BOSTON (EGMN) – The results of two 12-week, randomized, placebo-controlled phase III trials of linaclotide showed that the drug produced significant improvement in key end points related to chronic constipation.

Quality of life self-assessments also showed a favorable response, according to Dr. Anthony J. Lembo, who presented the results of both studies as a poster at Neurogastroenterology and Motility 2010.

At the same meeting, which was hosted by the American Neurogastroenterology and Motility Society, Dr. Jeffrey M. Johnston reported in an oral presentation the results of the 4-week randomized withdrawal period that followed one of the studies. The findings showed that no rebound effects were seen after linaclotide cessation.

Linaclotide is a minimally absorbed, 14-amino-acid peptide, guanylate cyclase-C agonist, said Dr. Lembo, a gastroenterologist at Beth Israel Deaconess Medical Center, Boston. It is produced by Ironwood Pharmaceuticals Inc., which supported the studies. Dr. Johnston is the chief medical officer at Ironwood Pharmaceuticals.

Two phase III trials were conducted, one with an intent-to-treat (ITT) population of 642 patients (Trial 303) and the other with an ITT population of 630 (Trial 01). The average age was 48 years, and approximately 12% of the participants were older than 65 years. About 90% of the subjects were female.

Subjects met Rome II criteria for chronic constipation, including fewer than three complete spontaneous bowel movements (CSBMs) per week, six or fewer spontaneous bowel movements per week (SBMs), or one or fewer SBMs on the Bristol Stool Form Scale (BSFS). At baseline, subjects reported 0.3 CSBMs per week and about 2 SBMs per week.

Subjects were treated with either 133 mcg or 266 mcg linaclotide or placebo. The linaclotide groups showed significant improvement, compared with placebo on the primary efficacy end point, which was the percentage of patients who had an increase of at least one spontaneous bowel movement over baseline for at least 9 of the 12 treatment weeks. In the first trial, 39.2% of those receiving low-dose linaclotide and 37.0% of those receiving high-dose linaclotide had an increase of one or more CSBMs per week for 9 of 12 weeks, compared with their baseline rate; these rates were significantly greater than the 11% rate observed in the placebo group (P less than .0001). Similar rates were seen in the second trial (31.0% low-dose, 40.1% high-dose, 13% placebo).

Patients also reported improvements in other bowel and abdominal symptoms associated with chronic constipation, such as the weekly rate of CSBMs, weekly rates of SBMs, better stool consistency, less severity of straining, less bloating, less abdominal discomfort, and less constipation severity.

For example, the weekly CSBM rate rose to 2 times per week, compared with 0.5 times per week in the placebo group (P less than .0001). In both trials at both doses tested, patients taking linaclotide reported better quality of life as measured on the 4-point Patient Assessment of Constipation–Quality of Life (PAC-QOL) questionnaire.

Eighty-four percent of enrollees in each trial completed treatment. Analysis of pooled safety results from both trials showed that 7% of those receiving the low dose and 7% of those receiving the high dose of linaclotide discontinued due to adverse events, compared with 4% of those receiving placebo.

One patient receiving low-dose linaclotide died as a result of a fentanyl patch overdose unrelated to the study drug. Diarrhea was the most common adverse event reported by those receiving linaclotide, and 4% of linaclotide-treated patients discontinued due to diarrhea.

During the 4-week randomized withdrawal period, those who were treated with linaclotide during the treatment period were rerandomized to either placebo or the linaclotide dose they had received. Those who had received placebo during the treatment period received high-dose linaclotide during the withdrawal period, explained Dr. Johnston. In total, 538 patients participated in the withdrawal phase.

The investigators found that those who had first received placebo and then received the study drug in the withdrawal phase showed improvements in their constipation symptoms similar to those of the patients who had previously been treated with linaclotide. Those who had received active treatment but were switched to placebo showed regression toward more constipation symptoms, similar to those of the patients who had previously received placebo. No rebound effect was seen after cessation of linaclotide. Sustained improvement was seen in those treated with linaclotide during both the treatment and withdrawal periods.

The trial was supported by Ironwood Pharmaceuticals Inc. Dr. Lembo is a paid consultant to Ironwood Pharmaceuticals. All other authors are employees of either Ironwood Pharmaceuticals or Forest Research Laboratories.

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

波士顿(EGMN)——美国神经胃肠病学与动力协会2010年度会议上报告的两项为期12周的随机、安慰剂对照III期研究显示，利那洛肽可显著改善与慢性便秘相关的关键终点，并改善患者生活质量。

 

利那洛肽是一种吸收率很低的14-氨基酸肽鸟苷酸环化酶-C激动剂，由支持这两项研究的Ironwood制药公司生产。

 

这两项研究的意向治疗(ITT)人群分别为642例患者(303号研究)和630例患者(01号研究)，平均年龄为48岁，65岁以上者占12%，女性占90%。受试者满足罗马II慢性便秘标准，包括每周完全自发排便(CSBM)次数少于3次、每周自发排便(SBM)次数≤6次、或粪便性状量表(BSFS)评定的SBM次数≤1次。基线时，受试者报告的每周CSBM次数为0.3次，每周SBM次数为2次，研究中接受133 μg或266 μg 利那洛肽或安慰剂治疗。主要疗效终点为12周治疗的至少9周内自发排便次数相比基线时增加至少1次的患者比例。

 

研究结果显示，利那洛肽组这一主要疗效终点的改善显著优于安慰剂组。在第1项研究中，利那洛肽低剂量组和高剂量组在12周治疗的9周内每周CSBM次数相比基线时增加≥1次的患者比例分别为39.2%和37.0%，显著高于安慰剂组的11%(P＜0.0001)。在第2项研究中，也观察到相似比例(低剂量组31.0%，高剂量组40.1%，安慰剂组13%)。

 

另外，利那洛肽治疗患者的其他与慢性便秘相关的肠道和腹部症状也获得改善，包括每周CSBM次数、每周SBM次数、粪便稠度增加、排便用力度减少、胀气减少、腹部不适减少、以及便秘严重程度减轻。例如，利那洛肽组每周CSBM次数增至2次/周，而安慰剂组才0.5次/周(P ＜0.0001)。在两项研究中，利那洛肽两个剂量组患者通过4分制便秘患者生活质量评估(PAC-QOL) 问卷测得的生活质量评分较高。

 

两项研究中完成治疗的患者比例均为84%。汇总两项研究的安全性结果进行分析发现，利那洛肽低剂量组、高剂量组和安慰剂组因不良事件而终止研究的患者比例分别为7%、7%和4%。

 

利那洛肽低剂量组1例患者因应用芬太尼贴剂过量而死亡，该死亡病例被认为与研究药物无关。利那洛肽治疗患者的最常见不良事件为腹泻，4%的利那洛肽治疗患者因腹泻而终止研究。

 

其中一项研究还设有1个为期4周的随机撤药期。共538例患者进入撤药期。在撤药期内，将在此前治疗期内接受利那洛肽治疗的患者随机分成安慰剂组和利那洛肽组(剂量如前)。此前在治疗期内接受安慰剂治疗的患者在撤药期内接受高剂量利那洛肽治疗。结果发现，那些先接受安慰剂治疗后在撤药期内接受利那洛肽治疗的患者在便秘症状方面的改善与那些此前接受利那洛肽治疗的患者相似。那些此前接受利那洛肽治疗但随后接受安慰剂治疗的患者重新出现更多便秘症状，这与在此前接受安慰剂治疗的患者中观察到的相似。在那些在治疗期和撤药期内均接受利那洛肽治疗的患者中观察到持续改善效果。

 

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