses when combined with PEG-IFNα
/RBV for 24 weeks and PEG-IFNα/RBV alone; an ASC08/r100/100 mg dose 
response-guided therapy (RGT) group tested a shorter overall treatment duration (12 
weeks) for subjects who achieved HCV RNA &lt; 15 IU/mL from Week 2 to Week 
10 and compared with those who did not (24 weeks). High SVR24 was achieved in 
89%, 79%, 66%, and 69% of all ASC08/r dose groups 200/100 mg, 100/100 mg, 
50/100 mg, and RGT, respectively, and 36% of PEG-IFNα/RBV alone. One hundred 
and eighty-seven Caucasian subjects were assigned to the 100/100 mg ASC08/r dose 
group, and 49 of these HCV genotype 1 subjects were treated for 12 weeks. The 
results showed that SVR was 100% in Caucasian subjects with 1b/IL28B CC 
genotype at 100/100 mg ASC08/r dose, regardless of 12-week treatment or 24-week 
treatment. 
The DAPSANG study was an open-label, parallel-group phase II study of 
ASC08/r fixed-dose combinations (FDCs) combined with PEG-IFNα and RBV in 
treatment-naive East or Southeast Asian patients with genotype 1 CHC with or 
without cirrhosis. Thirty-four subjects entered the non-cirrhotic group, including 17 
Taiwanese subjects; subjects in this group received ASC08/r FDC (125 mg/100 mg) 
in combination with PEG-IFNα and RBV for 12 weeks. The study results showed 
that the SVR12 of all subjects in the non-cirrhotic group was 88.2%; the SVR12 of 
subjects with genotype 1a and genotype 1b was 25% and 96.7%, respectively. The 
SVR12 of Taiwanese subjects in the non-cirrhotic group was 94.1%; the SVR12 of 
genotype 1b subjects was 100%. 
In an ongoing phase II study of ASC08/r in combination with PEG-IFNα and 
RBV in treatment-naïve non-cirrhotic patients with genotype 1 CHC (ASC-DNVr-
II/III-CTP-01) in mainland China, all 15 subjects who had received 4 weeks of 
treatment had achieved rapid virological response (RVR4) at 4 weeks. 
1.3.3 Clinical Safety 
In both multiple-dose and repeat-dose clinical pharmacology trials, ASC08/r was 
generally well tolerated when administered to healthy subjects or patients with CHC. 
More than 500 patients were treated with ASC08/r for 12 to 24 weeks in phase I 
and II clinical trials. ASC08/r was generally well tolerated, and ACTG grade 4 ALT 
elevations have occurred so far with ASC08/r treatment. 


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No Grade 4 ALT was observed with ASC08/r treatment in either ASC08/r dose-
finding (50/100 mg, 100/100 mg, and 200/100 mg BID). Grade 3/4 laboratory 
abnormalities were consistent between the groups with ASC08/r and the control 
group, mainly anemia, lymphopenia, neutropenia and thrombocytopenia. Although 
the incidence of grade 3/4 combined neutrophil abnormalities was similar in all 
groups, there was a higher incidence of grade 4 neutrophil abnormalities including 
ASC08/r. Considering the baseline neutrophil values of the affected patients, the mean 
and median values in the ASC08/r treatment group compared to the control group, 
and the incidence of serious infections and terminations, the increase in grade 4 
neutrophils does not appear to be clinically significant. The slight increases in 
triglycerides observed in the 4 ASC08/r treated subjects were not clinically significant 
and may be due to the addition of RTV to the treatment regimen. 
ASC08/r was generally well tolerated during the 12-week combination therapy 
period in Asian (including Taiwanese) CHC populations. There were no deaths during 
the study. There were no discontinuations due to adverse events (AEs) during the 
treatment period. No serious adverse events (SAEs) were reported during the study for 
subjects in the non-cirrhosis group. 
The types and severity of AEs during treatment of genotype 1 CHC with 
ASC08/r combined with PEG-IFNα and RBV were basically the same as those during 
P/R treatment; no new AEs were found during ASC08/r treatment, and the severity of 
AEs related to P/R treatment was not aggravated. The only AE related to ASC08/r that 
was observed at a higher incidence during the treatment period in the available 
clinical trials was diarrhea. Overall, RTV-intensified ASC08 for CHC had a high 
safety profile and was generally well tolerated by subjects.  
A clinical phase I study in healthy subjects in China showed that ASC08 was 
generally well tolerated, with no SAEs, no discontinuations due to AEs, and no 
withdrawals due to AEs. Clinical phase II study in domestic patients with genotype 1 
CHC showed that after 4 weeks of treatment with ASC08/r combined with PEG-IFN
α and RBV, the subjects generally tolerated well, without SAE or withdrawal due to 
AE; the AEs experienced by the subjects were common adverse reactions during 
PEG-IFNα and RBV treatment. 
ASC08 tablets are DAAs with independent intellectual property rights developed 
by Ascletis Pharmaceuticals Co., Ltd. in China. ASC08 tablets are now proposed for 


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the treatment of non-cirrhotic patients with chronic hepatitis C genotype 1 virus 
infection who are initially treated in China. 
2. test purpose 
The primary objective of this study was to (1) evaluate the rate of subjects 
achieving SVR12 after 12 weeks of ASC08/r in combination with PEG-IFNα and 
RBV in treatment-naive non-cirrhotic subjects with chronic hepatitis C genotype 1 
virus infection. 2) To evaluate the safety of ASC08/r in combination with PEG-IFNα 
and RBV in treatment-naive non-cirrhotic subjects with chronic hepatitis C genotype 
1 virus infection. 
The secondary objectives of this clinical study were: (1) to evaluate the rate of 
subjects achieving RVR4; (2) to evaluate the rate of subjects achieving SVR4; (3) to 
evaluate the rate of subjects achieving SVR24; (4) to evaluate the change in 
virological response rate over time during the clinical study; (5) to evaluate the 
kinetics of viral load changes during the clinical study; (6) to evaluate the relapse rate 
of combination therapy; and (7) to evaluate the viral resistance profile to ASC08. 
3. trial design 
This clinical study is a multicenter, open-label, single-arm clinical study with 
historical data as the control. All screened eligible subjects received the same 
treatment: 100 mg ASC08 tablets/100 mg RTV (ASC08/r) combined with PEG-IFNα 
and RBV therapy (triple therapy) for 12 weeks, followed by 24 weeks of post-
treatment follow-up. 
3.1 Rationality 
3.1.1 RTV Enhancement Strategy Rationale 
RTV is a peptidomimetic inhibitor that inhibits human immunodeficiency virus 
(HIV) -1 and HIV-2 proteases; it is used in combination with other antiretroviral 
agents for the treatment of HIV infection; the approved therapeutic dose is 600 mg 
twice daily (BID) (Norvir ®). Due to its poor tolerability and the availability of more 
effective HIV protease inhibitors, therapeutic doses of RTV are no longer available. 
Currently, RTV mostly uses low-dose, subtherapeutic doses (e.g., 100 − 200 mg/day) 
to increase or intensify the exposure of other protease inhibitors that can be 
extensively metabolized by cytochrome P450 (CYP) 3A isoenzymes. For example, 


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intensive HIV protease inhibitors with 100 mg RTV have been widely used in clinical 
practice for more than 10 years with good safety.  
The purpose of using RTV to strengthen ASC08 strategy is to improve the PK of 
ASC08, reduce the clinical dose of ASC08, ensure the clinical efficacy of ASC08, and 
enhance the safety of ASC08. 
The kinetics of ASC08 (ASC08/r) fortified with 100 mg RTV have been studied 
in healthy volunteers and CHC patients, respectively. In healthy Caucasian volunteers, 
RTV showed significantly "fortified" PK of ASC08; AUC0- ∞, Cmax of ASC08 100 
mg fortified with RTV were significantly increased by approximately 5.5-fold and 
3.25-fold, respectively, compared to unfortified ASC08 100 mg; and Cmin was 
particularly significantly increased by up to 42-fold. In healthy Chinese volunteers, 
RTV also showed significantly "fortified" PK of ASC08; AUC0- ∞, Cmax of ASC08 
100 mg fortified with RTV were significantly increased by approximately 6.6-fold 
and 3.6-fold, respectively, compared to unfortified ASC08 100 mg. In CHC patients, 
the PK parameters of ASC08 fortified with RTV from the DAUPHINE study were 
compared with those fortified with ATLAS (Table 1). 
Table 1 Comparison of steady-state (4-week) PK parameters in treatment-naïve patients 
with CHC genotype 1 
 
 
DAUPHINE (REINFORCED ASC08) 
ATLAS (unfortified 
ASC08) 
 
 
50/100 
mg 
BID 
100/100 mg 
BID 
200/100 mg 
BID 
600 mg 
BID 
900 mg 
BID 
 
Number of 
cases 
16 
33 
16 
15 
7 
AUC0-12h 
(ng · h/mL) 
Mean 
value 
Median 
CV% 
121 
83.4 
81.9 
320 
208 
114 
750 
458 
97.6 
878 
433 
92.2 
2450 
964 
131 
Cmax 
(ng/mL) 
Mean 
value 
Median 
CV% 
48.9 
33.4 
95.1 
126 
64.6 
130 
355 
195 
117 
915 
344 
129 
2150 
1100 
99.6 
Cmin 
(ng/mL) 
Mean 
value 
Median 
CV% 
1.21 
0.91 
98.4 
2.24 
0.97 
134 
5.36 
1.92 
159 
0.62 
0.50 
62.6 
1.37 
0.76 
102 


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The comparison results showed that low-dose RTV (100 mg) fortified ASC08 
significantly improved the PK parameters of ASC08. The trough concentration 
(Cmin) of RTV fortified 100 mg ASC08 was similar compared to unfortified 900 mg 
ASC08. One of the most important parameters (Cmin) required for ASC08 to produce 
clinical efficacy was still ensured with a 9-fold reduction in the dose.  
In the Phase 2 clinical study NV21075 (ATLAS), which did not intensify ASC08, 
a small proportion of subjects treated with ASC08 (4 subjects in total) experienced 
reversible ACTG Grade 4 ALT elevations. However, no ACTG grade 4 ALT elevation 
was observed during treatment in any of the clinical trials of ASC08 for CHC with 
RTV intensification. 
The literature confirms that the formation of reactive metabolites is associated 
with drug-induced liver dysfunction. The completed ASC08 study suggested that the 
reason why low-dose RTV improved the safety of ASC08 may be through reducing 
the formation of ASC08 metabolites. The ACTG grade 4 ALT elevations that have 
occurred in clinical studies of unintensified ASC08 are likely to be caused by reactive 
metabolites of ASC08. Qualitative analysis of human metabolites revealed that up to 
20 different metabolites were found in pooled plasma samples from 3 subjects 
receiving unfortified ASC08 900 mg q12h, whereas metabolites were detected in 
pooled plasma samples from 3 subjects receiving ASC08/r 200/100 mg q12h. The 
results of the mass balance study confirmed that the metabolism of [14C] -ASC08 
included a large number of oxidative metabolites as well as hydrolytic metabolites, 
and the levels of oxidative metabolites were greatly reduced in the excreta after the 
addition of RTV. The oxidative metabolites were approximately 25% of the total 
radioactivity in the excreta without ASC08 fortification, and approximately 2% of the 
total radioactivity in the excreta with ASC08 fortification, i.e., the oxidative 
metabolite of ASC08 fortified with RTV was decreased by 12.5-fold. In vitro 
experiments using human liver microsomes incubated with 14C-labeled ASC08 
showed that ASC08 caused significant covalent protein binding (512 pmol/mg/30 
min), presumably as a result of reactive metabolite formation. RTV was added to the 
incubation and covalent protein binding was reduced to background levels (11.5 
pmol/mg/30 min). These findings suggest that the ALT elevation observed in the 
unfortified ASC08 study may be related to the reactive metabolite of ASC08, and 
RTV may decrease the formation of reactive metabolites by inhibiting the metabolism 
of ASC08, thereby reducing the possibility of ALT elevation events and the degree of 


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ALT elevation and enhancing the safety of ASC08 application.  
3.1.2 Rationale for Dose Selection 
The dose of ASC08/r selected for this clinical study was: 100 mg/100 mg twice 
daily. The primary rationale for this dose selection is: 
The results of DAUPHINE study showed that, compared with control group E, 
SVR12 (32.5%) and SVR24 (35.0%) (Table 2), subjects with CHC genotype 1 
infection treated with ASC08/r achieved higher SVR rate, and SVR12 and SVR24 
were equal, 92.5% for group A, 81.5% for group B and 67.5% for group C (all results 
of PP set analysis), showing significant dose-dependent response relationship. The 
SVR of group C was significantly lower than that of groups A and B. The results 
showed that the dose of 50 mg/100 mg of ASC08/r for the treatment of CHC was 
significantly too low, and this dose for the treatment of CHC not only had low clinical 
efficacy but also easily made HCV virus resistant, which would be not conducive to 
the clinical treatment of CHC patients. Therefore, from the perspective that meeting 
the clinical efficacy is conducive to the treatment of patients, the clinical dose 
selection of 100 mg/100 mg or 200 mg/100 mg is more appropriate than 50 mg/100 
mg when ASC08/r is used to treat CHC. 
Table 2 SVR of three doses of ASC08/r for 24-week course treatment of genotype 1 CHC in 
DAUPHINE study 
Test 
DAUPHINE 
Treatment 
Group A: 
ASC08/r + PEG-
IFNα + RBV 
Group B: 
ASC08/r + PEG-
IFNα + RBV 
Group C: 
ASC08/r + PEG-
IFNα + RBV 
Group E: 
P/R 
ASC08/r dose 
200 mg/100 mg 
100 mg/100 mg 
50 mg/100 mg 
- 
Number of 
cases 
84 
85 
86 
41 
SVR12 
n/N 
(%) 
74/80 (92.5%) 
66/81 (81.5%) 
54/80 (67.5%) 
13/40 (32.5%) 
SVR24 
n/N 
(%) 
74/80 (92.5%) 
66/81 (81.5%) 
54/80 (67.5%) 
14/40 (35.0%) 
The results of NP25297 study showed that the plasma exposure of ASC08 in 
healthy Japanese subjects was approximately 1.6 times higher than that in Caucasian 


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subjects at the dose of ASC08/r 100 mg/100 mg (Table 3), and 2.9 times higher than 
that in Caucasian subjects at the dose of ASC08/r 200 mg/100 mg. The study results 
also showed that in Japanese subjects, the plasma exposure in the ASC08/r 200 mg/100 
mg dose group was approximately 7-fold higher than that in the 100 mg/100 mg dose 
group (Table 4), which greatly exceeded the proportion of dose increase. This may 
increase the safety risk of clinical medication, but has no significant effect on the 
efficacy. Therefore, ASC08/r 100 mg/100 mg is a more appropriate dose for Asian 
population. 
Table 3 Differences in ASC08 plasma exposure between Japanese and Caucasian populations 
in NP25297 study 
ASC08/r 
dose 
Number 
of cases 
Study 
Day 
Parameter 
Caucasian 
Subjects 
Japanese 
subjects 
Ratio 
100 mg/100 
mg 
18 
1 
AUC0- ∞ 
(ng · h/mL) 
108 
170 
1.57 
9 
AUC0-τ 
(ng · h/mL) 
104 
165 
1.58 
200 mg/100 
mg 
9 
1 
AUC0- ∞ 
(ng · h/mL) 
444 
1290 
2.90 
9 
AUC0-τ 
(ng · h/mL) 
391 
1140 
2.90 
 
 
Table 4 Differences in Plasma Exposure to ASC08 by Dose in Japanese Population in 
NP25297 Study 
ASC08/r dose 
Number 
of cases 
Study 
Day 
Parameter 
Japanese 
subjects 
Ratio 
100 mg/100 mg 
18 
1 
AUC0- ∞ 
(ng · h/mL) 
170 
-- 
9 
AUC0-τ (ng · h/mL) 
165 
-- 
200 mg/100 mg 
9 
1 
AUC0- ∞ 
(ng · h/mL) 
1290 
7.59 
9 
AUC0-τ (ng · h/mL) 
1140 
6.9 
Combining the study data of efficacy and plasma exposure in DUPHINE and 
NP25297, we speculated that the possible appropriate dose of ASC08/r was 100 
mg/100 mg when ASC08/r combined with PEG-IFNα + RBV was used for the 


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treatment of Asian CHC genotype 1 virus-infected population. 
According to relevant literature reports, the proportion of HCV genotype 1b 
patients in HCV genotype 1 infected population in Europe and the United States is 
less than 40%, while the proportion of HCV genotype 1b patients in HCV genotype 1 
infected population in China is 98%. Through computational analysis, we speculated 
that the use of ASC08/r 100 mg/100 mg dose and 12-week course of treatment in 
Chinese CHC genotype 1 infected population will have a higher rate of SVR than the 
Caucasian population treated for CHC genotype 1 infection, which may exceed 90%. 
To test the hypothesis, we conducted the DAPSANG study in an Asian population 
with CHC genotype 1 infection. 
The fixed-dose combination (ASC08/r FDC) was used in the DAPSANG trial. 
The results of NP28136 study showed that the plasma exposure of ASC08 at 125 
mg/100 mg of ASC08/r FDC was only 17% higher than that at 100 mg/100 mg of 
ASC08/r mono (Table 5), and this increase in exposure was not clinically significant. 
Table 5 Plasma exposure of FDC vs. ASC08/r 
Parameter 
Drug 
Dose 
Number of 
cases 
Mean value 
Ratio 
AUC (0-inf) 
(ng · h/mL) 
ASC08/r unilateral 
100 mg/100 
mg 
42 
65.5 
- 
ASC08/r FDC 
100 mg/100 
mg 
40 
51.5 
0.78 
125 mg/100 
mg 
42 
76.7 
1.17 
The results of the DAPSANG study (Table 6) showed that the primary endpoint, 
SVR12, after 12 weeks of treatment with ASC08/r FDC combined with PEG-IFNα 
+ RBV in non-cirrhotic Asian subjects with CHC genotype 1 infection was 88.2%, 
and SVR12 in subjects with CHC genotype 1a and 1b infection was 25% and 96.7%, 
respectively. SVR12 was 94.1%, 0, and 100% in genotype 1, genotype 1a, and 
genotype 1b infected Chinese subjects with CHC genotype 1 infection who received 
ASC08/r FDC in combination with PEG-IFNα + RBV for 12 weeks, respectively. 
 
