Double-Blind, Randomized, Placebo-Controlled Study to Assess Safety, Efficacy, and Pharmacokinetics (PK) of GSK2336805 in Combination With Peginterferon and Ribavirin in Treatment-naive Chronic Hepatitis C Subjects With Hepatitis C Virus Genotypes 1 or 4
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 16
- 试验地点
- 1
- 主要终点
- Number of Participant Achieving Rapid Virological Response (RVR) at Day 28, Nominal Analysis
研究概览
简要总结
GSK2336805 is a hepatitis C virus (HCV) NS5A inhibitor being developed for the treatment of chronic hepatitis C (CHC). This study will assess the safety, antiviral activity, and pharmacokinetics of GSK2336805 alone and in combination with peginterferon alfa 2a and ribavirin in subjects with chronic hepatitis C (CHC).
详细描述
HCV infection is a major public health problem globally and a leading cause of chronic liver disease. New medications are needed that are better tolerated and offer a greater chance of achieving sustained viral clearance compared to currently available therapy. GSK2336805 is a HCV NS5A inhibitor being developed for the treatment of subjects with CHC. This Phase II, double blind, randomized, placebo-controlled study will assess the safety, antiviral activity, and pharmacokinetics of GSK2336805 alone and in combination with peginterferon alfa 2a and ribavirin in subjects with CHC. Subjects will be randomly allocated on a 2:1 basis to GSK2336805 or matching placebo and will be stratified by IL28B status and HCV viral genotype (genotype 1 or 4). The study consists of 2 parts. In Part 1, GSK2336805 or matching placebo will be given as single-dose monotherapy (Day 1). In Part 2, GSK2336805 or matching placebo will be co-administered with peginterferon alfa-2a and ribavirin through 4 weeks of treatment (Days 2 to 28). After completion of Part 2, GSK2336805/matching placebo will be discontinued and subjects will be offered continued standard-of-care anti-HCV therapy.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Documented chronic genotype 1 or genotype 4 HCV infection
- •Naïve to all HCV antiviral treatment(s)
- •Agree to IL28B genotyping
- •A body mass index >18 kg/m2 but not exceeding 36 kg/m2
- •Liver biopsy obtained within 3 years (36 calendar months) prior to the Day 1 visit, with a fibrosis classification of non-cirrhotic. If no recent (<36 months) liver biopsy is available, a study qualifying biopsy must be performed prior to Baseline (Day 1)
- •All fertile males and females must use two forms of effective contraception between them during treatment and during the 24 weeks after treatment ends
- •Otherwise healthy as determined by the medical history, physical examination, ECG findings, and clinical laboratory measurements performed at Screening
排除标准
- •Positive test at Screening for hepatitis B surface antigen (HBsAg) or anti-human immunodeficiency virus antibody
- •History of any other clinically significant chronic liver disease
- •History of ascites, variceal hemorrhage, hepatic encephalopathy, or conditions consistent with decompensated liver disease
- •Positive results on urine screen for drugs of abuse test at Screening (unless used as medical treatment, e.g., with a prescription)
- •History of alcohol/drug abuse or dependence within 6 months of the study start (unless participating in a controlled rehabilitation program)
- •Screening ECG corrected QT interval value greater than 450 ms and/or clinically significant ECG findings
- •A personal or family history of Torsade de Pointes findings
- •Pregnant or nursing women
- •Males with a female partner who is pregnant
- •Abnormal hematological and biochemical parameters as specified in the protocol
- •History of major organ transplantation with an existing functional graft
- •Thyroid dysfunction not adequately controlled
- •Subjects with a history of suicide attempt or hospitalization for depression in the past 5 years and/or any current (within 6 months) severe or poorly controlled psychiatric disorder
