Gane Edward J, DeJesus Edwin, Janczewska Ewa, George Jacob, Diago Moises, Da Silva Mariliza Hendrique, Reesink Henk, Nikitin Igor, Hinrichsen Holger, Bourgeois Stefan, Ferenci Peter, Shukla Umesh, Kalmeijer Ronald, Lenz Oliver, Fevery Bart, Corbett Chris, Beumont Maria, Jessner Wolfgang
New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand.
Orlando Immunology Center, Orlando, FL, USA.
BMC Infect Dis. 2017 Jun 2;17(1):389. doi: 10.1186/s12879-017-2444-3.
This Phase 3, open-label, rollover study (NCT01323244) investigated the efficacy and safety of simeprevir plus peginterferon α-2a (PegIFNα-2a) and ribavirin (RBV) in a well-characterized population of HCV genotype 1 (GT1)-infected treatment-experienced patients.
Patients who had failed PegIFNα/RBV treatment in the placebo arm of a previous Phase 2/3 simeprevir study (Phase 2/3 group, n = 125), or had been exposed to HCV direct-acting antivirals (simeprevir or other) for up to 14 days in a selected Phase 1 study (Phase 1 group, n = 16), were eligible. Phase 2/3 group patients were classified according to prior relapse, breakthrough, or non-response (null response, partial response, non-classifiable non-response) to PegIFNα/RBV. Eight patients in the Phase 1 group received short-term (≤14 days) simeprevir. Treatment comprised simeprevir 150 mg once daily (QD) plus PegIFNα-2a/RBV for 12 weeks followed by PegIFNα-2a/RBV for 12 or 36 weeks (using response-guided therapy [RGT] to determine total treatment duration in Phase 2/3 prior relapsers or breakthrough) or 36 weeks fixed (Phase 2/3 group non-responders and Phase 1 group). The primary endpoint was sustained virologic response 12 weeks after planned end of treatment (SVR12).
Phase 2/3 group: SVR12 rate was 69.6% (87/125) overall; 92.7% (51/55), 60.0% (6/10), 64.3% (18/28), and 36.7% (11/30) in patients with prior relapse, viral breakthrough, partial response, or null response, respectively. SVR12 rates were similar for patients with HCV GT1a (66.0% [33/50]) and GT1b infection (72.0% [54/75]) and among HCV GT1a-infected patients with/without a baseline Q80K polymorphism (66.7% [8/12] and 65.8% [25/38], respectively). The majority of RGT-eligible patients (prior viral relapse or breakthrough) met RGT criteria (89.2% [58/65]); of these, 89.7% (52/58) achieved SVR12. Overall, 16.0% (20/125) of patients experienced on-treatment failure and 14.4% (18/125) experienced post-treatment failure (15 relapses, 3 missing data). Phase 1 group (simeprevir-naïve and -experienced patients combined): SVR12 rate was 37.5% (6/16). Safety and tolerability findings were comparable to those of the feeder studies.
The majority of RGT-eligible patients met criteria for shortening treatment to 24 weeks in total. Simeprevir 150 mg QD with PegIFNα-2a/RBV led to a high SVR rate among prior relapsers with HCV GT1 infection. No new safety signals were noted.
NCT01323244 . (date of registration: March 24, 2011).
这项3期开放标签的延用性研究（NCT01323244）在一组特征明确的丙型肝炎病毒1型（GT1）感染且经治患者中，研究了simeprevir联合聚乙二醇干扰素α-2a（PegIFNα-2a）和利巴韦林（RBV）的疗效和安全性。
在前一项2/3期simeprevir研究的安慰剂组中PegIFNα/RBV治疗失败的患者（2/3期组，n = 125），或在一项选定的1期研究中接触过丙型肝炎病毒直接作用抗病毒药物（simeprevir或其他）长达14天的患者（1期组，n = 16）符合入组条件。2/3期组患者根据既往对PegIFNα/RBV的复发、突破或无应答情况（无应答、部分应答、不可分类的无应答）进行分类。1期组中的8名患者接受了短期（≤14天）simeprevir治疗。治疗方案为simeprevir 150 mg每日一次（QD）联合PegIFNα-2a/RBV治疗12周，随后PegIFNα-2a/RBV治疗12周或36周（使用应答指导治疗[RGT]来确定2/3期既往复发者或突破者的总治疗疗程）或固定疗程36周（2/3期组无应答者和1期组）。主要终点为计划治疗结束后12周的持续病毒学应答（SVR12）。
2/3期组：总体SVR12率为69.6%（87/125）；既往复发、病毒突破、部分应答或无应答的患者中，SVR12率分别为92.7%（51/55）、60.0%（6/10）、64.3%（18/28）和36.7%（11/30）。丙型肝炎病毒GT1a（66.0% [33/50]）和GT1b感染患者的SVR12率相似，在丙型肝炎病毒GT1a感染且有/无基线Q80K多态性的患者中SVR12率也相似（分别为66.7% [8/12]和65.8% [25/38]）。大多数符合RGT标准的患者（既往病毒复发或突破）达到了RGT标准（89.2% [58/65]）；其中，89.7%（52/58）实现了SVR12。总体而言，16.0%（20/125）的患者出现治疗期失败，14.4%（18/125）的患者出现治疗后失败（15例复发，3例数据缺失）。1期组（未使用过和使用过simeprevir的患者合并）：SVR12率为37.5%（6/16）。安全性和耐受性结果与前期研究相当。
大多数符合RGT标准的患者符合将总疗程缩短至24周的标准。simeprevir 150 mg QD联合PegIFNα-2a/RBV在既往丙型肝炎病毒GT1感染复发患者中导致了较高的SVR率。未发现新的安全信号。
NCT01323244。（注册日期：2011年3月24日）