 


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Table 6 SVR12 of ASC08/r FDC in treatment of genotype 1 CHC in DAPSANG study 
Test 
DAPSANG 
Treatment 
ASC08/r FDC + PEG-IFNα + RBV 
Number of cases 
Asia 
Taiwan 
34 
17 
Response n/N (%) 
SVR12 
GT1 
30/34 (88.2) 
16/17 (94.1) 
GT1a 
1/4 (25) 
0/1 (0) 
GT1b 
29/30 (96.7) 
16/16 (100) 
The results of the DAPSANG study not only verified the study prediction that 
ASC08/r FDC 125 mg/100 mg dose combined with PEG-IFNα + RBV could achieve 
good efficacy in the treatment of CHC genotype 1 infection in Asian population for 12 
weeks, but also found that this treatment regimen was more effective for CHC genotype 
1 infection in Taiwanese population, especially for CHC genotype 1b infection in 
Taiwanese population. 
In an ongoing phase II study of ASC08/r in combination with PEG-IFNα and 
RBV in treatment-naïve non-cirrhotic patients with genotype 1 CHC (ASC-DNVr-
II/III-CTP-01) in mainland China, RVR4 has been obtained in all 15 subjects who had 
received 4 weeks of 100 mg/100 mg dose of ASC08/r in combination with PEG-IFNα 
and RBV. 
Therefore, 100 mg/100 mg q12h ASC08/r was selected in this clinical study to 
well demonstrate the safety and clinical efficacy of ASC08 in Chinese CHC subjects. 
Combined with PEG-IFNα and RBV, it would bring significant clinical benefits to 
the newly diagnosed non-cirrhotic Chinese subjects with chronic hepatitis C genotype 
1 infection who participated in this clinical study. 
3.1.3 Rationale for Course of Treatment 
The treatment cycles for the 100 mg/100 mg q12h ASC08/r dose group in the 
DAUPHINE study were 12 and 24 weeks. One hundred and eighty-seven Caucasian 
CHC subjects were assigned to the 100 mg/100 mg ASC08/r dose group, and 49 of 
these HCV genotype 1 subjects were treated for 12 weeks. The results showed that SVR 
was 100% in Caucasian subjects with 100 mg/100 mg ASC08/r dose 1b/IL28B CC 


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genotype, regardless of 12-week treatment or 24-week treatment. However, at the 100 
mg/100 mg ASC08/r dose, SVR values were not the same in Caucasian subjects with 
the 1b/IL28B non-CC genotype after 12 and 24 weeks of treatment, with an SVR of 
62.5% in the 12-week course and 95.5% in the 24-week course. Therefore, the use of a 
100 mg/100 mg ASC08/r dose and a 12-week course of treatment will make Caucasian 
CHC subjects with 1b/IL28B non-CC genotype less than the optimal treatment effect. 
However, among HCV genotype 1b patients in China, the proportion of patients with 
1b/IL28B non-CC genotype is much lower than that in Europe and the United States, 
only 16%; and 84% for patients with 1b/IL28B CC genotype. Therefore, SVR12 in 
domestic patients with HCV genotype 1b infection treated with 100 mg/100 mg 
ASC08/r dose and 12-week course of treatment can be simply speculated as follows 
(SVR of 1b/IL28B CC and 1b/IL28B non-CC is 100% and 62.5%, respectively): 
SVR12 = 100% × 84% + 62.5% × 16% = 94%.  
Among HCV genotype 1 infected patients in China, the proportion of HCV1b is 
about 98%. Therefore, it can be predicted that SVR12 can reach more than 90% in 
treatment-naive, non-cirrhotic patients with HCV genotype 1 infection treated with 
100 mg/100 mg ASC08/r dose and a 12-week course of treatment.  
According to the results of NP25297 study and DAPSANG study data, it is 
speculated that the plasma exposure of Chinese CHC patients receiving 100 mg/100 
mg ASC08/r dose should be slightly higher than the exposure of Caucasians receiving 
100 mg/100 mg ASC08/r dose. Therefore, SVR at the dose of 100 mg/100 mg 
ASC08/r and a 12-week course in Chinese CHC patients will result in a corresponding 
improvement in clinical efficacy due to an increase in ASC08 plasma exposure. The 
results of data analysis of Taiwanese CHC patients in the DAPSANG study further 
confirmed that SVR12 reached 94.1% in Taiwanese CHC patients and 100% in 
genotype 1b subjects after 12 weeks of treatment at an approximate 100 mg/100 mg 
ASC08/r dose. The results of the DAPSANG study not only verified the study 
prediction that ASC08/r combined with PEG-IFNα + RBV could achieve good 
efficacy in the treatment of CHC genotype 1 infection in Asian populations for 12 
weeks, but also found that this treatment regimen was more effective for CHC 
genotype 1 infection in the Taiwanese population, especially for CHC genotype 1b 
infection in the Taiwanese population. The CHC population in mainland China has 
the same ethnic characteristics as the CHC population in Taiwan. Genotype 1 is 


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predominant in the CHC population in mainland China (approximately 60% of the 
total CHC population), with genotype 1b accounting for approximately 98% of the 
genotype 1 population. Based on these epidemiological characteristics and the results 
of the DAPSANG study, we believe that ASC08/r combined with PEG-IFNα + 
RBV for 12 weeks will be suitable for the treatment of genotype 1 CHC in mainland 
China.  
In an ongoing phase II study (ASC-DNVr-II/III-CTP-01) in mainland China, the 
treatment duration of ASC08/r in combination with PEG-IFNα and RBV for 
treatment-naive patients with genotype 1 CHC without cirrhosis was also 12 weeks; 
RVR4 had been obtained in all 15 subjects who had received 4 weeks of ASC08/r at 
the dose of 100 mg/100 mg in combination with PEG-IFNα and RBV. 
Therefore, 12 weeks was selected as the treatment cycle of ASC08/r in this 
clinical study. 
3.1.4 Reasons for using an open single-arm trial design 
(1) After the marketing of DAA, a breakthrough has been made in the treatment 
of chronic hepatitis C internationally. However, so far, the current main treatment 
regimen for HCV genotype 1 chronic hepatitis C in China is still pegylated interferon 
combined with ribavirin for 48 weeks, with a low percentage of achieving SVR (about 
73.9%) and a long treatment cycle; in addition, the percentage of achieving SVR in 
HCV genotype 1 virus infection treated with common interferon combined with 
ribavirin in China is lower, about 40-50%. At present, there is no new DAA drug 
marketed in China, so no new DAA-based treatment regimen has been formed. The 
treatment regimen of ASC08 for HCV genotype 1 chronic hepatitis C is DAA-based 
triple therapy (ASC08/r + PEG-IFNα + RBV) administered for 12 weeks, so there is 
no appropriate treatment regimen that can be used as a control. 
(2) If the existing P/R regimen in China is used as a control, the 12-week treatment 
cycle of ASC08/r triple therapy is too different from the 48-week treatment cycle of 
P/R regimen, and it is difficult to implement a double-blind parallel control. After 12 
weeks of treatment, subjects in the ASC08/r triple therapy group ended treatment, and 
the clinical trial needed to be unblinded so that subjects in the P/R group could continue 
treatment; the double-blind parallel control design could not be further implemented 
after unblinding, so the double-blind parallel control could not be conducted in this 
clinical trial.  


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(3) The clinical efficacy of ASC08/r triple therapy is quite different from that of 
existing P/R regimens, and the implementation of parallel control is not conducive to 
ensuring the interests of subjects. The phase II clinical study (DAUPHINE) with P/R 
regimen as the control that has been completed in foreign countries has confirmed that 
ASC08 triple therapy has a significant clinical efficacy advantage over P/R regimen 
(SVR12 and SVR24 were 81.5% (66/81) in genotype 1 subjects and 35% (14/40) in 
P/R treatment group; SVR12 and SVR24 were 96.4% (27/28) in genotype 1b subjects 
in 100/100 mg ASC08 treatment group). The P/R regimen had more adverse effects and 
was also more severe and poorly tolerated by patients. Therefore, subjects in the control 
group who receive the P/R regimen for 12 weeks will have to continue to receive 
treatment and suffer adverse effects for up to 36 weeks, and have lower clinical efficacy 
than the experimental group even after completing treatment. This will not only harm 
the subject's own interests; but also cause the subject to continue to participate in the 
clinical trial and withdraw voluntarily due to the fact that the subject has generally 
received a long course of interferon treatment, resulting in a higher dropout rate, thus 
seriously imbalance the number of subjects in the control group and further causing 
serious bias in the clinical trial results.  
(4) In the case that the efficacy advantage has been verified in phase II clinical 
studies, there is also a precedent for no control group in phase III clinical studies of new 
anti-hepatitis C drugs approved by the FDA. In the phase III clinical study of Sofosbuvir, 
a new drug for the treatment of hepatitis C approved by the US FDA for marketing in 
December 2013 (NEUTRINO trial, Sofosbuvir + P/R), P/R was not used as a control 
group. The NEUTRINO trial used an open single-arm design to evaluate the treatment 
of genotype 1 CHC. The results of this trial were accepted by the FDA and became the 
only phase III clinical trial approved by the US FDA for Sofosbuvir for the treatment 
of genotype 1 CHC. In recent years, more and more phase III clinical trials of DAA 
studies have used single-arm design, for example, Gilead carried out phase III 
international multicenter clinical trials Sofosbuvir + P/R study (CTR20150250) and 
Harvoni (Ledipasvir/sofosbuvir) study in China without P/R control group.  
3.1.5 Reason for Drug Resistance Monitoring 
Multiple clinical trials have been completed confirming that the most common 
mutation regarding treatment failure in ASC08 treatment regimens is R155K in NS3 
protease, and most of them are in genotype 1a and less in genotype 1b. Different 
ASC08 resistance profiles were observed in subjects infected with HCV genotype 1b; 


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single mutations occurred at positions 168 and 80, and double mutations occurred at 
positions 155 and 168. The only current response to a treatment-emergent viral 
mutation is discontinuation of drug therapy. The mutated virus reverts to wild-type 
after stopping ASC08 treatment, rather than remaining resistant for a long time; the 
reverted virus reresponds to antiviral therapy. Therefore, this clinical study will 
monitor the occurrence and development of ASC08 resistance and reveal the 
characteristics of viral resistance to ASC08 through phenotypic and/or sequence 
analysis of drug-resistant viruses. 
3.2 Multicenter 
This clinical study is a multi-center clinical study. The leading site is Peking 
University People's Hospital and the principal investigator is Professor Wei Lai. All the 
units participating in clinical trials are drug clinical trial institutions approved by China 
Food and Drug Administration. 
Statistical institution: Peking University Clinical Research Institute. 
3.3 Number of cases 
According to the requirements of Provisions for Drug Registration and other 
relevant regulations and in combination with statistical requirements, a total of 127 
subjects were planned to be included in this clinical study. 
Regarding the P/R treatment response rate in Chinese genotype 1 chronic 
hepatitis C population, a meta-analysis showed that the percentage of patients 
achieving SVR24 was approximately 73.9% (see Reference 19 for details); the 
estimate of domestic clinical experts was also similar, approximately 65% ~ 75%. 
Therefore, the single-arm target value of the proportion of subjects achieving SVR12 
in this trial is set as 75%. The proportion of subjects achieving SVR12 after triple 
therapy with ASC08 is expected to be 85% based on the results of previous clinical 
trials. It was estimated by statistical methods that 127 subjects had 80% power, and 
there was a significant difference in the rate of subjects achieving SVR after treatment 
with ASC08/r combined with PEG-IFNα and RBV compared with P/R when the α 
was 0.025 and the lower limit of 95% confidence interval of the primary efficacy 
evaluation indicator (the rate of subjects achieving SVR12) was greater than 75%. 
There is only one group in this clinical study, i.e., the ASC08/r treatment group, 
and all included subjects will enter this group. The final number of enrolled and 
completed subjects is based on the number of subjects actually enrolled and 


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completed at the end of this clinical study. 
3.4 Study procedures 
3.4.1 Clinical study process 
(1) Screening period 
The subjects should receive the screening examination within 28 days before 
the start of drug treatment, and eligible subjects should be enrolled in this clinical 
study for treatment. Subjects may be re-screened only if there is a change in past 
medical history and/or treatment status and/or signs. 
(2) Baseline 
Baseline examination was done before the first dose in the morning of Day 1 
of combination therapy. 
(3) Treatment period 
During the treatment phase, subjects received a 12-week combination of 
ASC08/r + PEG-IFNα + RBV. 
(4) Post-treatment follow-up period 
All subjects were followed post-treatment for 24 weeks after the end of 
combination therapy. 
The trial procedures of this clinical study are shown in Appendix 4. 
3.4.2 End of Clinical Observations 
After treatment, the follow-up will be completed, and the subjects will be 
withdrawn from the study. The clinical observation of this clinical study will be 
completed after all the enrolled subjects have completed the trial (including drop-
out subjects). 
The end of clinical observation is defined as the last subject completed the last 
visit specified in the trial protocol or the last data collection required for statistical 
analysis. The latest of these two events is used as the end time of clinical 
observation in this clinical study. 
4. subjects 
4.1 Inclusion Criteria 
(1) Aged 18 years and above, male or female; 
(2) Establish the diagnosis of CHC must meet one of the following conditions: 


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(1) hepatitis C virus infection ≥ 6 months (6 months ago anti-HCV antibody 
positive, or HCV RNA positive); (2). Liver tissue biopsy within 1 year before 
inclusion consistent with CHC pathological features. 
(3) Anti-HCV positive. 
(4) Serum HCV RNA ≥ 1.0 × 104 IU/mL; 
(5) HCV genotyping is genotype 1. 
(6) Patients who have not received any interferon and/or other DAA treatment 
(regardless of the length of time); 
(7) Patients without cirrhosis; Non-cirrhosis is defined as: (1) Fibroscan value 
≤ 9.6kPa during screening, or liver biopsy within 1 year before inclusion confirmed 
as non-cirrhosis (Metavir score ≤ 3 points; See Appendix 1 for details of scoring 
method); II. 9.6 &lt; Fibroscan value ≤ 12.9 during screening, must be confirmed as 
non-cirrhotic by liver biopsy. 
(8) Patients who voluntarily sign the informed consent form; 
4.2 Exclusion criteria 
(1) Patients with Fibroscan &gt; 12.9kPa, or patients with liver cirrhosis by 
histopathological examination; 
(2) Patients with previous or existing evidence of chronic liver disease caused by 
non-HCV (such as hemochromatosis, autoimmune liver disease, Wilson's disease, α
1 antitrypsin deficiency, alcoholic liver disease, chronic drug-induced liver disease, 
etc.); 
(3) Patients with a history of hepatocellular carcinoma, or patients with suspected 
hepatocellular carcinoma before screening or screening, or patients with suspected 
hepatocellular carcinoma on color Doppler ultrasonography at screening, or AFP &gt; 
50 ng/mL; 
(4) Anti-HAV (IgM), HBsAg, anti-HEV (IgM), anti-HIV one of the positive; 
(5) BMI &lt; 18 or ≥ 30 kg/m2; 
(6) ANC (AbsoluteNeutrophil count) &lt; 1.5 × 109/L, PLT &lt; 100 × 
109/L, HB &lt; 110 g/L (female) or &lt; 120 g/L (male); INR &gt; 1.5; ALP ≥ 1.5 
times ULN (upper limits of normal); ALT or AST ≥ 5 times ULN; TBIL ≥ 2 
times ULN (DBIL ≥ 35% TBIL); Cr ≥ 1.5 times ULN; TSH &gt; ULN or TSH 
&lt; LLN (lower limits of normal); 


