A Multi-center, Placebo-Controlled, Dose Ranging Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Following Oral Administration of PSI-7977 in Combination With Pegylated Interferon and Ribavirin in Treatment-Naïve Patients With Chronic HCV Infection Genotype 1, and an Open Label Assessment of PSI-7977 in Patients With HCV Genotypes 2 or 3
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 147
- 试验地点
- 23
- 主要终点
- Percentage of Participants Who Experienced Adverse Events During the Sofosbuvir Treatment Period
研究概览
简要总结
Genotype 1: Participants with genotype 1 hepatitis C (HCV) infection were randomized to receive sofosbuvir (GS-7977; PSI-7977) 200 mg or 400 mg, or matching placebo, plus pegylated interferon alfa 2a (PEG) and ribavirin (RBV) for 12 weeks, followed by PEG+RBV for an up to an additional 36 weeks. Randomization was stratified by IL28B status (CC, CT, TT) and HCV RNA level (< 800,000 IU/ml or ≥ 800,000 IU/ml) at baseline. Participants were randomized in a 2:2:1 manner; those who achieved an extended rapid virologic response (eRVR) (HCV RNA < lower limit of detection [15 IU/mL] from Weeks 4 through 12) received an additional 12 weeks of PEG+RBV. Subjects not achieving eRVR received an additional 36 weeks of PEG+RBV.
Genotype 2 and 3: Participants with genotype 2 or 3 hepatitis C (HCV) received sofosbuvir 400 mg plus PEG+RBV for 12 weeks.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
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
- •Males or females aged 18 to 70 years, inclusive, at screening
- •Documented chronic genotype 1, 2, or 3 HCV infection
- •No previous treatment with HCV antiviral mediations
- •Body mass index (BMI) of greater than 18 kg/m2, but not exceeding 36 kg/m
- •Liver biopsy obtained within 3 years prior to the Day 1 visit, with a fibrosis classification of non-cirrhotic as judged by a local pathologist
- •Willing to refrain from beginning any new exercise regimens during the first 3 months of the study
- •Fasting blood glucose ≤ 300 mg/dl and/or glycosylated hemoglobin (HbA1c) ≤ 8
- •History of hypertension only if managed effectively on a stable regimen of two or fewer antihypertensives for at least three (3) months prior to screening
排除标准
- •Females who were breastfeeding
- •Males and females of reproductive potential who are unwilling to use an "effective", protocol-specified method(s) of contraception during the study
- •Positive test at Screening for HBsAg, anti-HBc IgM Ab, or anti-HIV Ab.
- •History of any other clinically significant chronic liver disease
- •Treatment with herbal/natural remedies with antiviral activity within 30 days prior to baseline.
- •Significant history of immunologically mediated disease, cardiac or pulmonary disease, seizure disorder or anticonvulsant use
- •History of ascites, variceal hemorrhage, hepatic encephalopathy, or conditions consistent with decompensated liver disease
- •Use of medications associated with QT prolongation within 30 days prior to dosing
- •Screening electrocardiogram (ECG) QTc value greater than 450 ms and/or clinically significant ECG findings
- •Personal or family history of Torsade de pointes.
- •Positive results for drugs of abuse test at screening
- •Abnormal hematological and biochemical parameters, including alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 5 times the upper limit of the normal range (ULN)
- •History of major organ transplantation with an existing functional graft
- •History of uncontrolled thyroid disease or abnormal thyroid-stimulating hormone (TSH) levels at screening
- •Clinically significant drug allergy to nucleoside/nucleotide analogs
- •History or current evidence of psychiatric illness, immunologic disorder, pulmonary, cardiac disease, seizure disorder, cancer or history of malignancy that in the opinion of the investigator makes the patient unsuitable for the study
- •History of systemic antineoplastic or immunomodulatory treatment within 6 months prior to dosing, or the expectation of such treatment during the study
研究组 & 干预措施
Sofosbuvir 200 mg (Genotype 1)
Participants with genotype 1 HCV infection were randomized to receive sofosbuvir 200 mg (2 x 100 mg tablets)+placebo to match sofosbuvir (2 tablets)+PEG+RBV for 12 weeks followed by PEG+RBV for up to an additional 36 weeks.
干预措施: Sofosbuvir (Drug)
Sofosbuvir 200 mg (Genotype 1)
Participants with genotype 1 HCV infection were randomized to receive sofosbuvir 200 mg (2 x 100 mg tablets)+placebo to match sofosbuvir (2 tablets)+PEG+RBV for 12 weeks followed by PEG+RBV for up to an additional 36 weeks.
