KW-136_III: KW-136 With Sofosbuvir for Chinese Adults With Chronic Hepatitis C

Sponsor

Kawin Technology Share-holding Co., Ltd. (Industry)

Overall Status

Completed

CT.gov ID

NCT03995485

Collaborator

KawinGreen Biotech Co., Ltd. (Other)

371

Enrollment

Locations

Arm

Actual Duration (Months)

19.5

Patients Per Site

2.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study aimed to confirm efficacy and safety of KW-136, an investigational anti-hepatitis C virus (HCV) drug, combined with sofosbuvir for treatment of naive and experienced adults chronically infected with HCV. Three hundred and sixty (360) non-cirrhotic and cirrhotic subjects were medicated with KW-136 60 mg daily and sofosbuvir 400 mg daily. The treatment course lasted 12 successive weeks; thereafter all the study participants entered into a 12-week treatment-free follow-up period and an additional 12-week extension treatment-free follow-up period.

Condition or Disease	Intervention/Treatment	Phase
Hepatitis C, Chronic	Drug: KW-136 capsule Drug: Sofosbuvir	Phase 3

Detailed Description

It is estimated that China has a population of over 10 million infected with HCV and also a highly variable HCV genotype geographic distribution. A simple, universal, non-genotype-specific treatment regimen is preferred for anti-HCV treatment in clinical practice and public health. KW-136 and sofosbuvir are potent anti-HCV agents targeting at different HCV proteins, namely, nonstructural protein 5A and 5B, respectively. The combination regimen of KW-136 and sofosbuvir is expected to completely suppress HCV replication in subjects chronically infected with HCV and achieve a sustained virologic response (SVR12), namely, HCV not detected or below a predefined limit in plasma, 12 or 24 weeks after cessation of treatment.

In a previous phase 2 exploratory study, an all-oral, ribavirin-free regiment of KW-136, an investigational HCV NS5A inhibitor, combined with sofosbuvir, demonstrated a ~99% SVR12 in treatment-naive adult subjects chronically infected with major genotypes of HCV found in China, including those with compensatory cirrhosis. This phase 3 study aimed to confirm the efficacy and safety of this combined regimen in a large scale of target patient population, including interferon-experienced subjects. This simple, uniform regimen is expected to be the solution to HCV eradication in China from the perspective of public health.

Study Design

Study Type:

Interventional

Actual Enrollment :

371 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Intervention Model Description:

Single-arm, external (historic) controlSingle-arm, external (historic) control

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Evaluation of Efficacy and Safety of KW-136 Capsule Combined With Sofosbuvir Tablet for Treatment of Adult Chronic Hepatitis C: an Open-label, Multi-center, Phase 3 Study

Actual Study Start Date :

Jun 7, 2017

Actual Primary Completion Date :

Jan 25, 2018

Actual Study Completion Date :

Mar 7, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: KW-136+SOF Treatment-naive and experienced subjects were medicated with KW-136 capsules 60 mg once daily and fixed-dose (400 mg once daily) sofosbuvir tablets for 12 successive weeks.	Drug: KW-136 capsule KW-136 60 mg was provided in a single capsule of 60 mg. Other Names: Coblopasvir Drug: Sofosbuvir Sofosbuvir was provided in a single tablet of 400 mg.

Arm

Intervention/Treatment

Experimental: KW-136+SOF

Treatment-naive and experienced subjects were medicated with KW-136 capsules 60 mg once daily and fixed-dose (400 mg once daily) sofosbuvir tablets for 12 successive weeks.

Drug: KW-136 capsule

KW-136 60 mg was provided in a single capsule of 60 mg.

Other Names:

Coblopasvir

Drug: Sofosbuvir

Sofosbuvir was provided in a single tablet of 400 mg.

Outcome Measures

Primary Outcome Measures

Sustained virologic response at 12 weeks after end of treatment (SVR12) [12 weeks after end of treatment]
Percentage of subjects with plasma HCV not detected or below the lower limit of quantitation (15 IU/mL)

Secondary Outcome Measures

Sustained virologic response at 4 weeks after end of treatment (SVR4) [4 weeks after end of treatment]
Percentage of subjects with plasma HCV not detected or below the lower limit of quantitation (15 IU/mL)
Rapid virologic response at 1 week after initiation of treatment (RVR1) [1 week after initiation of treatment]
Percentage of subjects with plasma HCV not detected or below the lower limit of quantitation (15 IU/mL)
Rapid virologic response at 2 weeks after initiation of treatment (RVR2) [2 weeks after initiation of treatment]
Percentage of subjects with plasma HCV not detected or below the lower limit of quantitation (15 IU/mL)
Rapid virologic response at 4 weeks after initiation of treatment (RVR4) [4 weeks after initiation of treatment]
Percentage of subjects with plasma HCV not detected or below the lower limit of quantitation (15 IU/mL)
Rapid virologic response at 8 weeks after initiation of treatment (RVR8) [8 weeks after initiation of treatment]
Percentage of subjects with plasma HCV not detected or below the lower limit of quantitation (15 IU/mL)
Rapid virologic response at 12 weeks after initiation of treatment (RVR12) [12 weeks after initiation of treatment]
Percentage of subjects with plasma HCV not detected or below the lower limit of quantitation (15 IU/mL)