- •History or current evidence of immunologic disorder; pulmonary, cardiac, or pulmonary disease; seizure disorder; cancer or history of malignancy that in the opinion of the investigator makes the subject unsuitable for the study
- •Participation in a clinical study with an investigational drug, biologic, or device within 3 months prior to first dose administration
研究组 & 干预措施
Placebo
Study Part 1
干预措施: GSK2336805 Matching Placebo (Drug)
GSK2336805 + pegylated interferon alfa-2a + ribavrin
Study Part 2
干预措施: GSK2336805 (Drug)
GSK2336805
Study Part 1
干预措施: GSK2336805 (Drug)
GSK2336805 + pegylated interferon alfa-2a + ribavrin
Study Part 2
干预措施: Pegylated interferon alfa-2a (Drug)
GSK2336805 + pegylated interferon alfa-2a + ribavrin
Study Part 2
干预措施: Ribavirin (Drug)
Placebo + pegylated interferon alfa-2a + ribavirin
Study Part 2
干预措施: Pegylated interferon alfa-2a (Drug)
Placebo + pegylated interferon alfa-2a + ribavirin
Study Part 2
干预措施: Ribavirin (Drug)
Placebo + pegylated interferon alfa-2a + ribavirin
Study Part 2
干预措施: GSK2336805 Matching Placebo (Drug)
结局指标
主要结局
Number of Participant Achieving Rapid Virological Response (RVR) at Day 28, Nominal Analysis
时间窗: Day 28
RVR was defined as the proportion of participants below the assay lower limit of detection (LOD) \<18 International units per milliliter (IU/mL) for Hepatitis C virus (HCV) ribonucleic acid (RNA) after 4 weeks of treatment (Day 28). Participants achieving RVR at Day 28 were considered treatment responders. Participants with missing HCV RNA values at Day 28 or discontinued before Day 28 were considered as treatment failure . Proportion of participants with HCV genotype 1 achieving RVR was the primary comparison of interest to show superiority of GSK2336805 over placebo in genotype 1 participants.
Number of Participant Achieving RVR at Day 28, (Primary and Supportive Analyses)
时间窗: Day 28
RVR was defined as the proportion of participants LOD \<18 IU/mL for HCV RNA after 4 weeks of treatment (Day 28). Participants achieving RVR at Day 28 were considered treatment responders. Participants with missing HCV RNA values at Day 28 or discontinued before Day 28 were considered as treatment failure. Proportion of participants with HCV genotype 1 achieving RVR was the primary comparison of interest to show superiority of GSK2336805 over placebo in genotype 1 participants. The primary and supportive analysis differs from the nominal analysis as supportive analysis is assessed at Day 28 ± 2 (2 days visit window) whereas, the nominal analysis was assessed at Day 28.
Probability of Participants With HCV Genotype 1 Achieving RVR At Day 28, Nominal Analysis
时间窗: Day 28
The primary comparison of interest was performed using a Bayesian probability model. Probability of achieving undetectable HCV RNA distribution analyzed by nominal analysis was reported.
Probability of Participants With HCV Genotype 1 Achieving RVR at Day 28, Primary and Supportive Analyses
时间窗: Day 28
The primary comparison of interest was performed using a Bayesian probability model. Probability of achieving undetectable HCV RNA distribution analyzed was reported.
Number of Participants With Any Adverse Events (AEs) and Any Serious Adverse Event (SAE) During Treatment Period
时间窗: Up to Day 28
AE was defined as any untoward medical occurrence in a participant temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE include AEs those result in death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal functions, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.
Number of Participants With HCV Genotype 1 With Virologic Response
时间窗: Day 7, 14 and 21
Serum for determination of HCV genotype was collected at the screening visit. Genotype was determined by the VERSANT HCV genotype 2.0 Assay (LiPA). Number of participants with HCV genotype 1 were reported.
