Division of Gastroenterology, Department of Medicine, University of Michigan Health System, Ann Arbor, Michigan, USA.
Am J Gastroenterol. 2012 Nov;107(11):1702-12. doi: 10.1038/ajg.2012.254.
Linaclotide is a minimally absorbed peptide guanylate cyclase-C agonist. The objective of this trial was to determine the efficacy and safety of linaclotide treatment in patients with irritable bowel syndrome with constipation (IBS-C) over 26 weeks.
This phase 3, double-blind, parallel-group, placebo-controlled trial randomized IBS-C patients to placebo or 290 μg of oral linaclotide once daily for a 26-week treatment period. The primary and the secondary efficacy assessments were evaluated over the first 12 weeks of treatment. Primary end points included the Food and Drug Administration's (FDA's) end point for IBS-C (responder: a patient who reported (i) improvement of ≥ 30 % from baseline in average daily worst abdominal pain score and (ii) increase of ≥ 1 complete spontaneous bowel movement (CSBM) from baseline, both in the same week for ≥ 6 / 12 weeks) and three other primary end points, based on improvements in abdominal pain and CSBMs for 9/12 weeks. Adverse events (AEs) were monitored.
In all, 804 patients (mean age = 44 years, female = 90 % , white = 78 % ) were evaluated; 33.7 % of linaclotide-treated patients were FDA end point responders, vs. 13.9 % of placebo-treated patients ( P < 0.0001) (number needed to treat = 5.1, 95 % confidence interval (CI): 3.9, 7.1). The pain responder criterion of the FDA end point was met by 48.9 % of linaclotide-treated patients vs. 34.5 % of placebo-treated patients (number needed to treat = 7.0, 95 % CI: 4.7, 13.1), and the CSBM responder criterion was met by 47.6 % of linaclotide-treated patients, vs. 22.6 % of placebo patients (number needed to treat = 4.0, 95 % CI: 3.2, 5.4). Remaining primary end points ( P < 0.0001) and all secondary end points ( P < 0.001), including abdominal pain, abdominal bloating, and bowel symptoms (SBM and CSBM rates, Bristol Stool Form Scale (BSFS) score, and straining), were also statistically significantly improved with linaclotide vs. placebo. Statistically significant differences from placebo were observed for responder and continuous end points over 26 weeks of treatment. AE incidence was similar between treatment groups, except for diarrhea, which caused discontinuation in 4.5 % of linaclotide patients vs. 0.2 % of placebo patients.
Linaclotide 290 μg once daily significantly improved abdominal and bowel symptoms associated with IBS-C over 26 weeks of treatment.
利那洛肽是一种吸收较少的肽类肠促胰酶素受体激动剂。本试验旨在确定利那洛肽治疗便秘型肠易激综合征（IBS-C）患者的疗效和安全性，治疗时间为 26 周。
这是一项为期 3 期、双盲、平行分组、安慰剂对照试验，将 IBS-C 患者随机分为安慰剂组或每天口服利那洛肽 290μg 组，治疗期为 26 周。主要和次要疗效评估在治疗的前 12 周进行。主要终点包括食品和药物管理局（FDA）针对 IBS-C 的终点（应答者：报告（i）平均每日最严重腹痛评分从基线改善≥30%，（ii）与基线相比，每周至少有 6/12 周完全自发排便（CSBM）增加≥1 次的患者）和其他 3 个主要终点，基于腹痛和 CSBM 的改善，持续 9/12 周。监测不良事件（AE）。
共有 804 名患者（平均年龄=44 岁，女性=90%，白人=78%）接受了评估；33.7%的利那洛肽治疗患者为 FDA 终点应答者，而安慰剂治疗患者为 13.9%（P<0.0001）（需要治疗的人数=5.1，95%置信区间（CI）：3.9，7.1）。FDA 终点的疼痛应答标准符合 48.9%的利那洛肽治疗患者，而符合 34.5%的安慰剂治疗患者（需要治疗的人数=7.0，95%CI：4.7，13.1），CSBM 应答标准符合 47.6%的利那洛肽治疗患者，而符合 22.6%的安慰剂患者（需要治疗的人数=4.0，95%CI：3.2，5.4）。其他主要终点（P<0.0001）和所有次要终点（P<0.001），包括腹痛、腹胀和肠道症状（SBM 和 CSBM 率、布里斯托粪便量表评分和用力排便），也与安慰剂相比，利那洛肽均有统计学显著改善。在 26 周的治疗中，利那洛肽在应答者和连续终点方面与安慰剂相比具有统计学显著差异。治疗组之间的不良事件发生率相似，除了腹泻，利那洛肽组有 4.5%的患者停药，而安慰剂组有 0.2%的患者停药。
利那洛肽 290μg 每日一次可显著改善 IBS-C 相关的腹痛和肠道症状，持续 26 周。
