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根据一项发表于美国肠胃科医学会（ACG）2008年科学座谈会与毕业后训练的第2b期临床研究结果，Linaclotide可以改善罹患便秘型大肠激躁症（IBS-C）成人病患腹部疼痛与缓解便秘症状。
这项研究是由麻州剑桥Ironwood药厂副总裁与医疗事务主任Jeffrey Johnson医师所进行，这项多中心研究被设计来评估每日剂量疗程75、150、300或是600 μg的linaclotide或是安慰剂使用于成人IBS-C病患的效果；研究的主要试验终点为完全自发性肠胃运动（CSBM）频率变化值。
在美国89个医学中心收纳的420位病患中，419位符合意向分析（ITT）标准，337位完成这项研究，其中包括两个星期的试验前评估，与12个星期的治疗期，以及两个星期的治疗后追踪期。在发表会上，Johnson医师报告ITT族群的平均年龄为44.4岁，其中92%的病患是女性，8%的病患是男性。
所有病患都使用一种互动式声音反应系统来进行肠胃排便习惯与症状严重度的每日评估，以及每周的整体评估，分数从5分（最严重的）到0分（最轻微的）；在试验前评估阶段，病患必须是每周有3次以下的CSBM，且每日平均腹痛严重度至少要是轻微的。治疗效果以共变异数与Cochran-Mantel-Haenszel检定分析。
Johnson医师报告，在治疗期结束时有达到主要试验终点以及次要试验终点；试验前后的变化，相较于安慰剂组，CSBM的改变在所有linaclotid组都有显著差异。除此之外，所有接受治疗的病患，其腹痛也有临床上与统计上显著的改善。相较于安慰剂组（改变-0.2），试验前后的改变在75 μg组为-0.8（P=.0236）、150 μg为-1.0（P=.0018）、300 μg为-1.2（P=.0002）、600 μg为-1.3（P=<.0001）。在300 μg与600 μg组，腹部绞痛、胀气、IBS症状严重度与整体评估都有统计上的显著差距。
所有剂量组别的疗效都在治疗的第一个星期就开始，且维持整个12个星期的治疗期；在发表会上，Johnston医师指出腹泻是最常报告的副作用，即使因为这个原因而停药的比例很低，仅有1~6%。
当被Medscape肠胃医学问到有关于他在这项研究中最令人兴奋的发现时，Johnston医师表示是对腹痛的效果；我们对于在肠胃运动得到的结果感到很有信心（根据我们过去的研究结果，我们不知道对于疼痛的影响）；我们知道，在临床前的研究中，我们应该可以看到对腹痛的效果，但是能够看到确切的数据与其效果的程度有多戏剧化，真的令人感到很兴奋。
他进一步表示，第一个需要带回去的讯息是，linaclotide具有这样的潜力，根据这些2b期的数据，这会影响IIBS的疼痛与不适感，以及改变肠胃道运动及IBS-C的便秘状况。
在发表会后的问答时间，佛州杰克逊维梅约诊所的医学教授，同时也是美国肠胃科医学会期刊的共同主编，Nicholas Talley医师表示对于这个研究族群的组成感到惊讶，他在仔细检视发表的数据后问道：“这些病患大部分在试验前都有便秘的问题，你有考虑将这些病患排除在试验外吗？”当Johnston医师回答他并没有这样考虑，Talley医师回应：那是非常有趣的。
之后，Talley医师向Medscape肠胃医学解释，这是个很小但很重要的发现。我想要看到如果排除了有骨盆腔阻塞病患之后的结果，特别是因为药物对这些病患效果不好。如果不是因为这个因素的话，研究人员们可能会看到更多正面的结果。
整体来说，虽然Talley医师说他是乐观的，但这是个全新的药物，特别是它对于运动的作用，对于IBS病患的不同形式症状都有显著的改善，且我没有看到任何安全性的问题，如果这样的结果可以在第三期临床研究中获得确认，对于这个领域来说将是个好消息。
这项研究由Ironwood药厂赞助。Johnston医师是Ironwood药厂的员工。他表示过去接受该公司的顾问费。
Linaclotide Improves Abdominal Pain, Constipation in Adults With IBS-C
By Deborah Brauser
Medscape Medical News
Linaclotide appears to significantly improve abdominal pain and relieve constipation and other symptoms in adults with irritable bowel syndrome with constipation (IBS-C), according to results from a large phase?2b study presented here at the American College of Gastroenterology (ACG) 2008 Annual Scientific Meeting and Postgraduate Course.