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(7) Patients who have or have had neurological and/or psychiatric psychiatric 
disorders, have poor self-control, and cannot express their wishes with certainty; 
(8) Patients with obvious cardiovascular dysfunction, such as heart function 
grade III or above or score &lt; 50%; or patients with severe cardiovascular disease 
(such as ventricular tachyarrhythmia, myocardial infarction, angina pectoris, coronary 
artery disease or other serious cardiovascular disease); or patients with existing 
uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg and/or diastolic 
blood pressure ≥ 100 mmHg); or patients with obvious clinical abnormal ECG 
results; 
(9) Patients with severe acute or chronic respiratory or severe urinary system 
diseases; 
(10) Have received solid organ transplantation or corneal transplantation or bone 
marrow transplantation, or plan to receive organ transplantation during this clinical 
study; 
(11) Patients with autoimmune diseases (such as dermatomyositis, immune 
(congenital) thrombocytopenic purpura, inflammatory bowel disease, interstitial lung 
disease, interstitial nephritis, polymyositis, psoriasis, rheumatoid arthritis, sarcoidosis, 
systemic lupus erythematosus, etc.) (ANA &gt; 1:80 and/or AMA positive and/or 
SMA positive); 
(12) Patients with uncontrolled diabetes (HbA1c &gt; 7.0%) or thyroid disease 
(such as hypothyroidism, hyperthyroidism) and other endocrine system diseases, or 
fundus examination suggests the presence of clinically significant retinal diseases 
(such as retinal hemorrhage, cotton wool exudation spots, papilledema, optic 
neuropathy, retinal artery or vein occlusion, etc.); 
(13) Patients with severe hematologic diseases or at increased risk of anemia 
(e.g., thalassemia, sickle cell anemia, spherocytosis, history of gastrointestinal 
bleeding); 
(14) Patients with or suspected malignant tumors; 
(15) Patients with gastrointestinal disorders or postoperative diseases that may 
interfere with the absorption of investigational drugs or severe digestive system 
diseases that may interfere with the absorption of investigational drugs; 
(16) Patients who are receiving or plan to receive hormone replacement therapy 
during clinical studies; 


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(17) Patients who need to take the following drugs during the clinical study: (1) 
liver enzyme CYP3A4 inducers (such as rifampicin, rifampicin, phenobarbital, 
phenytoin, carbamazepine) and CYP3A inhibitors (such as ketoconazole, 
voriconazole); (2) OATP inhibitors (such as cyclosporine, rifampicin) or substrates 
(such as rosuvastatin); Drugs with a narrow therapeutic window and extensively 
metabolized by CYP3A and/or substrates for p-glycoprotein transporters (e.g., 
alfuzosin, astemizole, terfenadine, dihydroergotamine, ergometrine, ergotamine, 
methylergometrine, cisapride, pimozide, midazolam, triazolam, atorvastatin, 
lovastatin, simvastatin, fluticasone propionate); IV. Hormonal contraceptives; V. 
Probenecid and bile acid-binding resins; VI. Immunosuppressive drugs; VII. Have 
cytotoxic effects or chemotherapeutic agents; VIII. Antiarrhythmic drugs (e.g., 
amiodarone, bepristone, flecainide, propafenone, quinidine); IX. Corticosteroids 
(other than topical hydrocortisone and dexamethasone); X. PDE5 inhibitors 
(sildenafil, tadalafil, vardenafil). The above list of drugs does not contain all drugs 
that are contraindicated for concomitant use with ritonavir. For a complete list of 
contraindicated drugs, refer to the Ritonavir Tablets package insert. 
(18) Blood donation or blood loss more than 400 mL within 2 months before 
inclusion; or received G-CSF, EPO, TPO within 6 months before inclusion, or 
received blood transfusion within 6 months before inclusion, or received other 
treatments with improved hematological parameters within 6 months before inclusion; 
(19) Allergic to test drugs (including RTV, PEG-IFN α, RBV), or have a history 
of multiple drug allergies, or have a history of specific reactions; 
(20) Women of childbearing age (18 years to 1 year after menopause) who are 
pregnant, lactating and take effective contraceptive measures and maintain until at 
least 6 months after stopping the experimental drug treatment; 
(21) Male patients with female partners of childbearing potential who take 
effective contraceptive measures and maintain them for at least 6 months after 
stopping the treatment with the investigational drug; 
(22) Patients with a history of alcoholism, drug abuse or drug abuse within 6 
months before enrollment that affects the evaluation of the test results; 
(23) Patients who participated in other clinical studies and received study drug 
treatment within 3 months before inclusion; 
(24) In addition to the above, patients who are not suitable for this clinical trial as 


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judged by the investigator. 
4.3 Drop-out cases 
4.3.1 Determination of dropout cases 
All subjects who have signed the informed consent form and passed screening to 
enter the trial have the right to withdraw from the clinical trial at any time; no matter 
when or why they withdraw, they are all dropouts as long as they do not complete the 
whole observation of the clinical trial. 
4.3.2 Reasons for dropout 
(1) Subjects actively withdraw from the trial, or do not clearly propose to 
withdraw from the trial, but no longer accept visits and lose follow-up; 
(2) Adverse events or adverse reactions, which are not suitable to continue 
the trial as judged by the investigator; 
(3) It is necessary to take measures to improve or restore the health status of 
subjects in violation of the trial protocol; 
(4) During the trial, it is not suitable to continue the trial due to special reasons as 
judged by the investigator. 
4.3.3 Handling of Drop-out Cases 
(1) The investigator should actively take measures (telephone, door-to-door, 
appointment for follow-up, letter, etc.) to contact the subjects who drop out of the 
trial, complete the follow-up items that can be completed as far as possible, and 
fill in the follow-up records. 
(2) For subjects who withdraw due to adverse events, the investigator should take 
corresponding treatment measures according to the actual situation of the subjects. 
(3) For all drop-out cases, the reason for drop-out should be filled in the case 
report form (CRF); if the adverse event is judged to be related to the investigational 
drug, the investigator should notify the sponsor. 
4.4 Excluded cases 
4.4.1 Reasons for removal 
(1) Subjects misincluded; 
(2) No medication after enrollment; 
(3) There is no evaluable record after medication; 
(4) Concomitant use of prohibited drugs, resulting in inability to perform 
efficacy and/or safety evaluation. 


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4.4.2 Handling of excluded cases 
(1) Reasons should be stated for excluded cases, and their records should be 
retained for future reference. 
(2) No efficacy analysis of data will be performed for the excluded cases; 
however, the excluded cases who receive at least one treatment and have safety data 
records can be included in the safety analysis as appropriate. 
4.5 Terminating the trial 
4.5.1 Reason for termination 
(1) Major errors in the clinical trial protocol, or serious deviations in the 
implementation of the protocol, making it difficult to evaluate the efficacy and/or 
safety of the drug; 
(2) The sponsor requests termination of the trial; 
(3) The national drug regulatory authority cancels the trial; 
(4) Other investigators believe that it is not appropriate to continue the trial or 
that it is difficult to continue the trial; 
4.5.2 Handling of terminating the trial 
In case of terminating the clinical trial, all parties shall be notified in a timely 
manner. The investigator shall record in detail the reasons for trial termination and the 
process leading to trial termination, etc., and all the records shall be retained for future 
reference. 
4.6 Subject Management 
4.6.1 Withdrawal 
Subjects participating in this clinical study should be withdrawn from the 
clinical study if they: 
(1) The subject is not willing to continue to participate in this clinical study, and 
actively requests to withdraw from this clinical study or his legal representative 
requests to withdraw from this clinical study. 
(2) The subject's serum HCV RNA content is &gt; 1,000 IU/mL at week 4 of the 
treatment period and confirmed 2 times later (at least 2 consecutive measurements); or 
the subject's HCV RNA continues to increase by ≥ 1 log10 IU/mL (at least 2 
consecutive measurements) compared with the lowest value during the treatment 
period (≥ 1 log10 IU/mL reduction from baseline HCV RNA after at least 2 weeks 
of treatment). 


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(3) Subjects with grade 4 ALT elevation, or grade 3 ALT elevation with TBIL 
(DBIL ≥ 35% TBIL) &gt; 2 times ULN, or grade 3 ALT elevation with INR &gt; 
1.5; and retest and confirm at 2. 
(4) Subjects with neutropenia and/or anemia, after adjusting the dose of PEG-
IFN α and/or RBV or using other drugs to improve neutropenia and/or anemia are 
ineffective; 
(5) Subjects with grade 3 and above and intolerable adverse events other than the 
above (3) and (4) are not suitable to continue to participate in clinical studies. 
(6) Received other treatments during the clinical study that affect the efficacy 
and safety evaluations specified in this protocol. 
(7) During the clinical study, the subject has other diseases requiring treatment, 
and the investigator judges that the disease will significantly affect the evaluation of 
the subject's clinical condition, and the treatment specified in this clinical study 
protocol needs to be stopped. 
(8) If a female subject becomes pregnant during combined treatment, she 
should withdraw from this clinical study; if a female subject becomes pregnant 
during post-treatment follow-up, she may not withdraw from this clinical study. 
(9) Other situations that the investigator considers it inappropriate for the subject 
to continue to participate in this clinical study. 
4.6.2 Compliance 
Each subject will receive a diary to record the medication during the clinical 
trial, including investigational drug and concomitant medication and dietary 
contraindication information, as well as AEs during the clinical trial. 
Each use of all investigational drugs must be recorded in a diary, including the 
name of the drug, strength, dosage each time, storage conditions, etc. The subject 
must return all used and unused medication and cartons at the time of the visit. The 
investigator should count the doses taken by the subject and make a record. All used 
drug and its containers returned by subjects and unused drug and containers must be 
returned to the investigator for destruction by the sponsor or by the sponsor's 
delegated site for destruction. 
All concomitant medications and dietary contraindications specified in the 
trial protocol must also be recorded in a diary, including the drug name (generic 
name), strength, dosage each time, duration of medication, name of diet, amount 


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of food eaten, number of meals, etc. 
All AEs occurring during study participation, whether or not related to the 
study drug, must be recorded in a diary. Such information includes type, severity, 
duration, treatment and outcome of AEs. 
5. investigational drugs 
5.1 Drug Name and Strength 
5.1.1 Investigational drug 
ASC08 Tablets 
Strength: 100 mg/tablet, 30 tablets/bottle. 
Storage condition: Sealed and stored at room temperature, protected from light. 
5.1.2 Intensive Medications 
Ritonavir tablet (abbreviation: RTV) 
Strength: 100 mg/tablet, 30 tablets/bottle. 
Storage condition: Store at room temperature (below 30℃). 
5.1.3 Concomitant Medications 
(1) Pegylated interferon alfa-2a injection (trade name: Pegasys ®; abbreviation: 
PEG-IFNα) 
Strength: 180 μg/0.5 mL/vial/box, 135 μg/0.5 mL/vial/box. 
Storage condition: 2 ~ 8 sealed, protected from light. 
(2) Ribavirin Tablets (trade name: Changle; abbreviation: RBV) 
Strength: 100 mg/tablet, 24 tablets/plate/box. 
Storage condition: Sealed storage. 
The above investigational drugs were uniformly provided by the Ascletis 
Pharmaceuticals Co., Ltd. to the clinical study site for this clinical study. 
5.2 Concomitant Medications and Diet 
5.2.1 Prohibited Drugs 
During this clinical study, except for the investigational drugs specified in this 
trial protocol, the following drugs are prohibited: 
(1) any traditional Chinese medicine or medicine containing traditional Chinese 
medicine ingredients; (2) other anti-HCV drugs, including anti-HCV drugs that are 
still under research and development; (3) liver drug enzyme CYP3A4 inducers (such 
as rifampicin, rifampicin, phenobarbital, phenytoin, carbamazepine) and CYP3A 


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inhibitors (such as ketoconazole, voriconazole); (4) OATP inhibitors (such as 
cyclosporine, rifampicin) or substrates (such as suvastatin, atorvastatin); (5) drugs 
with a narrow therapeutic window, and extensively metabolized by CYP3A and/or 
substrates for p-glycoprotein transporters (such as alfuzosin, astemizole, terfenadine, 
dihydroergotamine, ergometrine, ergotamine, methysergide, piazimod, midazolam, 
triazolam, lovastatin, simvastatin, fluticasone propionate); (6) oral contraceptives; (7) 
probenecid and bile acid binding resins; (8) Immunosuppressive drugs; (9) cytotoxic 
or chemotherapeutic drugs; (10) antiarrhythmic drugs (such as amiodarone, 
bepristone, flecainide, propafenone, quinidine); (11) corticosteroids (except topical 
hydrocortisone and dexamethasone); (12) PDE5 inhibitors (sildenafil, tadalafil, 
vardenafil). 
Refer to the ritonavir tablets package insert for more detailed information on 
contraindicated drugs. 
5.2.2 Available Medications 
During this clinical study, G-CSF (granulocyte colony-stimulating factor), TPO 
(thrombopoietin) and EPO (erythropoietin) can be used if needed to treat neutropenia, 
thrombocytopenia and anemia, but other drugs should not be used. 
When other drug therapy or other treatments are necessary during the study (such 
as other concomitant diseases with non-neutropenia and anemia), the investigator 
should obtain the consent in advance, and the drug should be used without affecting 
the efficacy and safety judgment of the study drug or for the purpose of protecting the 
health rights and interests of the subjects. All the used concomitant medications 
should be recorded in detail (including drug name, dosage, usage and medication 
duration).  
5.2.3 Dietary Contraindications 
Subjects should refrain from alcohol consumption during this clinical study. 
5.3 Drug Labeling 
Investigational drugs are packaged separately according to different strengths, 
and each packaging box and bottle is labeled for instructions. The format of drug 
package label is as follows: 
 
 
 
Clinical Trial Approval Letter No.: Subject No.: 
Investigational drug for ASC08 Tablets 
(For clinical trial use only, to avoid accidental ingestion by children) 
Number of deliveries:.  
Dispensing date: DD MMM YYYY.  
Drug name: Packaging specification:.  
Dosage and Administration:.  
Production lot number:. Expiry date:  
Storage condition:  


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5.4 Drug Storage 
The Site shall establish management system for investigational drugs. The 
investigational drugs should be kept by the person specially assigned by the 
director of the site. The investigational drugs should be stored in a special place. 
The investigational drugs should be stored according to the drug storage 
conditions provided by the sponsor, and the storage conditions of the 
investigational drugs should be inspected according to the investigational drug 
management system to ensure that the investigational drugs are applicable to 
this clinical trial. 
5.5 Drug Dispensing and Recovery 
The investigator should dispense the drugs in the order of subject time and 
subject number, and should not select the drugs. The investigator should timely and 
accurately record drug distribution, usage and recovery, including subject, date of 
distribution, quantity dispensed, date of recovery, quantity recovered and other 
information. The investigator should timely check the investigational drugs, and 
return the remaining drugs and their packages to the sponsor for destruction after the 
quantity is verified correct or the sponsor entrusts the study site to destroy them. 
6. Treatment regimen 
6.1 Dosage and Administration 
(1) ASC08 Tablets 
Oral; 100 mg (1 tablet) twice daily for 12 weeks. 
(2) RTV film 
Oral; 100 mg (1 tablet) twice daily for 12 weeks. 
(3) PEG-IFNα 
Subcutaneous injection in the abdomen or thigh; 180 μg (1 vial) once weekly 
for 12 weeks. 
(4) RBV 
Oral; body weight &lt; 75 kg, 500 mg (5 tablets) twice daily for a total of 1000 
mg/day; body weight ≥ 75 kg, 600 mg (6 tablets) twice daily for a total of 1200 
mg/day; for 12 weeks. 
Take ASC08 tablets and RTV together with food or within 1 hour after a meal; 
RTV must be taken orally with ASC08 tablets; RBV can be taken with ASC08 tablets 


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and RTV; the interval between doses is 12 ± 2 hours. Subjects may receive PEG-
IFNα injections at sites participating in this clinical study, and PEG-IFNα 
administration will be completed by the investigator or other study personnel 
participating in this clinical study. Subjects can also take the drug home to complete 
PEG-IFNα injection by themselves, provided that the subjects have received 
training on self-injection drugs provided by the investigator, and the investigator 
determines that the subjects can independently complete PEG-IFNα injection 
administration without the help of professional staff and be fully aware of the storage 
and management of the drug and return the used and unused drug and its package in 
accordance with the requirements of the trial protocol. 
6.2 Dose Modifications 
The investigator should clearly inform the subjects that it is important to 
follow the treatment regimen to receive the complete drug treatment to achieve 
the purpose of this clinical study and treat their CHC. If dose adjustment is 
necessary due to adverse events during the clinical study, the following principles 
should be followed for dose adjustment. 
(1) ASC08 and RTV 
During this clinical study, subjects were not advised to interrupt or discontinue 
taking ASC08 and RTV unless an intolerable AE occurred; neither the investigator 
nor the subject was able to increase or decrease the dose of ASC08 and RTV. 
If a subject forgets to take a daily dose of ASC08 and RTV, they may still take a 
daily dose of ASC08 and RTV, but must be at least 4 hours away from their next 
dose of ASC08 and RTV. Subjects cannot combine two doses of ASC08 and RTV at 
the same time, nor take two doses of ASC08 and RTV within 4 hours apart. 
(2) PEG-IFNα and RBV 
During this clinical study, the investigator can adjust the dose of PEG-IFNα 
and RBV according to the AE experienced by the subjects (see Appendix 2 for details 
of dose adjustment principles); the investigator can also adjust the dose of PEG-IFN
α and RBV according to his/her clinical experience and refer to the dose adjustment 
principles. 
If PEG-IFNα administration is delayed, the following principles should be 
followed when administering the next scheduled dose: 


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I. Dose Delay 1-2 Days: Administer the next dose on the regular dosing day of 
the week (e.g., if Monday is the regular dosing day and the dose is delayed until 
Wednesday of the same week, the next dose may be given as usual on Monday of the 
following week). 
II.Delay in Dosing for 3 to 5 Days: Subsequent doses should be given at 5- or 6-
day intervals until the subject returns to their original dosing schedule (e.g., if a 
Monday is a normal dosing day and the dose is postponed to a Saturday of the same 
week, the next dose should be given on the Thursday of the next week, and the next 
dose should be given on the Tuesday of the next week, after which the subsequent 
dose may be given on the Monday as usual). 
Delay in III. dosing by 6 days: Stop the dose for the week and then continue the 
dose as normally scheduled for the following week (e.g., if Monday is a normal 
dosing day, but the subject does not receive the dose until the next day of the week, 
the dose is considered discontinued and the next dose will be given on the Monday of 
the following week). 
A 7-day delay in IV.dosing: The investigator may resume the test dose at any 
time and, if necessary, may administer subsequent doses at 5- or 6-day intervals until 
the subject returns to their original dosing schedule. 
7. Clinical observation items 
Subjects will be required to undergo each evaluation according to the scheduled 
visits outlined in the trial procedures (Appendix 4). Baseline values for this clinical 
study were obtained on Day 1 of the Treatment Period prior to investigational product 
administration. In this clinical study, HCV genotyping and IL28B genotyping, HCV 
RNA detection and drug resistance testing were performed at the central laboratory, 
and the collection, processing, storage and transportation of blood samples from 
subjects for these four tests were performed according to the operation manual 
provided to each site; the Metavir scoring of liver biopsy specimens was performed at 
the central laboratory and performed according to the operation manual provided to 
each site. Other clinical observation items were completed in each study site. In this 
clinical study, if an unscheduled visit is required for a subject, the investigator may 
determine the evaluations required for the unscheduled visit according to the 
requirements of this trial protocol and the subject's personal condition. 
 