Other Outcome Measures

Sustained virologic response at 24 weeks after end of treatment (SVR24) [24 weeks after end of treatment]
Percentage of subjects with plasma HCV not detected or below the lower limit of quantitation (15 IU/mL)
Virologic breakthrough [2, 4, 8 and 12 weeks after initiation of treatment]
Percentage of subjects with on-treatment re-detected plasma HCV RNA after HCV RNA below the lower limit of quantitation
Virologic relapse [4,12 and 24 weeks after end of treatment]
Percentage of subjects with off-treatment re-detected plasma HCV RNA after end-of-treatment HCV RNA below the lower limit of quantitation

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

aged between 18 and 70 years (both inclusive) at the time of informed consenting and of either sex
with a body mass index (BMI) between 18 and 32 kg/m^2 (both inclusive)
chronically infected with HCV, namely, with positive anti-HCV, HCV RNA or genotyping results at least six (6) months before the screening, or with a liver biopsy confirming chronic hepatitis at most twelve (12) months before the screening or within the screening period
with anti-HCV positivity and at least once testing result with HCV RNA equaling to or above 10^4 IU/mL within the screening period
with gentoype 1, 2, 3, 4, 5, 6, mixed, indeterminate or other genotype by the centralized laboratory genotyping
no more than ten percent (10%) of the enrolled subjects having previously experienced interferon (defined as having received any regulatory agency approved or investigational interferon formulations, including pegylated and regular interferons at least six [6] months before the screening)
having not previously experienced any other approved, investigational or unapproved direct antiviral agents against HCV of any source
having not previously experienced oral or injective ribavirin within three (3) months before the screening
no more than ten percent (10%) of the enrolled patients having advanced fibrosis or compensatory cirrhosis (as documented by liver transient elastography [FibroScan] within the screening period, or liver biopsy within twelve [12] months before the screening or within the screening period, with an evidence priority over FibroScan result and with the most recent biopsy prevailing in case of inconsistency between liver biopsy and FibroScan result), in accordance with the following definitions of liver disease: no advanced fibrosis or cirrhosis, with a liver stiffness modulus (LSM) below 9.6 kPa and/or F0-2 on fibrosis staging; advanced fibrosis, with a LSM equaling to or above 9.6 kPa but below 14.6 kPa and/or F3 on fibrosis staging; and cirrhosis, with a LSM equaling to or above 14.6 kPa and/or F4 on fibrosis staging
women of childbearing potential (including postmenopausal women at or under 50 years of age) with negative blood pregnancy test results, and subjects of childbearing potential (including male subjects and their female partners) having no childbearing plan and consenting to voluntarily use effective contraceptive measures from the screening until six (6) months after the end of treatment
lactating women consenting to discontinue nursing from the screening until six (6) months after the end of treatment
voluntarily participating in this trial and being able to understand and sign the informed consent form

Exclusion Criteria:

