随机临床试验：linaclotide 在 IBS-C 中的 3 期研究 - 基于欧洲药品管理局规定终点的预先指定的进一步分析。
Randomised clinical trials: linaclotide phase 3 studies in IBS-C - a prespecified further analysis based on European Medicines Agency-specified endpoints.
机构信息
Alimentary Pharmabiotic Centre, University College Cork, Ireland.
出版信息
Aliment Pharmacol Ther. 2013 Jan;37(1):49-61. doi: 10.1111/apt.12123. Epub 2012 Nov 1.
BACKGROUND
Treatment options that improve overall symptoms of irritable bowel syndrome with constipation (IBS-C) are lacking.
AIM
A prespecified further analysis to evaluate the efficacy and safety of linaclotide, a guanylate cyclase C agonist, in patients with IBS-C, based on efficacy parameters prespecified for European Medicines Agency (EMA) submission.
METHODS
Two randomised, double-blind, multicentre Phase 3 trials investigated once-daily linaclotide (290 μg) for 12 weeks (Trial 31) or 26 weeks (Trial 302) in patients with IBS-C. Prespecified primary endpoints were the EMA-recommended co-primary endpoints: (i) 12-week abdominal pain/discomfort responders [≥30% reduction in mean abdominal pain and/or discomfort score (11-point scales), with neither worsening from baseline, for ≥6 weeks] and (ii) 12-week IBS degree-of-relief responders (symptoms 'considerably' or 'completely' relieved for ≥6 weeks).
RESULTS
Overall, 803 (Trial 31) and 805 patients (Trial 302) were randomised. A significantly greater proportion of linaclotide-treated vs. placebo-treated patients were 12-week abdominal pain/discomfort responders (Trial 31: 54.8% vs. 41.8%; Trial 302: 54.1% vs. 38.5%; P < 0.001) and IBS degree-of-relief responders (Trial 31: 37.0% vs. 18.5%; Trial 302: 39.4% vs. 16.6%; P < 0.0001). Similarly, significantly more linaclotide- vs. placebo-treated patients were responders for ≥13 weeks in Trial 302 (abdominal pain/discomfort: 53.6% vs. 36.0%; IBS degree-of-relief: 37.2% vs. 16.9%; P < 0.0001). The proportion of sustained responders (co-primary endpoint responders plus responders for ≥2 of the last 4 weeks of treatment) was also significantly greater with linaclotide vs. placebo in both trials (P < 0.001).
CONCLUSION
Linaclotide treatment significantly improved abdominal pain/discomfort and degree-of-relief of IBS-C symptoms compared with placebo over 12 and 26 weeks.
TRIAL REGISTRATION
ClinicalTrials.gov (identifiers: NCT00948818 and NCT00938717).
背景
目前缺乏能够改善便秘型肠易激综合征（IBS-C）整体症状的治疗选择。
目的
根据欧洲药品管理局（EMA）提交的预设疗效参数，对鸟苷酸环化酶 C 激动剂利那洛肽治疗 IBS-C 的疗效和安全性进行预设的进一步分析。
方法
两项随机、双盲、多中心的 III 期临床试验分别在 IBS-C 患者中考察了每日一次利那洛肽（290μg）治疗 12 周（试验 31）或 26 周（试验 302）的疗效。预设的主要终点为 EMA 推荐的共同主要终点：（i）12 周腹痛/不适缓解者[腹痛和/或不适平均评分较基线降低≥30%（11 分制），且无恶化，持续≥6 周]和（ii）12 周 IBS 缓解程度缓解者（症状“明显”或“完全”缓解持续≥6 周）。
结果
共 803 例（试验 31）和 805 例（试验 302）患者随机分组。与安慰剂相比，接受利那洛肽治疗的患者中，12 周腹痛/不适缓解者比例显著更高（试验 31：54.8% vs. 41.8%；试验 302：54.1% vs. 38.5%；P＜0.001），IBS 缓解程度缓解者比例也显著更高（试验 31：37.0% vs. 18.5%；试验 302：39.4% vs. 16.6%；P＜0.0001）。同样，在试验 302 中，接受利那洛肽治疗的患者在≥13 周时，缓解者比例也显著更高（腹痛/不适：53.6% vs. 36.0%；IBS 缓解程度：37.2% vs. 16.9%；P＜0.0001）。与安慰剂相比，在两项试验中，接受利那洛肽治疗的患者中持续缓解者（共同主要终点缓解者加上治疗最后 4 周中有≥2 周缓解者）的比例也显著更高（P＜0.001）。
结论
与安慰剂相比，利那洛肽治疗可显著改善 IBS-C 患者的腹痛/不适和 IBS 缓解程度，治疗时间为 12 周和 26 周。
临床试验注册
ClinicalTrials.gov（标识符：NCT00948818 和 NCT00938717）。
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