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7.1 Screening Period  
Demographic data, medical and medication history and other information of 
subjects should be collected within 28 days before the start of the trial, and relevant 
clinical examinations should be performed.  
(1) Vital signs and physical examination  
Complete examination of vital signs should include examination of pulse, blood 
pressure, respiratory rate, body temperature, etc.; complete physical examination 
should include at least examination of height, weight, skin, lymph nodes, head and 
neck, facial features, chest, heart and blood vessels, lungs, abdomen, spine and limbs, 
lymphatic system, nervous system, etc.  
(2) Determination of body mass index (BMI)  
Subject weight (kg) and height (m) were measured and BMI was calculated 
according to the following formula:  
BMI = weight/height2 (kg/m2)  
(3) Laboratory tests  
I. Hematology should include WBC with DC (NEUT, LYMPH, MONO, EO, 
BASO), RBC, HB, PLT;  
II.Urinalysis should include PRO, GLU, ERY, LEU;  
III. Blood biochemistry should include ALT, AST, ALP, γ-GT, TP, ALB, 
TBIL, DBIL, BUN, Cr, FBG, TC, TG, HDL-c, LDL-c, CK, LDH, UA;  
IV. Blood electrolyte examination should include K +, Na +, Ca2 +, Cl-;  
V. Coagulation tests should include APTT, PT, INR, Fg;  
VI.Thyroid function tests should include TSH, T3, and T4.  
(4) Glycosylated hemoglobin HbA1c  
HbA1 content was measured in the blood of diabetic subjects.  
(5) Immunological examination  
Antinuclear antibody (ANA), antimitochondrial antibody (AMA) and anti-
smooth muscle antibody (SMA) were detected.  
(6) AFP  
Serum AFP content was measured.  
(7) Color Doppler ultrasound  
Test the subject's abdomen (at a minimum, liver, gallbladder, pancreas, and 
spleen).  


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(8) HAV, HBsAg, HEV and HIV tests  
Detect anti-HAV (IgM), HBsAg, anti-HEV (IgM), and anti-HIV.  
(9) Fundus examination  
The subject's retinal condition was examined.  
(10) Pregnancy test  
HCG level was measured in female subjects of childbearing age (18 years to 1 
year after menopause).  
(11) Electrocardiogram  
Electrocardiogram (ECG) examination was routine 12 ECG examination.  
(12) IL28B and HCV genotyping assays  
IL28B and HCV genotypes and their subtypes were determined.  
(13) HCV test  
Detect anti-HCV antibody.  
(14) HCV RNA detection  
Blood samples were collected for HCV RNA content in the serum of the 
subjects.  
(15) Examination for liver cirrhosis  
The subject's liver status will be checked by FibroScan (transient liver 
elastography) or liver biopsy.  
(16) Drug resistance monitoring  
Blood samples were collected for viral phenotyping and/or sequence analysis.  
7.2 Baseline  
(1) Vital signs and physical examination.  
(2) Laboratory tests.  
(3) HCV RNA detection.  
(4) Pregnancy test.  
(5) Electrocardiography.  
(6) Drug resistance monitoring.  
See Appendix 4 for details.  
7.3 Treatment Period  
(1) Vital signs and physical examination.  
(2) Laboratory tests.  
(3) HCV RNA detection.  


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(4) Pregnancy test.  
(5) Drug resistance monitoring.  
See Appendix 4 for details.  
7.4 Post-Treatment Follow-up Period  
(1) Vital signs and physical examination.  
(2) Laboratory tests.  
(3) HCV RNA detection.  
(4) Pregnancy test.  
(5) Drug resistance monitoring.  
See Appendix 4 for details.  
8. Efficacy evaluation  
8.1 Primary evaluation indicators  
Rate of subjects achieving SVR12.  
SVR12 definition: HCV RNA < LLOQ at 12 weeks after the end of treatment.  
8.2 Secondary evaluation indicators  
(1) Rate of subjects achieving RVR4.  
RVR4 definition: HCV RNA < LLOQ at week 4 of treatment.  
(2) Rate of subjects achieving SVR4.  
SVR4 definition: HCV RNA < LLOQ at 4 weeks after the end of treatment.  
(3) Rate of subjects achieving SVR24.  
SVR24 definition: HCV RNA < LLOQ at week 24 after the end of treatment.  
(4) Virologic response rate over time: percentage of subjects with HCV RNA < 
LLOQ at each visit.  
(5) Change of HCV RNA over time: the logarithmic difference of serum HCV 
RNA content between subjects at each visit time point and baseline value.  
(6) Recurrence rate: the percentage of subjects who relapsed at the end of follow-
up compared with subjects who achieved virological response at the end of treatment 
and had at least one post-treatment HCV RNA evaluation.  
(7) Changes in viral resistance  
Blood samples will be collected from all subjects during this clinical study for 
monitoring of ASC08 resistance; however, only those subjects with viral 
breakthrough, partial response, non-response, and relapse will have phenotypic and/or 
sequence analysis performed to reveal the profile of changes in viral resistance. HCV 


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RNA ≥ 1000 IU/mL is necessary for sequence determination.  
Subjects who develop viral resistance should demonstrate one of the following:  
Viral breakthrough  
Subjects with sustained increase in HCV RNA of ≥ 1 log10 IU/mL (at least 2 
consecutive measurements) compared with the nadir during the treatment period (≥ 
1 log10 IU/mL decrease from baseline HCV RNA after at least 2 weeks of treatment).  
II. Partial response  
During ASC08/r treatment, HCV RNA in subjects first decreased (≥ 1 log10 
IU/mL decrease from baseline after at least 2 weeks of treatment) and then remained 
stable (< 1 log10 IU/mL increase from nadir for at least 2 consecutive measurements); 
or at the end of ASC08/r treatment (at least 4 weeks), HCV RNA in subjects ≥ 1000 
IU/mL (at least 2 consecutive measurements).  
III. No response  
The subject has a reduction in HCV RNA of < 1 log10 IU/mL from baseline (at 
least 2 consecutive measurements) after 2 weeks of treatment; or < 2 log10 IU/mL (at 
least 2 consecutive measurements) after 4 weeks of treatment.  
IV.RECURRENT  
The subject had a virological response to treatment at the end of treatment, but 
had a quantifiable viral load in the body (at least 2 consecutive measurements) at post-
treatment follow-up.  
9. Safety evaluation  
9.1 Safety indicators  
(1) Adverse events observed by the investigator and reported by the subject 
during the study;  
(2) Clinically significant changes in vital signs before and after treatment;  
(3) Clinically significant changes in laboratory values before and after treatment;  
(4) Changes in electrocardiogram before and after treatment.  
9.2 Adverse Events  
9.2.1 Definitions  
An AE is any untoward medical occurrence in a patient or clinical trial subject 
administered a pharmaceutical product, including placebo, and which does not 
necessarily have a causal relationship with this treatment. An AE can be any 


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unfavorable and unintended symptom (including an abnormal laboratory finding), 
sign, or temporary disease.  
AEs included the following:  
(1) All suspected adverse drug reactions.  
(2) All reactions due to overdose, abuse, discontinuation, allergy, or toxicity.  
(3) Obviously unrelated diseases, including aggravation of pre-existing diseases;  
(4) Injury or accident.  
(5) Abnormal results found by physical examination or laboratory tests, requiring 
further examination or clinical treatment;  
Significant adverse event: It refers to any adverse event and hematological or 
other significant laboratory abnormalities resulting in the use of targeted medical 
measures (such as drug withdrawal, dose reduction and other important treatment) in 
addition to serious adverse events.  
9.2.2 Recording of adverse events  
At each follow-up visit, the investigator asked the subject about AEs. The 
investigator should describe all AEs directly observed or spontaneously reported by 
the subjects with concise medical terms, and record truthfully and in detail any AE 
occurred during the trial in the AE form of CRF, including the onset time, symptoms, 
severity, duration, treatment measures and outcome of AE, etc.  
9.2.3 Severity of Adverse Events  
All AEs were assessed by the investigator for severity according to the Common 
Terminology Criteria for Adverse Events (CTCAE) v.4.03 published by the National 
Cancer Institute (NCI), and adverse events were graded and described (see Appendix 
3 for common adverse events in CTCAE v.4.03).  
Grade 1 (mild): asymptomatic or mildly symptomatic, clinical or diagnostic 
observations not requiring medical intervention.  
Grade 2 (moderate): minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living.  
Grade 3 (severe): serious or medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care activities of daily living.  
Grade 4 (Life-threatening): Life-threatening, urgent medical intervention 
indicated.  
Grade 5 (Death): Death related to adverse event.  


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Comments:  
(1) Instrumental activities of daily living refer to cooking, purchasing daily 
necessities or clothes, using the telephone, financial management, and so on.  
(2) Self-care activities of daily living refer to bathing, dressing and undressing, 
eating, washing, and taking medication and are not bedridden.  
9.2.4 Judgment on the relationship between adverse events and investigational 
drug  
9.2.4.1 Basis for Judging Interrelationships  
All adverse events in the clinical study, including any abnormal symptoms, signs, 
laboratory tests or other special examinations experienced by the subjects, should be 
evaluated for relevance while being recorded in detail; the investigator should track 
and obtain sufficient information to judge whether the cause of adverse events is 
related to the investigational product. Judgment criteria are as follows:  
①Whether there is a reasonable temporal relationship between drug 
administration and the occurrence of suspected adverse event.  
②Whether the suspected adverse event is a known adverse reaction of the drug.  
③Whether the suspected adverse event can be explained by the subject's clinical 
condition, concomitant medication, current therapy and previous therapy.  
④Suspected adverse events can be relieved or disappeared after drug withdrawal 
or dose reduction.  
⑤Whether the same adverse event occurs again after re-exposure to the same 
drug.  
9.2.4.2 Judgment Results of Interrelationships  
The relationship between adverse events and investigational product is evaluated 
according to the judgment basis of the interrelationship (see Section 9.2.4.1): 
definitely related, possibly related, possibly unrelated, definitely unrelated and 
indeterminable (Table 7).  
(1) Definitely related: The type of adverse event has been identified as a side 
effect of the drug that must occur and cannot be explained by other reasons, such as 
concomitant drugs or concomitant diseases. The time of onset of an adverse event 
strongly suggests a causal relationship, such as a response to withdrawal and re-
administration.  
(2) Possibly related: The occurrence of adverse events may be caused by the 


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investigational drug. The occurrence of adverse events cannot rule out whether it may 
be caused by other factors, such as concomitant drugs or concurrent diseases. The 
adverse event occurs in a reasonable temporal sequence with the use of the 
investigational drug, and causal relationship between the event and the investigational 
drug cannot be ruled out.  
(3) Unlikely related: The occurrence of adverse events is likely related to other 
factors, such as concomitant drugs or concomitant diseases. The timing of the event 
suggests that it is unlikely to be causally related to the use of the study drug.  
(4) Definitely unrelated: There is no correlation between adverse events and the 
use of drugs.  
(5) Unable to judge: the existing information is either contradictory or 
insufficient to judge the correlation between adverse events and drugs.  
Table 7 Relationship between adverse events and investigational product  
Judgment 
results  
Judgment basis  
① 
② 
③ 
④ 
⑤ 
Definitely 
related  
+  
+  
−  
+  
+  
Possibly 
related  
+  
+  
+  
 
?  
Unlikely 
related  
+  
−  
 
 
?  
Definitely 
unrelated  
−  
−  
+  
−  
−  
Unable 
to 
judge  
?  
?  
?  
?  
?  
9.2.4.3 Incidence of adverse reactions  
The investigator should make every effort to determine the relationship of 
adverse events (including serious adverse events) to the drug. If the judgment results 
are definitely related, possibly related and indeterminable, these three results will be 
considered as adverse drug reactions; the number of adverse reactions is counted 
according to the sum of the number of cases with these three results, and the incidence 
of adverse reactions is calculated within the scope of all the test cases with available 
adverse reaction evaluation.  
9.3 Non-Serious Adverse Events of Special Interest  
9.3.1 Determination of Non-Serious Adverse Events of Special Interest  
Non-serious adverse events of special interest (AESI): It refers to elevation of 


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ALT or AST ≥ 10 times ULN combined with elevation of TBIL ≥ 2 times ULN 
(DBIL ≥ 35% TBIL); or clinical jaundice; and suspected transmission of pathogens 
caused by the investigational product.  
9.3.2 Reporting of Non-Serious Adverse Events of Special Interest  
Upon awareness of an AESI, the Investigator must collect and record relevant 
information in a timely manner and notify the Sponsor and/or CRO within 48 hours 
after awareness.  
9.4 Serious Adverse Events  
9.4.1 Determination of Serious Adverse Events  
SAEs include:  
(1) Leading to death;  
(2) Life threatening;  
(3) Causing congenital abnormalities or birth defects;  
(4) Causing significant or permanent human disability or organ function damage;  
(5) Leading to hospitalization or prolongation of hospitalization;  
(6) Other important medical events (after medical judgment, it may cause harm 
to subjects or require medical or surgical treatment to avoid the occurrence of the 
above conditions);  
Some events that require hospitalization or prolong hospitalization may not be 
considered as SAEs, including: hospitalization for other reasons than adverse events, 
such as administrative/social/welfare admission, hospitalization for collection of 
blood sample for PK analysis, pre-specified admission before enrollment (such as 
hospitalization for screening examination, but excluding conditions requiring early 
admission due to aggravation of original disease), emergency stay for observation for 
no more than 24 hours; or hospitalization for predefined surgery or other treatment or 
examination purpose before the study.  
9.4.2 Reporting of Serious Adverse Events  
After being informed of the occurrence of SAE, the investigator must complete 
the SAE Report Form as required within 24 hours, and report to the Drug Study 
Supervision Department, Department of Drug and Cosmetics Registration, CFDA, the 
Hospital Authority of the National Health and Family Planning Commission, the 
Ethics Committee of the site, the provincial drug regulatory authority in the place 
where the site and the sponsor are located, and notify the sponsor and/or CRO.  


