Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomised, double-blind, placebo-controlled, dose-escalation trial
Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomised, double-blind, placebo-controlled, dose-escalation trial
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DOI：
10.1016/s0140-6736(10)61384-0
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发表时间：
2010-10-01
期刊：
影响因子：
168.9
通讯作者：
Smith, Patrick F.
中科院分区：
文献类型：
--
作者：
Gane, Edward J.;Roberts, Stuart K.;Smith, Patrick F.
目前以干扰素为基础的慢性丙型肝炎病毒（HCV）感染的标准护理治疗受到疗效和耐受性的限制。我们评估了两种实验性抗hcv药物的全口服联合治疗的安全性、耐受性和抗病毒活性：一种核苷聚合酶抑制剂rg7128；和danoprevir（一种NS3/4A蛋白酶抑制剂）在慢性HCV感染患者中的应用。方法来自新西兰和澳大利亚6个中心的慢性HCV基因型1感染患者接受RG7128 （500 mg或1000 mg，每日2次）和danoprevir （100 mg或200 mg，每8小时或600 mg或900 mg，每日2次）或安慰剂的口服联合治疗长达13天。符合条件的患者依次进入七个治疗队列之一，并通过交互式语音或网络应答系统随机分配到积极治疗或安慰剂组。患者在每个队列中被单独随机分配，其块大小反映了队列中患者的数量和治疗与安慰剂的比例。随机分配计划由计算机生成。HCV治疗初期患者开始剂量递增；标准护理治疗经验的患者，包括先前无应答者，被纳入高剂量danoprevir队列。研究人员、研究中心工作人员和患者对治疗分配不知情。然而，准备剂量的药剂师，参与药代动力学样本分析的人员，准备数据摘要的统计学家，以及在决定在下一个队列中开始给药之前审查数据的临床药理学家，都没有受到治疗分配的影响。主要结局是接受13天联合治疗的患者从基线到第14天HCV RNA浓度的变化。所有完成研究药物治疗的患者都被纳入分析。本研究已在ClinicalTrials.gov注册，编号NCT00801255。88名患者被随机分配到研究药物治疗方案（n=74人，7个治疗组；73人至少接受一剂研究药物）或安慰剂（n=14人，所有人至少接受一剂药物）。在接受13天联合治疗的队列中，HCV RNA浓度从基线到第14天的中位变化范围为-3.7至-5.2 log(10) IU/mL。在测试的最高联合剂量下（1000mg RG7128和900mg danoprevir，每日两次），从基线到第14天HCV RNA浓度的中位数变化在未接受治疗的患者中为-5.1 log(10) IU/mL (IQR为-5.6至-4.7)，在先前的标准护理无效应答者中为-4.9 log(10) IU/mL(-5.2至-4.5)，而安慰剂组增加了0.1 log(10) IU/mL。RG7128联合danoprevir耐受性良好，没有治疗相关的严重或严重不良事件，没有实验室参数3级或4级变化，也没有与安全性相关的治疗中断。这种核苷类似物聚合酶抑制剂和蛋白酶抑制剂的口服组合有望作为一种无干扰素治疗慢性丙型肝炎的方法。
Background Present interferon-based standard of care treatment for chronic hepatitis C virus (HCV) infection is limited by both efficacy and tolerability. We assessed the safety, tolerability, and antiviral activity of an all-oral combination treatment with two experimental anti-HCV drugs-RG7128, a nucleoside polymerase inhibitor; and danoprevir, an NS3/4A protease inhibitor in patients with chronic HCV infection.Methods Patients from six centres in New Zealand and Australia who were chronically infected with HCV genotype 1 received up to 13 days oral combination treatment with RG7128 (500 mg or 1000 mg twice daily) and danoprevir (100 mg or 200 mg every 8 h or 600 mg or 900 mg twice daily) or placebo. Eligible patients were sequentially enrolled into one of seven treatment cohorts and were randomly assigned by interactive voice or web response system to either active treatment or placebo. Patients were separately randomly assigned within each cohort with a block size that reflected the number of patients in the cohort and the ratio of treatment to placebo. The random allocation schedule was computer generated. Dose escalation was started in HCV treatment-naive patients; standard of care treatment-experienced patients, including previous null responders, were enrolled in higher-dose danoprevir cohorts. Investigators, personnel at the study centre, and patients were masked to treatment allocation. However, the pharmacist who prepared the doses, personnel involved in pharmacokinetic sample analyses, statisticians who prepared data summaries, and the clinical pharmacologists who reviewed the data before deciding to initiate dosing in the next cohort were not masked to treatment allocation. The primary outcome was change in HCV RNA concentration from baseline to day 14 in patients who received 13 days of combination treatment. All patients who completed treatment with the study drugs were included in the analyses. This study is registered with ClinicalTrials.gov, NCT00801255.Findings 88 patients were randomly assigned to a study drug treatment regimen (n=74 over seven treatment groups; 73 received at least one dose of study drug) or to placebo (n=14, all of whom received at least one dose). The median change in HCV RNA concentration from baseline to day 14 ranged from -3.7 to -5.2 log(10) IU/mL in the cohorts that received 13 days of combination treatment. At the highest combination doses tested (1000 mg RG7128 and 900 mg danoprevir twice daily), the median change in HCV RNA concentration from baseline to day 14 was -5.1 log(10) IU/mL (IQR -5.6 to -4.7) in treatment-naive patients and -4.9 log(10) IU/mL in previous standard of care null responders (-5.2 to -4.5) compared with an increase of 0.1 log(10) IU/mL in the placebo group. The combination of RG7128 and danoprevir was well tolerated with no treatment-related serious or severe adverse events, no grade 3 or 4 changes in laboratory parameters, and no safety-related treatment discontinuations.Interpretation This oral combination of a nucleoside analogue polymerase inhibitor and protease inhibitor holds promise as an interferon-free treatment for chronic HCV.