干预措施: Placebo to match sofosbuvir (Drug)
Sofosbuvir 200 mg (Genotype 1)
Participants with genotype 1 HCV infection were randomized to receive sofosbuvir 200 mg (2 x 100 mg tablets)+placebo to match sofosbuvir (2 tablets)+PEG+RBV for 12 weeks followed by PEG+RBV for up to an additional 36 weeks.
干预措施: PEG (Drug)
Sofosbuvir 200 mg (Genotype 1)
Participants with genotype 1 HCV infection were randomized to receive sofosbuvir 200 mg (2 x 100 mg tablets)+placebo to match sofosbuvir (2 tablets)+PEG+RBV for 12 weeks followed by PEG+RBV for up to an additional 36 weeks.
干预措施: RBV (Drug)
Sofosbuvir 400 mg (Genotype 1)
Participants with genotype 1 HCV infection were randomized to receive sofosbuvir 400 mg (4 x 100 mg tablets)+PEG+RBV for 12 weeks followed by PEG+RBV for up to an additional 36 weeks.
干预措施: PEG (Drug)
Sofosbuvir 400 mg (Genotype 1)
Participants with genotype 1 HCV infection were randomized to receive sofosbuvir 400 mg (4 x 100 mg tablets)+PEG+RBV for 12 weeks followed by PEG+RBV for up to an additional 36 weeks.
干预措施: RBV (Drug)
Placebo (Genotype 1)
Participants with genotype 1 HCV infection were randomized to receive placebo to match sofosbuvir (4 tablets)+PEG+RBV for 12 weeks followed by PEG+RBV for up to an additional 36 weeks.
干预措施: Placebo to match sofosbuvir (Drug)
Placebo (Genotype 1)
Participants with genotype 1 HCV infection were randomized to receive placebo to match sofosbuvir (4 tablets)+PEG+RBV for 12 weeks followed by PEG+RBV for up to an additional 36 weeks.
干预措施: PEG (Drug)
Placebo (Genotype 1)
Participants with genotype 1 HCV infection were randomized to receive placebo to match sofosbuvir (4 tablets)+PEG+RBV for 12 weeks followed by PEG+RBV for up to an additional 36 weeks.
干预措施: RBV (Drug)
Sofosbuvir 400 mg (Genotype 2/3)
Participants with genotype 2 or 3 HCV infection received sofosbuvir 400 mg (4 x 100 mg tablets)+PEG+RBV for 12 weeks.
干预措施: Sofosbuvir (Drug)
Sofosbuvir 400 mg (Genotype 2/3)
Participants with genotype 2 or 3 HCV infection received sofosbuvir 400 mg (4 x 100 mg tablets)+PEG+RBV for 12 weeks.
干预措施: PEG (Drug)
Sofosbuvir 400 mg (Genotype 2/3)
Participants with genotype 2 or 3 HCV infection received sofosbuvir 400 mg (4 x 100 mg tablets)+PEG+RBV for 12 weeks.
干预措施: RBV (Drug)
结局指标
主要结局
Percentage of Participants Who Experienced Adverse Events During the Sofosbuvir Treatment Period
时间窗: Baseline to Week 12 plus 30 days
Adverse events (AEs) occurring during the sofosbuvir treatment period and for 30 days following the last dose of sofosbuvir were summarized across the participant population. A participant was counted once if they had a qualifying event.
次要结局
- Change in HCV RNA From Baseline to Week 12(Baseline to Week 12)
- Percentage of Participants With Rapid Virologic Response at Week 4(Week 4)
- Percentage of Participants With Complete Early Virologic Response at Week 12(Week 12)
- Percentage of Participants With Extended Rapid Virologic Response(Week 4 to Week 12)
- Percentage of Participants With Virologic Response at the End of Treatment(Week 48 (genotype 1) or Week 12 (genotype 2/3))
- Percentage of Participants With Sustained Virologic Response at Post-treatment Week 12 (SVR12) and 24 (SVR24)(Post-treatment Weeks 12 and 24)
- Plasma Pharmacokinetics of GS-331007 (Cmax at Day 8)(1, 2, 4, 8, and 12 hours postdose)
- Plasma Pharmacokinetics of GS-331007 (Cmax at Day 15)(1, 2, 4, 8, and 12 hours postdose)
- Plasma Pharmacokinetics of GS-331007 (Cmax at Day 29)(1, 2, 4, 8, and 12 hours postdose)
- Plasma Pharmacokinetics of GS-331007 (AUCtau at Day 8)(1, 2, 4, 8, and 12 hours postdose)
- Plasma Pharmacokinetics of GS-331007 (AUCtau at Day 15)(1, 2, 4, 8, and 12 hours postdose)
- Plasma Pharmacokinetics of GS-331007 (AUCtau at Day 29)(1, 2, 4, 8, and 12 hours postdose)
- Percentage of Participants Who Developed Resistance to Sofosbuvir(Baseline to Week 12)