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9.5 Handling of Adverse Events  
9.5.1 Sponsor Responsibilities  
(1) Provide legal and economic guarantees to investigators in accordance with 
GCP requirements, except for those caused by medical accidents;  
(2) Provide the corresponding treatment and compensation or economic 
compensation for the adverse events that may be related to the trial or the 
investigational drug;  
(3) Adverse events that occur rapidly with the investigator;  
(4) Timely notifying the investigators to the relevant units for cooperation;  
(5) Provide the corresponding drug R & D data as considered necessary by the 
investigator;  
(6) Other matters requiring the assistance of the sponsor.  
9.5.2 Investigator Responsibilities  
(1) Take necessary and reasonable medical measures for subjects to ensure the 
safety of subjects;  
(2) Judge the relationship between adverse events and investigational drug;  
(3) Recording and follow-up of adverse events;  
(4) Timely notify relevant units and institutions of the information in accordance 
with GCP requirements.  
9.5.3 Follow-up of Adverse Events  
The follow-up of adverse events is not only conducted during the trial, but also 
the unresolved adverse events (including laboratory abnormalities) at the end of the 
trial or early withdrawal of subjects must be followed up until one of the following 
conditions is met:  
(1) Event resolution;  
(2) The event is stable;  
(3) The event returns to the baseline level;  
(4) The event can be attributed to drugs other than the test drug or unrelated to 
the study;  
(5) When more information is impossible to obtain (the subject refuses to 
provide more information, or the subject is lost to follow-up, or the subject has died);  
Before the end of follow-up, the investigator may take necessary and reasonable 
medical measures according to relevant regulations to ensure the safety and rights and 


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interests of the subjects.  
10. data management and statistical analysis  
10.1 Data Safety Monitoring Committee  
The Data Safety Monitoring Committee (DMC) assists the investigators in 
monitoring safety data. The DMC consisted of investigators, biostatisticians, 
independent clinical scientists, representatives from the sponsor, etc. The DMC will 
develop and implement a safety data review plan.  
10.2 Data Management  
An electronic data capture (EDC) system was used for data management in this 
clinical study. The data management unit undertaking this study is responsible for 
establishing the database. The data manager builds the database according to the study 
protocol, and at the same time sets logic check for data validity, so as to check the 
data. The observation records of each enrolled case (including drop-out cases) must be 
timely, completely, accurately and normatively recorded in the eCRF. Completed 
eCRFs must be reviewed and signed (electronically) by the investigator and data 
management performed by the clinical trial data manager.  
The data manager checked the data and inquired the investigator about the 
doubts through the EDC system. The data manager checked and modified the data 
according to the investigator's answers and issued the doubts again when necessary. 
After all data queries are resolved, the "clean" data are exported and transferred to the 
statistical analyst. The principal investigator, sponsor and statistical analyst review the 
data, finalize the statistical plan, lock the database and perform the statistical analysis 
according to the statistical analysis plan.  
10.3 Statistical Analysis  
10.3.1 Statistical Analysis Datasets  
(1) Full Analysis Set (FAS) population  
All patients who were screened as eligible and took the study drug at least once 
and had data for post-dose evaluation at least once. The FAS was the primary analysis 
set.  
(2) Per-Protocol Set (PPS) population  
The collection of cases that meet the inclusion criteria, do not meet the exclusion 
criteria and complete the treatment plan, that is, to analyze the cases that meet the trial 


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protocol, have good compliance and complete the content specified in the CRF (PP 
analysis). The PP analysis was primarily used for efficacy measures.  
(3) Safety Set (SS) Population  
Received at least one treatment with actual data recorded for safety measures. 
Missing safety values should not be carried forward; some excluded cases that can be 
evaluated are included, such as those with age exceeding the inclusion criteria, but 
excluding those whose use of prohibited drugs makes safety judgment impossible. 
The incidence of adverse reactions takes the number of cases in the safety set as the 
denominator.  
10.3.2 Statistical Analysis Plan  
General Principles:  
All statistical tests were performed using the test, and a P value of less than or 
equal to 0.05 was considered statistically significant for the tested difference, and a 
confidence interval of 95% was used.  
Baseline data were analyzed by the full analysis set, and all efficacy measures were 
analyzed by the full analysis set and per protocol set; safety analysis was performed 
using the safety analysis set.  
This clinical study is a single-arm superiority study, and the superiority 
hypothesis tests are:  
H0: π test group — 75% ≤ 0  
H1: π Test Group — 75% > 0  
Α = 0.025  
The 95% confidence interval for the proportion of subjects achieving SVR12 was 
calculated using the binomial distribution, and superiority was considered established 
if the lower bound of the 95% confidence interval for the proportion of subjects 
achieving SVR12 was greater than 75%.  
10.3.2.1 Analysis of Subjects  
(1) List the total number of included subjects and the number of completed 
subjects in each site, and determine three analysis sets (FAS, PPS and SS).  
(2) List the dropouts and excluded cases and their reasons.  
10.3.2.2 Demographic data and baseline analysis  
Descriptive statistics of demographic data and other baseline characteristics:  
Continuous variables will be calculated by their number of cases, mean, standard 


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deviation, median, minimum and maximum.  
Frequency and proportion were calculated for count and grade data.  
Baseline parameters (including demographic data, medical history, history of other 
diseases, physical examination, vital signs, etc.) will be statistically described.  
10.3.2.3 Efficacy Analysis  
10.3.2.3.1 Analysis of Primary Efficacy Indicators  
To count the proportion of subjects achieving SVR12:  
The proportion of subjects achieving SVR12 will be calculated according to the 
definition of SVR12 in this protocol. The binomial distribution will be used to calculate 
the 95% confidence interval, and the superiority will be judged based on this.  
10.3.2.3.2 Analysis of Secondary Efficacy Indicators  
(1) Statistics RVR4:  
The rate of subjects achieving RVR4 values will be calculated based on the 
definition of RVR4 in this protocol, with 95% confidence intervals calculated using the 
binomial distribution.  
(2) Statistics SVR4:  
The proportion of subjects achieving SVR4 will be calculated according to the 
definition of SVR4 in this protocol, and 95% confidence interval will be calculated 
using binomial distribution.  
(3) Statistics SVR24:  
The proportion of subjects achieving SVR24 will be calculated according to the 
definition of SVR24 in this protocol, and 95% confidence interval will be calculated 
using binomial distribution.  
(4) Statistics of virological response rate at each visit:  
Virologic response rates were calculated by visit as specified in this protocol, and 
95% confidence intervals were calculated using the binomial distribution.  
(5) Statistics of the logarithmic difference between HCV RNA at each visit and 
baseline value:  
Calculate the difference between the log value of HCV RNA at each visit and the 
log value at baseline as specified in this protocol.  
(6) Statistics of the recurrence rate after the end of treatment.  
Recurrence rates will be calculated as specified in this protocol and 95% 
confidence intervals will be calculated using the binomial distribution.  


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(7) Drug resistance analysis  
Collect blood samples from subjects according to the trial procedures. Samples for 
drug resistance monitoring studies were selected for phenotypic and/or sequence 
analysis based on HCV RNA test results.  
10.3.2.4 Safety Analysis  
(1) Coding of adverse events and concomitant medication  
AEs were classified and coded using MedDRA by system organ class and 
preferred term.  
Concomitant medications were coded using WHO DD.  
(2) Calculate the incidence of adverse events and adverse reactions:  
Frequency and frequency of adverse events and adverse reactions will be listed 
by system, and percentage will be calculated.  
Detailed listing of cases of each adverse event.  
Detailed listing of cases of each adverse reaction.  
Number and conversion rate of vital signs and physical examination, laboratory 
indicators and ECG "normal to abnormal" or "abnormal intensification" after the trial.  
Cases and clinical interpretations of abnormal vital signs and physical 
examinations, laboratory parameters, and electrocardiograms were listed.  
10.3.3 Interim Analysis  
An interim analysis meeting drug registration requirements will be completed 
when 12-week follow-up data or early termination data are available for all subjects.  
11. Risk control of clinical study  
In addition to the following, the Sponsor has developed a more comprehensive and 
detailed "Risk Management Plan for ASC08 Tablets" to be used as an attachment to this 
clinical trial protocol in order to better identify, analyze and manage various risks that 
may be encountered during the clinical use of ASC08 Tablets.  
11.1 Main risks  
In previous clinical trials of ASC08/r in combination with PEG-IFNα and RBV 
in CHC, the identified risks were neutropenia, anemia, gastrointestinal side effects, and 
drug interactions.  
11.2 Risk control measures for clinical study  
11.2.1 Neutropenia  
Subjects with grade 4 neutropenia, investigators can take appropriate measures: (1) 


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PEG-IFNα dose reduction or discontinuation; (2) with other treatment measures, such 
as the use of G-CSF treatment. If the intervention is ineffective (neutrophil count 
continues to decrease), the subject is withdrawn from the trial and followed up to the 
outcome as specified in the protocol; medical care and appropriate care is provided to 
the subject during the follow-up period.  
11.2.2 Anemia  
(1) Subjects with HB < 110 g/L (female) or < 120 g/L (male) and any risk of 
anemia at baseline were excluded during the screening period;  
(2) HB changes were monitored during the treatment and post-treatment follow-
up periods, and subjects experienced severe HB reduction (HB < 85 g/L), and 
investigators could take appropriate measures: (1) RBV dose reduction or 
discontinuation; (2) treatment with other therapeutic measures, such as EPO therapy. If 
the intervention was ineffective (HB continued to decrease), the subject was withdrawn 
from the trial and followed up to the outcome specified in the protocol; medical care 
and appropriate care was provided to the subject during the follow-up period.  
11.2.3 Gastrointestinal Adverse Reactions  
Gastrointestinal adverse reactions were observed during clinical studies. The 
investigator will grade the gastrointestinal adverse reactions and take corresponding 
treatment measures according to different grades to help the subjects recover.  
11.2.4 Drug Interactions  
ASC08 is a substrate of the following transporters: OATP1B1, OATP1B3, Pgp. It 
is also a strong inhibitor of OATPs and UGT1A1, but not an inducer of UGT1. Drugs 
that inhibit OATPs or Pgp may affect the exposure of ASC08. ASC08 may also affect 
the exposure of other drugs that are substrates of OATPs and UGT1A1.  
ASC08 is metabolized by CYP3A4. CYP3A4 inhibitors or inducers may alter the 
metabolism of ASC08. CYP3A4 inducers include rifampin, rifambutine, phenobarbital, 
phenytoin, carbamazepine, and St. John's Wort. Strong inhibitors of CYP3A4 include 
ketoconazole and ritonavir. In addition, certain foods, such as grapefruit and Seville 
oranges, inhibit CYP3A4. However, when ASC08 was co-administered with RTV, 
CYP3A4 was almost completely inhibited, and the effect of other CYP3A inhibitors 
was minimal.  
For drugs that should not be used concomitantly or should be restricted or used 
with caution during this clinical study, see "5.2 Concomitant Medications".  
11.2.5 Elevated ALT  


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In the phase II clinical trial ATLAS study, ACTG grade 4 ALT elevation occurred 
in the 600 mg and 900 mg ASC08 tablets groups. However, none of the subsequent 
clinical studies with ASC08 intensified with RTV had grade 4 ALT elevations during 
treatment. ALT changes will also be observed during this clinical study.  
Subjects with grade 4 ALT elevation, as well as subjects with grade 3 ALT 
elevation combined with total bilirubin > 2 × ULN (DBIL ≥ 35% TBIL) or grade 3 ALT 
elevation combined with INR > 1.5 should discontinue the study drug treatment and 
withdraw from the trial, be followed up to the outcome specified in this trial protocol, 
and provide medical care and appropriate treatment for the subjects when necessary.  
11.2.6 Adverse Reactions of Combination Drugs  
During this clinical study, RTV, PEG-IFNα, and RBV used in combination with 
ASC08 Tablets may have adverse reactions. The investigators should inquire, observe 
and record the known adverse reactions of these three drugs and other safety issues of 
concern according to the contents of the package inserts of RTV, PEG-IFNα and RBV, 
and take corresponding treatment measures.  
11.2.7 Monitoring of safety indicators  
The vital signs, blood and urine routine, blood biochemistry, coagulation function, 
ECG and other safety indicators of the subjects are monitored during the screening 
period, treatment period and post-treatment follow-up period. For the safety problems 
occurred, the investigator should give the subjects appropriate treatment according to 
the requirements of the trial protocol and the clinical medical principles to protect the 
interests of the subjects.  
11.2.8 Remedial Measures for Combination Failure  
During this clinical study, subjects who have failed combination therapy as defined 
by the protocol (including viral breakthrough, partial response, non-response, and 
relapse) will continue to be offered PEG-IFNα and RBV for up to 48 weeks as rescue 
therapy, and the specific rescue therapy regimen and implementation of this therapy 
regimen will be decided by the investigator according to the actual situation of the 
subjects.  
11.2.9 Investigator Training  
Relevant knowledge training was provided to investigators participating in the trial 


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during this clinical study to ensure that all investigators had a full understanding of risk 
factors and management measures.  
12. Quality control and quality assurance of clinical trials  
12.1 Clinical Trial Site and Study Personnel  
Before the trial, the sponsor and/or CRO should confirm that the study site has 
been qualified to participate in the trial, including the qualification of drug clinical 
trial institution approved by CFDA, various inspection equipment related to the trial, 
sufficient number of subjects, etc. Standard operating procedures were established for 
all study processes in this trial, and standard operating procedures and quality control 
procedures for test indicators were established. The investigators participating in the 
clinical trial must have received the training related to the clinical trial and have the 
professional background and ability to carry out the clinical trial.  
12.2 Clinical Monitoring  
The trained monitor will call and conduct on-site monitoring on the study sites 
during the study progress, mainly to control the study progress and study quality.  
The monitor must ensure that the clinical facilities of the participating institution 
meet the requirements, ensure that the investigators follow the trial protocol and 
accurately record the trial results, and ensure that each subject participating in the trial 
signs the informed consent form. The monitor regularly makes on-site monitoring 
visits, checks the trial data, checks the storage and use of the investigational drug, 
pays attention to adverse events, understands the completion of medical records and 
eCRFs, and makes timely corrections to the errors and omissions found during the 
monitoring process, which shall be recorded in writing.  
12.3 Clinical Audits  
According to the requirements of GCP, the study site must also accept the audit 
of clinical trial by the auditor appointed by the sponsor. The auditors conduct 
systematic inspection of clinical trial-related activities and documents to evaluate 
whether the trial is conducted in accordance with the trial protocol, standard operating 
procedures and relevant regulatory requirements, and whether the trial data are 
recorded in a timely, true, accurate and complete manner. The audit does not directly 
involve the personnel conducting the clinical trial.  
13. Ethics  


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13.1 Ethics Committee  
The study protocol, informed consent form, subject diary card and other study 
data to be reviewed should be reviewed and approved by the Ethics Committee of the 
study site before the start of the study. The clinical study can only be initiated after the 
approval document is obtained. The above changes can only be implemented after 
approved by the Ethics Committee.  
13.2 Guidance on GCP  
The study must be carried out in accordance with the guidelines of China GCP 
(2003 Edition), Declaration of Helsinki (2013 Edition) and ICH-GCP (2002 Edition), 
so as to provide effective guarantee for protecting the rights, safety and interests of the 
subjects and ensure the reliability of clinical trial data.  
13.3 Informed Consent Form  
Before the subjects are included in this trial, the investigator must fully introduce 
to the subjects or their legal guardians or agents the purpose, procedures, possible 
benefits and risks of this clinical trial, other alternative treatments, and the rights and 
obligations of the subjects in accordance with the Declaration of Helsinki; and shall 
let the subjects know that they have the right to withdraw from this trial at any time, 
without causing any damage to their personal interests. Each subject or his/her legal 
guardian or representative must sign an informed consent prior to enrollment. It was 
the responsibility of the investigator to have each subject obtain a copy of the signed 
informed consent form prior to study entry and to retain a copy of the signed informed 
consent form for the study file.  
13.4 Confidentiality of Subject Information  
Study personnel must protect the privacy of clinical trial subjects. During the 
clinical trial, except for the necessary documents (such as informed consent form), 
only letters, numbers and/or codes can be used to identify subjects in other study 
documents, rather than the real names of subjects. The investigator must properly 
keep the record documents of subject code, name and address. The investigator must 
maintain strict confidentiality on documents that identify the subject.  
14. Trial management  
14.1 Ethics Management  
Before the clinical study is initiated, the investigator should provide the clinical 


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trial protocol, CRF, informed consent form and other documents to the Ethics 
Committee, so as to obtain the approval document for the implementation of clinical 
study through ethical review. All changes to the clinical trial protocol shall be 
maintained as protocol supplements. Any amendments to the study protocol and 
informed consent form should be submitted to the ethics committee for approval 
before implementation.  
During the clinical study, any issues related to the safety of the clinical study, 
such as changes to the clinical study protocol or patient information sheet and serious 
adverse reactions during the clinical study, must be reported to the Ethics Committee 
in a timely manner. The end or early termination of the clinical study must also be 
reported to the Ethics Committee.  
The information on subject recruitment shall be released during the clinical trial. 
No matter which method is adopted, the recruitment can be implemented only after 
the approval of the Ethics Committee is obtained.  
14.2 Training  
Training of study personnel: The principal investigator must ensure that all 
personnel participating in this clinical trial receive the training required for this trial. 
Before this trial is officially started, the study site must hold a kick-off meeting to 
provide a unified training for the personnel participating in the trial to ensure that the 
trial is conducted in accordance with the protocol and GCP. The main contents of 
training include: the development of investigational drug, the introduction of 
preliminary research results; the detailed explanation of protocol content; the 
explanation of informed consent form and the precautions when signing; the recording 
and reporting of serious adverse events and other adverse events; and the precautions 
for filling in CRF. During the course of this trial, the sponsor and the principal 
investigator may decide on the method and content of re-training based on the actual 
situation.  
Training of subjects: The investigator should explain the trial protocol and 
requirements to the subjects in detail from signing the ICF, and inform the subjects of 
some important examination, medication or precautions for return visit by phone 
before return visit (including the return of investigational drug, return of diary card, 
etc.), so as to ensure that the subjects follow the trial protocol.  
14.3 Protocol Deviations and Violations  