According to the study, presented in a plenary session by Jeffrey Johnston, MD, vice president and chief medical officer at Ironwood Pharmaceuticals, in Cambridge, Massachusetts, this multicenter trial was designed to evaluate the safety and efficacy of a daily regimen of 75-, 150-, 300- or 600-μg doses of linaclotide or placebo in adults with IBS-C. The study's primary end point was the change from baseline for complete spontaneous bowel-movement (CSBM) frequency.
Of the 420 patients enrolled in 89 centers across the United States, 419 were in the intent-to-treat (ITT) population, and 337 completed the study — which comprised a 2-week baseline evaluation, a 12-week treatment period, and a 2-week posttreatment phase. During his presentation, Dr. Johnston reported that the mean age of the ITT population was 44.4 years, and that 92% of the patients were female and 8% were male.
All patients used an interactive voice-response system to make daily assessments of bowel habits and symptom severity, and weekly global assessments, using a rating scale from 5 (very severe) to 1 (none). During the baseline period, patients had to report less than 3 CSBMs per week and mean daily abdominal pain of at least mild severity. Treatment effects were estimated using an analysis of covariance and the Cochran–Mantel–Haenszel test.
"At the end of the treatment period," reported Dr. Johnston, "the primary end point, as well as all secondary end points, was met." The change from baseline, compared with placebo, for CSBM frequency was significant in all linaclotide groups. In addition, abdominal pain showed clinically and statistically significant improvement for all treated patients. For patients with severe or very severe baseline abdominal pain, the improvement was even more dramatic. Its dose breakdown for change from baseline was –0.8 for 75?μg (P?= .0236), –1.0 for 150?μg (P?= .0018), –1.2 for 300?μg (P?= .0002), and –1.3 for 600?μg (P?=< .0001), compared with placebo (–0.2 change). In the 300-μg and 600-μg dosage groups, results were statistically significant for straining, bloating, IBS symptom severity, and global assessments.
Effects from all dosage groups were apparent within the first week of treatment and were maintained throughout the full 12-week treatment period. In his presentation, Dr. Johnston said that diarrhea was the most common adverse event reported, although discontinuation for this reason was low, at only 1% to 6%.
When asked by Medscape Gastroenterology what he found to be the most exciting finding of this study, Dr. Johnston said: "That would be the effect on abdominal pain. We were pretty confident that we would get good effects on bowel habits [based on previous studies], but we really didn't know about pain. We knew that preclinically we should see an effect on abdominal pain, but it was really exciting to see the actual data and see how dramatic the magnitude of the effect was."
He continued: "The number?1 takeaway is that linaclotide has the potential, based on these phase?2b data, to affect both the pain and discomfort of IBS, as well as to alter the bowel habit and constipation of IBS-C."
During the question-and-answer event immediately after the presentation, session moderator Nicholas Talley, MD, professor of medicine at Mayo Clinic Jacksonville, in Florida, and coeditor of ACG's American Journal of Gastroenterology, expressed surprise about the makeup of the trial population. Looking at the data presented, he asked: "Most of these patients were very constipated at baseline — did you ever consider excluding them from your study?" When Dr. Johnston answered that he hadn't, Dr. Talley replied: "That could have been interesting."
Later, Dr. Talley explained to Medscape Gastroenterology that "the devil's in the details. I would like to have seen the trial exclude patients with pelvic-outlet obstruction, especially since drugs don't usually work in these types of patients. [The investigators] may have seen even more positive results if not for that issue."
Overall, though, Dr. Talley said he was optimistic. "Clearly, this is a novel drug, especially in its motor action. There were significant improvements in multiple types of symptoms in IBS patients. And I didn't see any safety issues. It's good news for the field if the results are confirmed in phase?3 trials."
This study was supported by an industry grant from Ironwood Pharmaceuticals. Dr. Johnston is an employee of Ironwood. Dr. Talley has consulted for Ironwood in the past.
American College of Gastroenterology (ACG) 2008 Annual Scientific Meeting and Postgraduate Course: Abstract 35. Presented October 6, 2008.