having previously experienced any investigational or experimental direct antiviral agents against HCV, including protease inhibitor, nonstructural protein (NS) 5A inhibitor or NS5B polymerase inhibitor, before the screening NS5B polymerase or NS5A inhibitors, before the screening
having previously experienced interferon-based antiviral regimens within six (6) months before the screening
having previously experienced oral or injective ribavirin within three (3) months before the screening
having previously experienced any systemic potent immunomodulatory agents, such as steroids or thymosin alfa, excluding nasal, inhalational, topical steroids and/or others, for more than two (2) weeks within six (6) months before the screening, or expected to be exposed to these agents during the study period
with hepatitis B virus surface antigen (HBsAg) or anti-human immunodeficient virus (HIV) positivity
with evidence of decompensatory liver function, including but not limited to total serum bilirubin (TBIL) above twice (2) of the upper limit of normal (ULN), serum albumin (ALB) below 35 g/L or prothrombin activity (PTA) below 60% confirmed on repeated testing, previous or present history of ascites, upper gastrointestinal bleeding and/or hepatic encephalopathy, or with a liver function reserve of Child-Pugh class B or C
with primary liver cancer confirmed or evidenced by serum alfa-fetoprotein (AFP) above 100 ng/ml or liver imaging study showing suspected nodules
with a previous history of liver disease of other causes, including alcoholic liver disease, nonalcoholic steatohepatitis, drug-induced hepatitis, autoimmune hepatitis, Wilson disease or hemochromatosis
with serum alanine aminotransferase (ALT) or asparate aminotransferase (AST) above ten (10) times of the ULN confirmed on repeated testing
with white blood cell (WBC) count below 3×10^{9 per liter, neutrophil count below
1.5×10}9 per liter (or below 1.25×10^{9 per liter for cirrhotics), platelet count below
50×10}9 per liter, or hemoglobin below 100 g/L confirmed on repeated testing
with serum creatinine clearance (CLcr) below 50 ml/min using the Cockcroft-Gault formula confirmed on repeated testing
with poorly controlled diabetes mellitus (hemoglobin A1c [HbA1c] above 8.0% confirmed on repeated testing)
with psychiatric or neurologic disorders, including previous or family history of psychiatric disorders (especially depression, depressive state, epilepsy or hysteria)
with serious cardiovascular disorders, including uncontrolled hypertension (systolic blood pressure at or above 160 mmHg and/or diastolic blood pressure at or above 100 mmHg), heart insufficiency of New York Heart Association class III or above, history of myocardial infarction within six (6) months before the screening, history of percutaneous transluminal coronary angioplasty within six (6) months before the screening, unstable angina pectoris, or QTc interval (Fridericia correction formula QTc = QT×RR^-1/3) at or above 450 msec for males or 470 msec for females, second- or third-grade atrioventricular block or any other uncontrolled arrhythmias confirmed on repeated electrocardiography on screening
with serious hematologic disorders, such as anemia, hemophilia and others
with serious kidney diseases, such as chronic kidney disease, kidney insufficiency and others
with serious gastrointestinal disorders, such as peptic ulcer, colitis and others
with serious respirator disorders, such as active pulmonary tuberculosis, lung infection, chronic obstructive pulmonary disease, pulmonary interstitial disease and others
with active or suspected malignant tumors, or with a previous history of malignant tumors, excluding skin basal cell carcinoma or cervical carcinoma in situ, within five (5) years before the screening
with a history of major organ transplantation
with a hypersensitive predisposition or a known history of serious allergy, especially to the investigational products and substances
with a history of active alcohol or drug abuse within six (6) months before the screening
pregnant women or lactating women rejecting or unable to discontinue nursing
being unable to discontinue prohibited medications as defined by the protocol
having previously participated in clinical studies of any other drugs within three (3) months before the screening
being unable or unwilling to provide informed consent, or unable to follow the protocol requirements
with any other conditions of ineligibility at the discretion of the investigators

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Chinese PLA 302 Hospital	Beijing	Beijing	China	100039
2	Capital Medical University Affiliated Beijing Youyi Hospital	Beijing	Beijing	China	100050
3	Capital Medical University Affiliated Beijing You'an Hospital	Beijing	Beijing	China	100069
4	Capital Medical University Affiliated Beijing Ditan Hospital	Beijing	Beijing	China	100102
5	Chinese PLA Third Military Medical University First Affiliated Hospital	Chongqing	Chongqing	China	400038
6	Chongqing Sanxia Central Hospital	Wanzhou	Chongqing	China	404000
7	Sun Yat-sen University Affiliated Third University	Guangzhou	Guangdong	China	510630
8	Guangzhou Municipal Eighth People's Hospital	Guanzhou	Guangdong	China	510060
9	Liuzhou People's Hospital	Liuzhou	Guangxi	China	545006
10	He'nan Provincial Hospital of Infectious Disease (Zhengzhou Municipal Sixth People's Hospital)	Zhengzhou	Henan	China	450015
11	Huazhong University of Science and Technology Affiliated Tongji Hospital	Wuhan	Hubei	China	430030
12	Nanjing Municipal Second Hospital	Nanjing	Jiangsu	China	210003
13	Jilin University First Hospital	Changchun	Jilin	China	130021
14	Yanbian University Affiliated Hosptial	Yanbian	Jilin	China	133000
15	Shenyang Municipal Sixth People's Hospital	Shenyang	Liaoning	China	110006
16	Chinese PLA Fourth Military Medical University Tangdu Hospital	Xi'an	Shaanxi	China	710038
17	Ji'nan Municipal Hospital of Infectious Disease	Ji'nan	Shandong	China	250021
18	Sichuan Provincial People's Hospital	Chengdu	Sichuan	China	610072
19	Xinjiang Uygur Autonomous Region Traditional Chinese Medicine Hospital	Ürümqi	Xinjiang	China	830000