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This clinical trial is conducted in accordance with the clinical trial protocol 
approved by the Ethics Committee and the GCP regulations.  
In the process of clinical trials, the phenomenon of deviation from the trial 
protocol due to some reasons occurs, for example: (1) the subject does not meet the 
inclusion criteria, but is included in the trial; (2) the subject does not sign the 
informed consent form, or the subject only signs the informed consent form after 
participating in the trial; (3) the blood sample coagulation for clinical test leads to 
missing test; (4) some laboratory tests are performed that are not approved by the 
Ethics Committee; (5) the subject is not followed up within the time window specified 
in the protocol; (6) the investigator fails to confirm whether the subject meets the 
requirements, so that the subject can use the drug; (7) the subject fails to use the drug 
on time or omits the drug; (8) the investigator issues the wrong test drug or uses the 
wrong drug dose; (9) the serious adverse event is missed or not reported in time; (10) 
the subject uses the prohibited drug, etc. During the clinical trial, in order to ensure 
the safety and health of subjects in emergencies, the investigator may make a decision 
not to comply with the provisions of the trial protocol to implement emergency 
intervention measures.  
The investigator should record in detail the discovery time, occurrence time and 
reason, occurrence process and treatment of the event of deviation and violation of 
trial protocol, and archive them for review. In the event of an emergency, accident, or 
error that results in a significant deviation from, or violation of the protocol, the 
Investigator should promptly notify the Clinical Monitor or Sponsor so that a decision 
can be made as soon as possible regarding the subject's continued participation in the 
clinical trial. The investigator and the clinical monitor should take appropriate 
measures to deal with the deviation and protocol violation. For the clinical trial data 
generated due to deviation and violation of the trial protocol, the handling measures 
shall be discussed and decided when reviewing the trial data.  
14.4 Data Tracking and Verification  
The investigator must ensure that the eCRFs are completed in a timely, 
standardized, complete, and accurate manner. Only one subject's data will be recorded 
on each eCRF. All the data or text filled in incorrectly may not be altered arbitrarily, 
nor may the original record content be masked, and must be modified as required. All 
subjects who have signed the informed consent form to participate in this trial, 


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regardless of whether they complete the trial or not, must keep their eCRFs.  
The investigator must cooperate with the CRA and auditors to view and review 
the data in this clinical trial so as to confirm the authenticity, completeness and 
accuracy of the original data and understand the actual progress of the study.  
14.5 Replacement of Study Sites  
The study site should only be replaced in case of reasons such as slow enrollment 
of subjects, poor compliance with the study protocol and/or GCP, and should not be 
replaced due to drug-related adverse reactions in the trial. Site substitutions must be 
documented.  
14.6 Study Termination and Closure  
14.6.1 Study Termination  
The Sponsor reserves the right to discontinue the study site at any time to 
continue the study. The investigator may also request to terminate the trial, but 
appropriate reasons should be given in advance and agreed by the sponsor. Reasons 
for discontinuation from the trial may include failure of the investigator to comply 
with the trial protocol, operating procedures or GCP requirements, drug safety issues, 
insufficient subjects, etc.  
14.6.2 End of Study  
The completion of the last visit of the last subject during the course of this 
clinical trial is considered the end of the clinical observation process for this clinical 
study. Only when the study site completes the clinical trial summary report and 
transfers it to the sponsor can this clinical study be considered as completed.  
15. Data storage and information use  
15.1 Storage of Materials  
After completing the data entry and verification as required, the original case 
report forms shall be archived and stored in the order of number and filled in the 
retrieval catalogue for reference. Electronic data files, including databases, inspection 
procedures, analysis procedures, analysis results, codebook and description files, shall 
be stored by classification, and multiple backups shall be stored on different disks or 
recording media, and properly kept to prevent damage. All the original files shall be 
preserved according to the time limit specified in Good Clinical Practice for Drugs.  
In order to ensure the evaluation by China Food and Drug Administration and the 


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sponsor, the study site should retain all study data, including all original signed 
informed consent forms, all subject screening and inclusion records, all CRFs, drug 
storage and use records, inpatient records and examination records, etc., in accordance 
with relevant national regulations. The preservation period of all the study data shall 
be at least 5 years; upon the expiry of the preservation period, the study site shall 
contact the sponsor to decide the processing method of the study data and dispose of it 
by itself.  
The ownership of all the data of this clinical trial belongs to the sponsor. Without 
the written consent of the sponsor, the study site and/or investigator should not 
transfer to other units or individuals in any form.  
15.2 Use of Information  
All unpublished information provided by the Sponsor to the Study Site and/or the 
Investigator, including but not limited to information related to the study drug, 
business information of the Sponsor (such as patent situation, formula, production 
process, basic research data, previous clinical data and prescription data), and any 
information derived from the trial and containing the benefit of copyright protection, 
shall be kept confidential and proprietary to the Sponsor. Except for the information 
that must be informed in obtaining the ICF signed by subjects who are willing to 
participate in the trial, the Study Site and the Investigator must keep such information 
confidential and use such information only for the completion of this clinical study 
instead of using such information for other purposes, without the written authorization 
of the Sponsor.  
The Study Site and the Investigator shall understand that the scientific or medical 
information obtained in this clinical trial may be of commercial value to the Sponsor 
or may be used by the Sponsor for further drug development, and thus the Study Site 
and the Investigator are obliged to provide the Sponsor with all the information 
obtained from this trial.  
The sponsor has the right to publicly release the data and information related to 
this study without the consent of the study site and/or investigator. If the Study Site 
and/or the Investigator wishes to release trial-related information to the public, the 
consent of the Sponsor shall be obtained in advance, and the information to be 
published shall be provided to the Sponsor for review and approval 60 days prior to 
submission or presentation before public release. The signature of the public release 


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information related to this study shall be determined by the Sponsor through 
negotiation with the Study Site and the Investigator. Prior to publication of the overall 
clinical study results of a multi-center clinical study, the information from each study 
site may not be published separately.  
Main responsibilities assumed by all parties  
16.1 Principal Investigator Responsibilities  
(1) The investigator should agree with the sponsor on the trial protocol and sign 
it, and report it to the Ethics Committee for review and approval before 
implementation.  
(2) The investigator must read and understand the contents of the trial protocol in 
detail and strictly follow the protocol.  
(3) The investigator should understand and be familiar with the nature, effect, 
efficacy and safety of the investigational drug (including the relevant data of the 
preclinical study of the drug), and should also master all the new information related 
to the drug found during the clinical trial.  
(4) Investigators must conduct clinical trials in medical institutions with good 
medical facilities, laboratory equipment and personnel allocation. Such institutions 
should have all the facilities for dealing with emergencies to ensure the safety of 
subjects; laboratory test results should be accurate and reliable.  
(5) The investigator shall obtain the consent of the medical institution or 
competent unit where he/she is located, and ensure that there is sufficient time to be 
responsible for and complete the clinical trial within the time limit specified in the 
protocol.  
(6) The investigator shall explain the materials, provisions and responsibilities of 
the trial to all the personnel participating in the clinical trial, so as to ensure that a 
sufficient number of subjects who meet the trial protocol enter the clinical trial.  
(7) The investigator should explain the details of the trial approved by the ethics 
committee to the subjects and obtain the informed consent signed by the subjects.  
(8) The investigator is responsible for making medical decisions related to the 
clinical trial to ensure that the subjects receive appropriate treatment when adverse 
events occur during the trial.  
(9) The investigator is obliged to take necessary measures to ensure the safety of 
subjects, and record them. When a serious adverse event occurs during the clinical 


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trial, the investigator should immediately take appropriate therapeutic measures for 
the subject, and report to the national drug regulatory authority, the sponsor and the 
Ethics Committee with his/her name and date signed on the report.  
(10) The investigator should ensure that the data are truthfully, accurately, 
completely, standardized, timely and legally recorded in the medical records and case 
report forms.  
(11) The investigator should accept the monitoring and audit of the clinical 
monitor and/or auditor appointed by the sponsor as well as the audit and inspection of 
the national drug regulatory authority to ensure the quality of the clinical trial.  
(12) The investigator shall negotiate with the sponsor on the cost of clinical trial, 
and specify it in the contract. During the clinical trial, the investigator shall not charge 
the subject any fees necessary for the trial. Upon completion of the clinical trial, the 
investigator must prepare, sign and date the final report, and then submit it to the 
sponsor.  
16.2 Main Responsibilities of Sponsor  
(1) The sponsor should obtain the approval of China Food and Drug 
Administration before carrying out the clinical trial.  
(2) The sponsor is responsible for initiating and applying for clinical trials and 
providing trial funds.  
(3) The sponsor provides the investigator's brochure, which includes the 
pharmaceutical, toxicological, pharmacological and clinical (including previous and 
ongoing trials) data and data of the investigational drug.  
(4) The sponsor and the investigator agree on the clinical trial protocol and sign 
the trial protocol and contract agreed by the two parties.  
(5) The sponsor provides the investigator with investigational drugs that are 
easily identified, correctly coded and labeled with special labels, and ensures that the 
quality is qualified. Investigational medicinal products should be appropriately 
packaged as specified in the trial protocol and stored under validated conditions. The 
sponsor shall establish management system and record system for investigational 
drugs.  
(6) The sponsor shall appoint a qualified clinical research associate and auditor, 
who shall be accepted by the investigator.  
(7) Sponsors shall establish a quality control and quality assurance system for 


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clinical trials, and may organize the audit of clinical trials to ensure the quality.  
(8) The sponsor and the investigator should quickly study the serious adverse 
events occurred, take necessary measures to ensure the safety and rights and interests 
of subjects, and timely report to the national drug regulatory authorities.  
(9) The sponsor shall be responsible for submitting the final report of the trial to 
China Food and Drug Administration.  
(10) The sponsor shall provide necessary guarantee for the subjects participating 
in the clinical trial, and bear the cost of treatment and corresponding economic 
compensation for the subjects with damage or death related to the trial. Except for the 
medical negligence, the Sponsor shall provide guarantee for the Investigator both 
legally and economically.  
17. Expected progress of the trial  
This clinical trial will be carried out after the approval of the Ethics Committee is 
obtained, the investigational drug is in place, and the cooperation agreement is signed. 
The trial period is about 15 months.  
18. References  
(1) Drug Administration Law of the People's Republic of China. 2001.  
(2) Regulation on the Implementation of the Drug Administration Law of the People's 
Republic of China. 2013.  
(3) Provisions for Drug Registration. 2007.  
(4) Good Clinical Practice for Drugs. 2003.  
(5) Declaration of Helsinki. 2013.  
(6) ICH-GCP E6. 2002.  
(7) Investigator's Brochure, Version 3.0. March 2016.  
(8) NCI. CTCAE v4.03. 14 June 2010.  
(9) Chinese Society of Hepatology and Chinese Society of Infectious Diseases. 
Hepatitis C prevention and treatment guidelines (2015 update). Chinese Journal of 
Hepatology. December 2015.  
(10) Expert Committee on Antiviral Therapy for Chronic Hepatitis C. Expert 
consensus on antiviral therapy for chronic hepatitis C. Chinese Journal of 
Experimental and Clinical Infectious Diseases. 2009, 3 (3): 343-352.  
(11) Liver stiffness assessment team. Expert opinion on the diagnosis of liver fibrosis 
by transient elastography. Chinese Journal of Hepatology. 2013, 21 (6): 420-424.  


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(12) Maurizio Bonacini. Use of FibroScan ® inClinical Practice. Medical 
Writers'Circle. 2014. 7.  
(13) CFDA. Guideline on the Requirements for Application Dossier for Virology 
Studies of Antiviral Drugs. Issued on May 15, 2012.  
(14) FDA. Chronic Hepatitis C Virus Infection: Developing Direct-Acting Antiviral 
Drugs for Treatment. October 2013.  
(15) FDA. Guidance for Submitting HCV Resistance Data. February 2013.  
(16) EMA. Guideline on medicinal clinical evaluation of products for the treatment of 
chronic hepatitis C. 2011.01.  
(17) Chen J, Florian J, Carter W, et al. Earlier virologic response end points for 
regulatory approval and dose selection of hepatitis C therapies. Gastroenterology. 
2013, 144 (7): 1450-1455. E2.  
(18) Scott JD. Simplifying the treatment of HIV infection with ritonavir-boosted 
protease inhibitors in antiretroviral-experienced patients. Am J Health Syst Pharm 
2005; 62:805 − 15.  
(19) Quantitative systematic review report on the clinical efficacy of pegylated 
interferon combined with ribavirin in the treatment of hepatitis C in Asian population. 
September 2014.  
(20) Shanghai Roche Pharmaceutical Co., Ltd. Package Insert for Peginterferon Alfa-
2a Injection. 14 January 2013.  
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 1 Liver Biopsy Scores  
Liver biopsy results must be scored as described below. Metavir score ≤ 3 was 
classified as non-cirrhotic.  
METAVIR Fibrosis Score:  
Score 0: No fibrosis  
1 point: Stellate enlargement of portal tract but without septa formation  
2 points: Enlargement of portal tract with rare septa formation  
3 points: Numerous septa without cirrhosis  
4 points: Cirrhosis  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 2 Dose Modification Principles  
For subjects who must have their dose adjusted due to moderate and severe 
adverse reactions, including clinical manifestations and/or laboratory abnormalities, 
PEG-IFNα and RBV therapy should follow the principles described below for dose 
adjustment. Gradual increase or return to the initial dose may be considered as 
adverse effects abate.  
If PEG-IFNα and/or RBV dose adjustment is required, subjects should undergo 
hematological parameters every 1 week or every 2 weeks; investigators should 
promptly assess subjects for AEs (especially neutropenia, anemia, and 
thrombocytopenia) and take appropriate management measures (including PEG-IFN
α and/or RBV dose adjustment and other necessary medical measures) until the AE 
resolves or maintains a stable state.  
1. Hematological parameters  
(1) PEG-IFNα  
Dose reduction should be considered when absolute neutrophil count (ANC) is 
less than 0.75 × 109/L; temporary discontinuation should be considered when ANC is 
less than 0.50 × 109/L, and treatment can be resumed until ANC recovers to greater 
than 1.0 × 109/L. Re-treatment should be started with 90 micrograms and neutrophil 
counts should be monitored.  
When PLT is less than 50 × 109/L, PEG-IFNα dose should be reduced to 90 μg; 
when PLT is less than 25 × 109/L, drug withdrawal should be considered (Table 8).  
If PEG-IFNα is not tolerated, treatment with ASC08/r + RBV can be continued.  
(2) RBV  
The subject has no significant cardiovascular disease and presents HB < 100 g/L 
and ≥ 85 g/L; or when the subject has stable cardiovascular disease and any 4 HB 
drops ≥ 20 g/L during treatment, RBV should be reduced to 600 mg/day. 
Restoration to the original dose is not recommended.  
RBV should be withheld in the following circumstances: the subject has no 
significant cardiovascular disease and HB does drop below 85 g/L; or the subject has 
stable cardiovascular disease and HB persists below 120 g/L after 4 weeks of dose 
reduction. RBV 600 mg/day may be resumed when normal values are restored and 
further increased to 800 mg/day at the discretion of the investigator, but return to the 
original dose is not recommended (Table 8).  


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The dose of RBV may be tapered according to the severity of the AE (Table 9).  
If intolerant to RBV, treatment with ASC08/r + PEG-IFNα can be continued.  
 
 
 
Table 8 Dose Modifications Based on Hematologic Therapy  
PEG-IFNα Dose Modification  
ANC  
< 0.75 × 109/L  
PEG-IFNα was reduced to 135 μg.  
< 0.50 × 109/L  
Withhold PEG-IFN α  until ANC ≥ 1.0 ×  109/L, 
initiate treatment at 90 μg and monitor for changes in 
ANC.  
PLT  
< 50.0 × 109/L, > 
25.0 × 109/L  
PEG-IFNα was reduced to 90 μg.  
< 25.0 × 109/L  
PEG-IFNα therapy was stopped and PLT changes were 
monitored at a frequency of 1 ~ 2 times/week.  
RBV Dose Modification  
HB 
(without 
heart disease)  
< 100 g/L, ≥ 85 
g/L  
Reduce RBV dose to 1000 mg (body weight ≥ 75 kg), or 
800 mg (body weight < 75 kg).  
< 85 g/L  
RBV therapy was suspended.  
HB 
(stable 
cardiac 
disease)  
Any decrease ≥ 
20 g/L  
RBV was reduced to 800 mg (body weight ≥ 75 kg), or 
600 mg (body weight < 75 kg).  
Dose reduction 
for 4 weeks is 
still < 120 g/L  
RBV therapy was suspended.  
 