Change From Baseline in HCV Viral Load During 24 Hour (h) Following a Single Dose of GSK2336805 on the Log 10 Scale
时间窗: Day 1 (Baseline [Pre-dose], 1, 2, 4, 6, and 8 and 24 h)
Blood samples for determination of HCV RNA levels were collected at immediately prior to and 1, 2, 4, 6, and 8 and 24 h after the first dose in Part 1 (Day 1). Measurement of HCV viral load was analyzed by the central laboratory using the COBAS AmpliPrep/COBAS TaqMan HCV test. Baseline was defined as the last non-missing assessment on or before the first dose of study drug. Change from Baseline was computed as value at post Baseline specified time point minus Baseline value. Virus RNA levels reported as \<43 are undetectable levels. If the result for HCV RNA (IU/ML) was \<43, then change from Baseline was calculated using 42, and the change from Baseline on the log scale was calculated using log (42).
Change From Baseline in QTcF Interval at Day 2 and 28
时间窗: Baseline (Day 1, Pre-dose ), Day 2 and Day 28
Single 12-lead electrocardiogram (ECG) was obtained. The standard ECG criteria of potential clinical importance were 1) absolute QTc Interval, \> 450 milliseconds (msec), 2) absolute PR Interval, \<110 msec, 3) absolute QRS Interval, \< 75 msec and 4) increase from baseline in QTc \> 60 msec. QTc Interval was calculated using Frederica correction formula: QTcF = QT / (RR)\^1/3. Change from Baseline was calculated by subtracting the Baseline assessment value from post Baseline visit value. Baseline was defined as the last non-missing assessment on or before the first dose of study drug. The change from Baseline in QTc Interval at Day 2 and 28 were reported.
次要结局
- Number of Participants With Shift From Baseline to Worst Post Baseline Toxicity Grade Hematology Parameters for Day 1 to Day 28(Baseline (Day 1) to Day 28)
- Mean Serum HCV RNA Levels at Baseline (Day 1), Day 2 and Day 28(Baseline (Day 1, pre-dose), Day 2 (24 h, Post-dose) and Day 28)
- Number of Participants With Shift From Baseline to Worst Post Baseline Toxicity Grade for Serum Chemistry Parameters for Day 1 to Day 28(Baseline (Day 1) and 28)
- Number of Participants With Shifts in Urinalysis Parameters From Normal at Baseline to Abnormal(Day 14, 28, Follow-up (Day 42))
- Number of Participants With Vital Signs of Potential Clinical Concern(Up to 42 days)
- Mean Change From Baseline in Serum HCV RNA Levels at Day 2 and Day 28(Baseline (Day 1, Pre -dose ) and Day 2 (24 h, post-dose), Day 28)
- Median Serum Alanine Aminotransferase at Baseline, Day 7, 14, 21, 28 and 42(Baseline (Day 1, Pre-dose), Day 7, 14, 21, 28 and 42)
- Mean Area Under the Concentration-time Curve (AUC[0-24]), AUC From Time 0 Extrapolated to Infinity (AUC[0-inf]) of GSK2336805, at Day 1(0.0 (pre-dose) and 1, 2, 4, 6, 8, and 24 h post-dose (morning of Day 2))
- Median Time of Maximal Plasma Concentration (Tmax) of GSK2336805 and Lag Time Before First Observation of Quantifiable Concentration (Tlag) at Day 1(0.0 (pre-dose) and 1, 2, 4, 6, 8, and 24 h post-dose (morning of Day 2))
- Mean Maximum Plasma Concentration of GSK2336805 (Cmax) and Concentration at 24 h (C24) at Day 1(0.0 (pre-dose) and 1, 2, 4, 6, 8, and 24 h post-dose (morning of Day 1))
- Mean Apparent Clearance (CL/F) of GSK2336805(0.0 (pre-dose) and 1, 2, 4, 6, 8, and 24 h post-dose (morning of Day 1))
- Change From Baseline in Serum Alanine Aminotransferase Levels(Baseline (Day 1, Pre-dose), Day 7, 14, 21, 28 and 42)
- Mean Pre-dose Concentration and Concentration at 2 to 4 h Post-dose of GSK2336805 at Days 7, 14, 21, and 28(0 (pre-dose), 0 to 2 h, > 2 h up to 4 h, > 4 h up to 6 h, or > 6 h up to 10 h on Days 7, 14, 21 and 28)