Linaclotide was associated with significant improvement in symptoms of irritable bowel syndrome with constipation, including abdominal pain, within 1 week of starting therapy, Dr. Jeffrey M. Johnston and colleagues reported in the December issue of Gastroenterology.

However, diarrhea was a common side effect, leading to study withdrawal by more than a dozen patients.

Linaclotide is a novel, 14–amino acid peptide that binds to guanylate cyclase-C receptors on intestinal enterocytes, wrote Dr. Johnston, who is employed by the drug’s manufacturer, Ironwood Pharmaceuticals Inc.

In animal models, it has been shown to increase fluid secretion and transit, he added.

In the current study, Dr. Johnston and colleagues randomized 420 patients in a double-blind, placebo-controlled, phase IIB study. All patients were aged 18 years or older and met the Rome II criteria for irritable bowel syndrome (IBS). The mean patient age was 44 years, and 92% were female (Gastroenterology 2010 December [doi:10.1053/j.gastro.2010.08.041]).

All participants also reported having fewer than three spontaneous bowel movements per week, and at least one of the following symptoms occurring with 25% or more of their bowel movements: straining, lumpy or hard stools, or a sensation of incomplete evacuation.

Patients were randomized into five groups. One received a daily placebo, and the rest received once-daily linaclotide in doses of 75 mcg, 150 mcg, 300 mcg, or 600 mcg, taken orally before the first meal of the day.

According to daily assessments that were completed over the phone via an interactive voice-response system, all patients receiving active treatment who completed the study met the primary end point, which was an increase in complete spontaneous bowel movements (CSBMs), measured at 12 weeks, compared with baseline.

At week 12, the group receiving 75 mcg had an increase of 2.90 CSBMs per week; the 150-mcg group increased by 2.49 CSBMs per week; the 300-mcg group had an increase of 3.61 bowel movements per week; and the 600-mcg group increased by 2.68 CSBMs per week over their baseline (P less than or equal to .01 for all doses).

The group receiving placebo, in contrast, had a mean increase of 1.01 CSBM per week.

There were also significant decreases in abdominal pain – which was measured on a 5-point scale, with 1 signifying no pain and 5 being very severe pain – among patients taking linaclotide.

Compared with baseline, by 12 weeks the 75-mcg treatment group reported a mean reduction in the pain scale of 0.71 points, as did the 150-mcg group. The 300-mcg group had a reduction of 0.90 points, and the 600-mcg dosing group had a mean decrease of 0.86 points, compared with 0.49 points for placebo patients (P less than or equal to .05 for all doses).

Moreover, linaclotide’s effects “occurred within the first week of therapy and were sustained for the entire 3-month duration of this study,” wrote the investigators.

The treatment was not without side effects. According to the researchers, the most frequent of these was diarrhea. They noted that the diarrhea was dose dependent, reported by 11.4%, 12.2%, 16.5%, and 18.0% of patients in the 75-, 150-, 300-, and 600-mcg dose groups, respectively, compared with 1.2% in the placebo group. “No dehydration, electrolyte changes, or other adverse clinical sequelae from diarrhea were reported,” the authors wrote.

“Linaclotide resulted in sustained effects in the treatment of a common condition for which few therapies are currently available,” concluded Dr. Johnston and associates.

The results of this placebo-controlled, dose-range–finding, phase IIB study “support further development of linaclotide for treatment of adults with [IBS constipation]”.

Several of Dr. Johnston’s coinvestigators are also employees of linaclotide’s manufacturer, Ironwood Pharmaceuticals Inc., which also funded the study.

Copyright (c) 2010 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

Jeffrey M. Johnston博士及其同事在12月出版的《胃肠病学》杂志上发表文章指出，利那洛肽在服药1周内即可显著改善包括腹部疼痛在内的便秘型肠易激综合征症状(Gastroenterology 2010 December [doi:10.1053/j.gastro.2010.08.041])。

利那洛肽(Linaclotide)是由Ironwood制药公司研发的一种14-氨基酸肽，为肠上皮细胞尿苷酸环化酶C受体激动剂。动物模型实验表明，该药物可促进液体分泌和转运。

本研究为双盲、安慰剂对照的利那洛肽IIB期临床试验，共纳入420例患者，患者年龄≥18岁且符合罗马II肠易激综合征(IBS)诊断标准，平均年龄44岁，92%为女性。所有受试者自诉每周自发排便次数少于3次，且出现排便费力、块便或硬便以及排便不尽感症状的排便次数不少于25%。患者被随机分为5组，分别在每日首次进食前口服安慰剂、75mg、150mg、300mg和600mg利那洛肽，试验周期为12周。首要终点为与基线相比完全自发排便(CSBMs)次数增加。研究者每日通过电话借助互动式语音反应系统对患者进行评估。

结果显示，完成试验的所有药物治疗患者均达到首要终点。12周时与基线相比， 75mg、150mg、300mg和600mg组患者每周CSBMs分别增加2.90、2.49、3.61和2.68次(各组P≤0 .01)，而安慰剂组每周CSBMs增加1.01次。此外，药物治疗组患者腹部疼痛也显著减轻，与基线相比，12周时75mg、150mg、300mg和600mg组疼痛量表分值平均降低0.71、0.71、0.90和0.86，安慰剂组降低0.49(各组P ≤0.05)。利那洛肽的疗效从治疗第1周开始，且一直持续至整个3个月的研究期结束。最常见副作用为腹泻且呈剂量依赖性，10余人因腹泻而退出研究。75mg、150mg、300mg和600mg组发生率分别为11.4%、12.2%、16.5%和18.0%，安慰剂组为1.2% 。但没有腹泻导致脱水、电解质变化或其他不良临床后遗症的报告。

研究表明，利那洛肽对便秘型肠易激综合征常见症状具有持续疗效，而目前几乎没有针对这些症状的药物。研究结果支持利那洛肽用于治疗成人便秘型肠易激综合征的进一步开发研究。

Ironwood制药公司资助本研究，研究者为该公司职员。

爱思唯尔  版权所有