Table 9 RBV Dose Modification Levels  
Dose  
Weight ≥ 75 kg  
Weight < 75 kg  
Full Dose  
1200 mg/day a.m. (: 600 mg; 
p.m.: 600 mg)  
1000 mg/day a.m. (: 500 mg; 
p.m.: 500 mg)  
Level 1  
1000 mg/day a.m. (: 500 mg; 
p.m.: 500 mg)  
800 mg/day a.m. (: 400 mg; p.m.: 
400 mg)  
2nd level  
800 mg/day a.m. (: 400 mg; p.m.: 
400 mg)  
600 mg/day a.m. (: 300 mg; p.m.: 
300 mg)  
 
2. ALT  
Liver function often fluctuates in patients with chronic hepatitis. Increases in 
ALT occur after treatment with PEG-IFNα, including in patients with improved viral 
response. A dose reduction to 135 μg should be considered when patients with 
hepatitis C present with persistent elevations of ALT up to 10-fold and TBIL more 
than 2 ULN. After dose reduction, if ALT elevation persists, or bilirubin elevation or 
hepatic decompensation occurs, immediate discontinuation should be considered.  
 
 
 


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Appendix 3 NCI CTCAE (v4.03)  
Common toxicity grades  
Adverse events  
Grading  
1  
2  
3  
4  
5  
Blood/lymphatic system  
Anemia  
Hemoglobin (Hgb) < LLN - 
100 g/L  
Hgb from 80 to 100 g/L  
Hgb < 80 g/L  
Life-threatening; 
urgent 
treatment indicated  
Death  
Febrile 
neutropenia  
-  
-  
Absolute 
neutrophil 
count 
(ANC) < 1.0 × 109/L with body 
temperature > 38.3℃ or body 
temperature  38℃ for more 
than 1 hour  
Life-threatening; 
urgent 
treatment indicated  
Death  
Leukopenia  
< LLN-3.0 × 109/L  
< 3.0-2.0 × 109/L  
< 2.0-1.0 × 109/L  
< 1.0 × 109/L  
-  
Neutropenia  
< LLN-1.5 × 109/L  
< 1.5-1.0 × 109/L  
< 1.0-0.5 × 109/L  
< 0.5 × 109/L  
-  
Thrombocytope
nia  
< LLN- 75.0 × 109/L  
< 75.0-50.0 × 109/L  
< 50.0 - 25.0 × 109/L  
< 25.0 × 109/L  
-  
Lymph 
node 
pain  
Mild pain  
Moderate pain; interference 
with instrumental activities of 
daily living  
Severe pain; interfere with 
personal activities of daily 
living  
-  
-  
Blood/lymphati
c system  
(Others)  
Asymptomatic 
or 
mild 
symptoms; 
no 
treatment 
required  
Moderate; minimal, local, or 
noninvasive 
treatment; 
influence 
age-appropriate 
instrumental sexual activity  
Severe or significant clinical 
symptoms, 
but 
not 
life-
threatening; hospitalization or 
prolongation of hospitalization 
indicated; disabling; interfering 
with personal activities of daily 
living  
Life-threatening; 
urgent 
treatment indicated  
Death  
Coagulation function  
Activated 
partial 
thromboplastin 
time (Aptt)  
> 1-1.5 x ULN  
> 1.5-2.5 x ULN  
> 2.5 x ULN; bleeding  
-  
-  


Number：NCT03020082                                                                            ID：ASC-DNVr-II/III-CTP-02 
 
72 / 83 
Adverse events  
Grading  
1  
2  
3  
4  
5  
Fibrinogen 
decreased  
< 1.0 - 0.75 x lower limit of 
normal or < 25% decrease 
from baseline  
< 0.75 - 0.5 x lower limit of 
normal or 25% - < 50% 
decrease from baseline  
< 0.5 - 0.25 x lower limit of 
normal or 50 - < 75% decrease 
from baseline  
< 0.25 x lower limit of normal 
or 75% decrease from baseline, 
or absolute value < 50 mg/Dl  
-  
Metabolism and malnutrition  
Anorexia  
Decreased appetite without 
change in eating habits  
Change in food intake without 
weight loss or malnutrition; 
oral 
nutritional 
supplementation required  
Significant 
weight 
loss 
or 
symptoms of malnutrition (e.g., 
inadequate 
caloric 
intake); 
requiring nasogastric or total 
parenteral nutrition  
Life-threatening; 
urgent 
treatment indicated  
-  
Dehydration  
Increased fluid intake; dry 
mucous 
membranes; 
inadequate filling of cutaneous 
vessels  
Infusion required < 24 hours  
Requires 
infusion 
or 
hospitalization  
Life-threatening; 
urgent 
treatment indicated  
Death  
TBIL  
> ULN-1.5x ULN  
> 1.5-3.0x ULN  
> 3.0-10.0 × ULN  
> 10.0Xuln  
-  
ALT  
> ULN - 3.0 × ULN  
> 3.0-5.0 × ULN  
> 5.0-20.0 × ULN  
> 20 × ULN  
-  
AST  
> ULN - 3.0 × ULN  
> 3.0-5.0 × ULN  
> 5.0-20.0 × ULN  
> 20 × ULN  
-  
GGT  
> ULN - 2.5 × ULN  
> 2.5-5.0 × ULN  
> 5.0-20.0 × ULN  
> 20 × ULN  
-  
ALP  
> ULN - 2.5 × ULN  
> 2.5-5.0 × ULN  
> 5.0-20.0 × ULN  
> 20 × ULN  
-  
Hypercholester
olemia  
> ULN- 300 mg/Dl;  
> ULN-7.75 mmol/L  
> 300-400 mg/Dl; > 7.75-10.34 
mmol/L  
> 400-500 g/Dl; > 10.34-12.92 
mmol/L  
> 500 mg/Dl; > 12.92 mmol/L  -  
Hyperglycaemi
a  
Fasting 
glucose 
concentration > ULN - 160 
mg/dL; 
fasting 
glucose 
concentration > ULN - 8.9 
mmol/L  
Fasting 
glucose 
concentration 
> 
160-250 
mg/Dl; 
fasting 
glucose 
concentration 
> 
8.9-13.9 
mmol/L  
> 250-500 mg/Dl; > 13.9-27.8 
mmol/L; 
hospitalization 
indicated  
> 500 mg/Dl; > 27.8 mmol/L; 
life-threatening  
Death  
Hypoalbumine
mia  
< LLN-3.0 g/Dl  
< 3.0-2.0 g/Dl  
< 2.0 g/Dl  
Life-threatening; 
urgent 
treatment indicated  
Death  
Hypocalcemia  
< LLN-8.0 mg/Dl;  
< LLN-2.0 mmol/L  
< 8.0-7.0 mg/Dl;  
< 2.0-1.75 mmol/L;  
Symptomatic  
< 7.0-6.0 mg/Dl;  
< 1.75-1.5 mmol/L;  
Requires hospitalization  
< 6.0 mg/Dl;  
< 1.5 mmol/L;  
Life Threatening  
Death  
Hyponatremia  
< LLN - 130 mmol/L  
-  
< 130-120 mmol/L  
< 120 mmol/L;  
Deat


Number：NCT03020082                                                                            ID：ASC-DNVr-II/III-CTP-02 
 
73 / 83 
Adverse events  
Grading  
1  
2  
3  
4  
5  
Life Threatening  
h  
Hypokalemia  
< LLN - 3.0 mmol/L  
< 
LLN 
- 
3.0 
mmol/L; 
symptomatic; 
treatment 
required  
< 
3.0-2.5 
mmol/L; 
hospitalization indicated  
< 2.5 mmol/L; life-threatening  
Deat
h  
Alimentary tract  
Oral mucositis  
Asymptomatic 
or 
mild 
symptoms; 
no 
treatment 
required  
Moderate 
pain; 
does 
not 
interfere with food intake; 
requires dietary modification  
Severe pain; affecting eating in 
panic  
Life-threatening; 
urgent 
treatment indicated  
Death  
Nausea  
Loss of appetite, but no change 
in eating habits  
Reduced food intake without 
significant 
weight 
loss, 
dehydration, or malnutrition  
Insufficient intake of energy or 
water; 
nasogastric 
feeding 
required; 
total 
parenteral 
nutrition 
or 
hospitalization 
required  
Life-threatening; 
urgent 
treatment indicated  
-  
Vomiting  
1-2 episodes in 24 hours (5 
minutes apart)  
3-5 episodes in 24 hours (5 
minutes apart)  
More than 6 episodes within 24 
hours 
(5 
minutes 
apart); 
required nasogastric feeding; 
total parenteral nutrition or 
hospitalization  
Life-threatening; 
urgent 
treatment indicated  
Death  
Diarrhea  
< 4 stools/day increase from 
pretreatment; mild increase in 
ostomy output  
4-6 
stools/day 
more 
than 
pretreatment; 
moderate 
increase in ostomy output  
Increase in stool frequency ≥ 7 
stools/day from pretreatment; 
fecal 
incontinence; 
severe 
increase in ostomy output; 
interference 
with 
personal 
activities of daily living  
Life-threatening; 
urgent 
treatment indicated  
Death  
Constipation  
Occasional 
or 
intermittent 
symptoms; occasional need 
for stool softeners, laxatives, 
dietary 
modification, 
or 
enemas  
Persistent symptoms, regular 
use of laxatives or enemas; 
interference with instrumental 
activities of daily living  
Obstinate 
constipation 
requiring 
manual 
dredging; 
influence on personal activities 
of daily living  
Life-threatening; 
urgent 
treatment indicated  
Death  
Gastrointestinal 
haemorrhage  
Mild; no treatment required  
Moderate; requires medical 
treatment or minor hemostatic 
Requirement for transfusion, 
radiology, 
endoscopic 
or 
Life-threatening; 
urgent 
treatment indicated  
Death  


Number˖NCT03020082                                                                            ID˖ASC-DNVr-II/III-CTP-02 
 
74 / 83 
Adverse events  
Grading  
1  
2  
3  
4  
5  
treatment  
elective surgery  
Gastrointestinal 
perforation  
-  
Symptomatic; 
medical 
treatment indicated  
Severe 
symptoms; 
elective 
surgery indicated  
Life-threatening; 
urgent 
treatment indicated  
Death  
Renal/Urinary  
Acute 
kidney 
injury  
Increase in creatinine level of 
greater than 0.3 mg/dl; or 
between 1.5 and 2.0 times the 
baseline  
Creatinine 2-3 fold above 
baseline  
Creatinine greater than 3 x 
baseline or greater than 4.0 
mg/dl; hospitalization indicated 
Life-threatening; 
requiring 
dialysis  
Death  
Chronic kidney 
injury  
Glomerular filtration rate or 
creatinine clearance less than 
60ml/min/1.73 m2, proteinuria 
2 +; urine protein greater than 
0.5  
Glomerular filtration rate or 
creatinine 
clearance 
59-30 
ml/min/1.73 m2  
 
Glomerular filtration rate or 
creatinine 
clearance 
29-15 
ml/min/1.73 m2  
 
Glomerular filtration rate or 
creatinine clearance  
Rate less than 15 ml/min/1.73 
m2; 
requiring 
dialysis 
or 
transplant  
Death  
Renal 
hemorrhage  
Mild symptoms, intervention 
not indicated  
Analgesic 
use 
requiring 
hematocrit monitoring  
Requires transfusion, radiology, 
hospitalization; 
requires 
elective radiology, endoscopy, 
or surgery  
Life-threatening; 
urgent 
radiation required  
Medical or surgical treatment  
Death  
Creatinine  
> ULN-1.5 × ULN;  
> 1 — 1.5 times of baseline 
value;  
> 1.5-3.0 × ULN;  
> 1.5 — 3.0 times baseline 
value  
> 3.0-6.0 × ULN;  
> 3.0 times baseline value;  
> 6.0 × ULN  
Death  
Proteinuria  
Proteinuria 1 +, 24 hour urine 
protein less than 1.0g  
Adults: proteinuria 2 +, 24-
hour urine protein 1.0-3.4g, 
children: 
urine 
(protein/creatinine) ratio 0.5-
1.9  
Adults: 24-hour urine protein  
3.5g, 
children: 
urine 
protein/creatinine ratio greater 
than 1.9  
-  
-  
Haematuria  
Asymptomatic, 
clinical 
observations 
or 
diagnostic 
findings only, no treatment 
required  
Mild 
symptoms 
requiring 
urinary catheter or bladder 
cleansing; interference with 
instrumental activities of daily 
living  
Extensive hematuria requiring 
transfusion, 
intravenous 
administration, 
or 
hospitalization; 
elective 
endoscopic, 
radiation, 
or 
surgical intervention indicated; 
Life-threatening; 
urgent 
radiological 
or 
surgical 
intervention indicated  
Death  


Number：NCT03020082                                                                            ID：ASC-DNVr-II/III-CTP-02 
 
75 / 83 
Adverse events  
Grading  
1  
2  
3  
4  
5  
influence on personal activities 
of daily living  
Renal 
and 
urinary 
disorders 
(other)  
Asymptomatic 
or 
mild 
symptoms, 
clinical 
observations 
or 
diagnostic 
observations 
only; 
intervention not indicated  
Moderate symptoms; local or 
noninvasive 
intervention 
indicated; interference with 
instrumental activities of daily 
living  
Severe or significant clinical 
symptoms not life-threatening; 
hospitalization or prolongation 
of hospitalization indicated; 
influence on personal activities 
of daily living  
Life-threatening; 
urgent 
treatment indicated  
Death  
Respiratory  
Cough  
Mild symptoms; require over 
the counter treatment  
Moderate symptoms; clinical 
drug 
therapy 
indicated; 
interference with instrumental 
activities of daily living  
Severe symptoms; influence 
personal activities of daily 
living  
-  
-  
Dyspnea  
Shortness 
of 
breath 
with 
moderate activity  
Shortness 
of 
breath 
with 
minimal activity; instrumental 
activities 
of 
daily 
living 
affected  
Shortness of breath at rest; 
influence personal activities of 
daily living  
Life-threatening; 
urgent 
treatment indicated  
Death  
Epistaxis  
Mild symptoms; intervention 
not indicated  
Moderate 
symptoms; 
intervention indicated (cotton 
wool 
packing, 
hemostasis, 
topical vasoconstrictor)  
Need 
for 
transfusion, 
radiotherapy, 
endoscopy, 
surgery (hemostasis at bleeding 
site)  
Life-threatening; 
urgent 
treatment indicated  
Death  
Pneumonia  
Asymptomatic; 
clinical 
examination 
or 
diagnostic 
finding only; intervention not 
indicated  
Symptomatic; 
intervention 
indicated; 
instrumental 
activities 
of 
daily 
living 
affected  
Severe symptoms; influence 
personal activities of daily 
living; 
require 
oxygen 
inhalation  
Life-threatening 
respiratory 
disorder; 
urgent 
treatment 
indicated (tracheostomy or  
Cannula)  
Death  
Cardiac/Cardiovascular  
Acute coronary 
syndrome  
-  
Symptomatic, 
progressive 
angina; 
normal 
cardiac 
enzymes; 
hemodynamically 
stable  
Symptomatic, unstable angina 
with/or 
acute 
myocardial 
infarction, abnormal cardiac 
enzymes, 
hemodynamically 
stable  
Symptomatic, unstable angina 
with/or 
acute 
myocardial 
infarction, abnormal cardiac 
enzymes, 
hemodynamic 
instability  
Death  


Number：NCT03020082                                                                            ID：ASC-DNVr-II/III-CTP-02 
 
76 / 83 
Adverse events  
Grading  
1  
2  
3  
4  
5  
Hypertension  
Prehypertension 
(systolic 
blood pressure between 120 
and 139 mmHg, diastolic 
blood pressure between 80 and 
89 mmHg)  
Stage I hypertension (systolic 
blood 
pressure 
140-159 
mmHg, 
diastolic 
blood 
pressure 
90-99 
mmHg); 
medical intervention indicated; 
recurrent or persistent (greater 
than or equal to 24 hours); 
symptomatic 
increase 
in 
systolic blood pressure greater 
than 20 mmHg or to greater 
than 
140/90 
mmHg 
after 
previous 
normal 
blood 
pressure; medical treatment 
indicated.  
Pediatrics: 
Repeated 
or 
persistent (greater than or equal 
to 24 hours) blood pressure 
above the upper limit of 
normal; requiring treatment.  
Stage II hypertension (systolic 
blood pressure greater than or 
equal to 160 mmHg, diastolic 
blood pressure greater than or 
equal to 100 mmHg); medical 
intervention 
indicated; 
polypharmacy indicated;  
Pediatrics: Same as adults  
Life-threatening (eg, malignant 
hypertension, 
transient 
or 
persistent 
neurologic 
impairment, 
hypertensive 
crisis); 
urgent 
intervention 
indicated;  
Pediatrics: Same as adults  
Death  
Thromboemboli
c events  
Venous 
thrombosis 
(e.g., 
superficial)  
Venous 
thrombosis 
(e.g. 
uncomplicated 
deep 
vein 
thrombosis) requiring medical 
intervention  
Thrombus (e.g. uncomplicated 
pulmonary embolism (venous), 
non-embolic 
cardiovascular 
thrombosis (arterial)) requiring 
medical intervention  
Life-threatening 
(e.g., 
pulmonary 
embolism, 
cerebrovascular 
event, 
insufficient arterial supply); 
hemodynamic or neurological 
dysfunction; urgent treatment 
indicated  
Death  
Myocardial 
infarction  
-  
Asymptomatic, 
minimally 
abnormal cardiac enzymes, no 
regional absence, no evidence 
of ischemic ECG changes  
Severe symptoms; myocardial 
enzyme 
changes; 
haemodynamic stability; ECG 
changes consistent with the 
diagnosis 
of 
myocardial 
infarction  
Life-threatening; 
hemodynamic imbalance  
Death  


Number˖NCT03020082                                                                            ID˖ASC-DNVr-II/III-CTP-02 
 
77 / 83 
Adverse events  
Grading  
1  
2  
3  
4  
5  
Left ventricular 
systolic 
dysfunction  
-  
-  
- Symptoms associated with 
decreased 
heart 
rate 
and 
response to treatment  
Refractory 
or 
uncontrolled 
heart failure due to a reduced 
score; 
requiring 
ventricular 
assist 
device, 
intravenous 
vasopressor therapy, or heart 
transplantation  
Death  
Cardiac 
troponin 
I 
(cTnI) increased 
Above the upper limit of 
normal, 
below 
the 
level 
defined by the manufacturer 
for 
the 
diagnosis 
of 
myocardial infarction  
-  
Achieve the level defined by the 
manufacturer for myocardial 
infarction  
-  
-  
Cardiac 
troponin 
T 
(cTnT) 
increased  
Above the upper limit of 
normal, 
below 
the 
level 
defined by the manufacturer 
for 
the 
diagnosis 
of 
myocardial infarction  
-  
Achieve the level defined by the 
manufacturer for myocardial 
infarction  
-  
-  
QT 
prolongation  
QTc 450-480 ms  
QTc 481-500 ms  
QTc  501 ms on at least two 
ECGs  
QTc ≥ 501 or change from 
baseline 
> 
60 
ms 
and 
signs/symptoms of Torsade de 
Pointes or severe arrhythmia  
-  
Decrease 
in 
score  
-  
Resting EF 40-50%; 10-19% 
below baseline  
Resting EF 20-39%; > 20% 
below baseline  
Resting score (EF) < 20%  
-  
Nervous system  
Ataxia  
Asymptomatic; 
clinical 
symptoms 
or 
diagnostic 
findings only; intervention not 
indicated  
Moderate 
symptoms; 
interference with instrumental 
activities of daily living  
Severe symptoms; influence 
personal activities of daily 
living; mechanical assistance 
required  
-  
-  
Cognitive 
impairment  
Mild cognitive impairment; no 
influence on work/life/study; 
no need for special educational 
services/devices  
Moderate 
cognitive 
impairment; 
work/life/study 
related, but independent; short 
term care by specialized staff  
Severe cognitive impairment; 
significant 
impact 
on 
work/life/study  
-  
-  


Number：NCT03020082                                                                            ID：ASC-DNVr-II/III-CTP-02 
 
78 / 83 
Adverse events  
Grading  
1  
2  
3  
4  
5  
Headache  
Mild headache  
Moderate headache; affecting 
instrumental days  
Regular life activities  
Severe 
headache; 
personal 
everyday  
Activities of life  
-  
-  
Vertigo  
Mild instability or movement 
sensation  
Moderately unstable; affecting 
instrumental activities of daily 
living  
Severe instability; influence 
personal activities of daily 
living  
-  
-  
Other  
Hypothyroidis
m  
Asymptomatic; clinical exam 
or diagnostic findings only; no 
treatment required  
Symptomatic; thyroid hormone 
replacement 
therapy; 
instrumental activities of daily 
living affected  
Serious; influence on personal 
activities 
of 
daily 
living; 
hospitalization indicated  
Serious; influence on personal 
activities 
of 
daily 
living; 
hospitalization indicated  
Death  
Adrenal 
insufficiency  
Asymptomatic; clinical exam 
or diagnostic findings only; no 
treatment required  
Moderate symptoms; medical 
intervention indicated  
Severe 
symptoms; 
hospitalization indicated  
Life-threatening; 
urgent 
treatment indicated  
Death  
Insomnia  
Mild 
difficulty 
sleeping, 
staying asleep or waking up 
early  
Moderate difficulty sleeping, 
staying asleep or waking up 
early  
Severe 
difficulty 
sleeping, 
staying asleep or waking up 
early  
-  
-  
Alopecia  
Hair loss is not more than 
50%, there is no difference in 
the distance, but it can be seen 
in the near. Hair loss needs to 
be concealed by changing the 
hair style, but no wig or wig 
block is needed to conceal it  
Hair loss greater than 50%, 
significant symptoms, need for 
a 
wig 
or 
wig 
block, 
psychologically influential  
-  
-  
-  
Hand-foot 
syndrome  
Slight painless skin changes or 
dermatitis 
(e.g. 
erythema, 
edema, hyperkeratosis)  
Painful skin changes (e.g. 
flaking, blistering, bleeding, 
swelling, 
hyperkeratosis); 
interference with instrumental 
activities of daily living  
Severe skin changes (flaking, 
blistering, bleeding, edema, 
hyperkeratosis) 
with 
pain; 
influence personal activities of 
daily living  
-  
-  
Pain (not due to 
tumor)  
Mild pain  
Moderate pain; interference 
with instrumental activities of 
Severe pain; influence personal 
activities of daily living  
-  
-  


Number：NCT03020082                                                                            ID：ASC-DNVr-II/III-CTP-02 
 
79 / 83 
Adverse events  
Grading  
1  
2  
3  
4  
5  
daily living  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Number：NCT03020082                                                                            ID：ASC-DNVr-II/III-CTP-02 
 
80 / 83 
Appendix 4 Test Flow  
 
Screening 
Period  
Treatment Period 11  
Post-Treatment Follow-up Period  
Number of visits  
V1  
V2  
V3  
V4  
V5  
V6  
V7  
V8  
V9  
V10  
Visit time  Day  
- 28-1  
1  
8  
15  
29  
57  
85  
113  
169  
253  
Week  
- 4-0  
 
1  
2  
4  
8  
12  
16  
24  
36  
Window (day)  
 
± 0  
± 0  
± 1  
± 1  
± 2  
± 2  
± 7  
± 7  
± 7  
Signed 
informed 
consent  
×  
 
 
 
 
 
 
 
 
 
Check 
inclusion/exclusion 
criteria  
×  
 
 
 
 
 
 
 
 
 
Demographic data  
×  
 
 
 
 
 
 
 
 
 
Past 
medical/medication 
history  
×  
 
 
 
 
 
 
 
 
 
Vital Signs  
×  
× 10  
×  
×  
×  
×  
×  
×  
×  
×  
Physical Exam 1  
×  
× 10  
×  
×  
×  
×  
×  
×  
×  
×  
BMI  
×  
 
 
 
 
 
 
 
 
 
Anti-HAV (IgM)  
×  
 
 
 
 
 
 
 
 
 
HBsAg  
×  
 
 
 
 
 
 
 
 
 
Anti-HEV (IgM)  
×  
 
 
 
 
 
 
 
 
 
Anti-HIV  
×  
 
 
 
 
 
 
 
 
 
Anti-HCV  
×  
 
 
 
 
 
 
 
 
 
Fundoscopy  
×  
 
 
 
 
 
 
 
 
 


Number：NCT03020082                                                                            ID：ASC-DNVr-II/III-CTP-02 
 
81 / 83 
FibroScan Scan 2  
×  
 
 
 
 
 
 
 
 
 
Liver biopsy 3  
×  
 
 
 
 
 
 
 
 
 
HCV Genotyping 4  
×  
 
 
 
 
 
 
 
 
 
IL28B Genotyping 4 
×  
 
 
 
 
 
 
 
 
 
HCV RNA4  
×  
× 10  
×  
×  
×  
×  
×  
×  
×  
×  
TEST PROCEDURES (Continued)  
 
Screenin
g Period  
Treatment Period 10  
Post-Treatment Follow-up Period  
Number of visits  
V1  
V2  
V3  
V4  
V5  
V6  
V7  
V8  
V9  
V10  
Visit time  Day  
- 28-1  
1  
8  
15  
29  
57  
85  
113  
169  
253  
Week  
- 4-0  
 
1  
2  
4  
8  
12  
16  
24  
36  
Window (day)  
 
± 0  
± 0  
± 1  
± 1  
± 2  
± 2  
± 7  
± 7  
± 7  
Drug Resistance 
Surveillance 4  
×  
× 10  
×  
×  
×  
×  
×  
×  
×  
×  
Blood routine 5  
×  
× 10  
×  
×  
×  
×  
×  
×  
×  
×  
Urinalysis 5  
×  
× 10  
×  
×  
×  
×  
×  
×  
×  
×  
Blood chemistry 5  
×  
× 10  
×  
×  
×  
×  
×  
×  
×  
×  
Blood electrolytes 5  
×  
× 10  
 
 
 
 
×  
 
 
 
Coagulation 5  
×  
× 10  
 
 
×  
×  
×  
 
 
 
Thyroid Function 6  
×  
× 10  
 
 
×  
×  
×  
 
 
 
HbA1c7  
×  
 
 
 
 
 
 
 
 
 
Immunological 
examination  
×  
 
 
 
 
 
 
 
 
 
AFP  
×  
 
 
 
 
 
 
 
 
 
Color Doppler 
×  
 
 
 
 
 
 
 
 
 


Number：NCT03020082                                                                            ID：ASC-DNVr-II/III-CTP-02 
 
82 / 83 
Ultrasound  
ECG  
×  
× 10  
 
 
×  
×  
×  
 
 
 
Pregnancy test 8  
×  
× 10  
 
 
×  
×  
×  
×  
×  
×  
Dispense drug9  
 
×  
 
×  
×  
×  
 
 
 
 
Recovered Drug 9  
 
 
 
×  
×  
×  
×  
 
 
 
Issue diary  
×  
×  
 
×  
×  
×  
×  
×  
×  
 
Recycling diary  
 
×  
 
×  
×  
×  
×  
×  
×  
×  
Record concomitant 
medication  
×  
×  
×  
×  
×  
×  
×  
×  
×  
×  
Recording AEs  
×  
×  
×  
×  
×  
×  
×  
×  
×  
×  
1. The height of the subject is measured only during the screening period, and may not be measured during the treatment period and post-
treatment follow-up period.  
2. If the subject has been examined at the study site within 1 month before screening, the examination may not be performed at the screening 
period.  
3. Only perform this examination when necessary according to the inclusion criteria; this project completes the pathological examination at the 
study site; and the Metavir score for the pathological specimen is completed at the central laboratory.  
4. For this project, blood samples will be collected at the study site and tested at the central laboratory.  
5. These tests may not be performed at Visit 2 if they were performed within 3 days before Visit 2.  
6. Only TSH, T3 and T4 are measured at screening, and only TSH is measured at baseline and during treatment.  
7. Test this only in diabetic patients.  
8. Only for women of childbearing potential.  


Number：NCT03020082                                                                            ID：ASC-DNVr-II/III-CTP-02 
 
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9. Parosin can be distributed, recovered, and destroyed together with ASC08 tablets, RTV, and RBV, or separately. Only one dose of Pegasys ® 
can be dispensed at V2 and V3, respectively; multiple doses of Pegasys ® can be dispensed at visits during the remaining treatment periods.  
10. It should be completed before the first dose in the morning of the same day as the baseline.  
11. The first dose in the morning of each visit should be administered after completion of fasting (at least 8 hours) blood sample collection.  

SAP_000.pdf: 
                                                               PUCRI Plan and Budget 
2016-04-21                                                                               1 
 
Peking University Clinical Research Institute  
Statistical Analysis Plan  
 
Customer Name:  
Ascletis Pharmaceuticals Co., Ltd.  
Project title:  
Evaluate ritonavir-intensified ASC08 tablets in combination
pegylated interferon and  
Ribavirin in treatment-naive patients with chronic hepati
virus genotype 1 infection  
Multicenter, open-label phase III clinical study of the efficac
safety in non-cirrhotic patients  
Main content:  
Protocol design, statistical analysis  
Contact person:  
Yan Xiaoyan 010-82805838-1022  
Responsible Person:  
Prof. Yao Chen  
 
 
Date: March 21, 2017  
 
 


                                                               PUCRI Plan and Budget 
2016-04-21                                                                               2 
1.1 Protocol design  
1.1.1 Test design  
Participate in the design of the protocol and design the trial protocol jointly with the leading 
site, including whether the control, blind method, hypothesis test method, setting of main efficacy 
indicators and other links are used.  
1.1.2 Sample Size Calculation  
The required sample size was calculated from the primary efficacy measures and trial design 
using PASS11 software.  
1.2 Statistical Analysis  
1.2.1 Biostatistics and Analysis Report  
The statistician designates a biostatistician to complete the corresponding statistical analysis 
and prepare the corresponding analysis table and list. The biostatistician completes the statistical 
analysis report.  
1.2.2 Statistical Analysis Plan and Tables  
The statistician expands and designs a statistical analysis plan (SAP) based on the statistical 
methods provided in the protocol. The SAP will provide a reasonable description of the analysis 
population, an objective analysis of the study's efficacy and safety, and a presentation of statements 
and summaries to make the abstract of the data contained in the final study report understandable 
and allow for appropriate statistical testing.  
The SAP will be drafted by the Biostatistician, reviewed and revised by the Sponsor's 
representative and the Principal Investigator, and finalized. The SAP served as a guideline for 
programming, analysis, and report writing. The SAP is subject to 2 rounds of sponsor review prior 
to finalization.  
The biostatistician prepares the sample of statistical tables, which will describe the format of 
the upcoming tables and can truly describe the information reflected in the analysis results. These 
tables have a certain format on the basis of SAP. The form will also be sent to the investigator and 
sponsor for further review and discussion.  
1.2.3 Statistical procedures  
The statistician's biostatistician and programmer will prepare the 
corresponding programming plan, analyze the program, simulate the run and produce 


                                                               PUCRI Plan and Budget 
2016-04-21                                                                               3 
the statistical analysis and summary table according to the above SAP.  
1.2.4 Statistical Analysis of Data  
Generates the draft analysis report based on SAP and program run results.  
1.2.5 Procedure and report review  
Check possible logic errors in the program, browse the draft analysis report, 
perform the analysis twice, and write the quality control report.  
1.2.6 Statistical Report  
The Biostatistician will submit the draft analytical report with the complete analytical results 
to the Sponsor, solicit comments from the Sponsor and the Investigator, make corresponding 
revisions, and finalize it.  
1.3 Project Management  
1.3.1 Sponsor Meetings  
The sponsor and the statistician discuss some main points, reiterate some 
necessary reports, review the schedule, and clarify other issues of common 
concern.  
1.3.2 Project Schedule Management  
The statistician will designate a project manager within the company to contact the sponsor. 
His responsibility is to carry out daily communication between the sponsor and the statistician's 
project team, and to convey the progress of the project, problems arising, suggestions and decisions 
to solve the problems to the sponsor. The statistician shall discuss the project schedule and relevant 
issues with the Data Management Project Team on a regular basis to make scientific preparations 
for the project.  
1.3.3 Periodic Reports  
The PM shall prepare the monthly report and send it to the Sponsor on a 
regular basis, in the format fixed by the statistician or provided by the Sponsor 
itself, and report at an interval of 4 weeks.  


                                                               PUCRI Plan and Budget 
2016-04-21                                                                               4 
1.3.4 Consumables  
Perform and archive essential office consumables for the project.  
 
2 Project Overview  
Project Overview: A Multi-centered, Open Label, Phase III Study on Efficacy, 
Safety of Ritonavir-boosted ASC08 (Danoprevir) in Combination With Peg-IFN and 
RBV in Treatment-Naive Non-Cirrhotic Patients Who Have Chronic Hepatitis Genotype 
1  
Design: Single arm open  
Data collection: Tigermed EDC  
Random system: None  
This offer is a supplemental interim analysis offer.  
3 Project Team Composition  
Project Team Composition  
Number of people  
Senior Statistician (SBS)  
1  
Statistician (BS)  
1  
Programmer (PR)  
1  
 
4 Service Content  
Service Content  
SBS  
BS  
PR  
Man-hour  
Man-hour  
Man-hour  
Write statistical analysis 
plan  
0  
0  
0  
Data arrangement and docking  
0  
16  
24  
Review Statistical Analysis 
Plan  
0  
0  
0  
Writing Statistical Analysis 
Procedures  
0  
0  
0  
Writing Statistical Analysis 
Report (Chinese)  
12  
48  
0  
Statistical report review  
16  
0  
0  
Total  
28  
64  
24