Linaclotide for Irritable Bowel Syndrome With Constipation: A 26-Week, Randomized, Double-blind, Placebo-Controlled Trial to Evaluate Efficacy and Safety

Chey, William D.; Lembo, Anthony; Lavins, Bernard J.; Shiff, Steven J.; Kurtz, Caroline B.; Currie, Mark G.; MacDougall, James E.; Jia, Xinwei D.; Shao, James; Fitch, Donald A.; Baird, Mollie; Schneier, Harvey; Johnston, Jeffrey M.

doi:10.1038/ajg.2012.254

Cited by 384 publications

(455 citation statements)

References 30 publications

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“…These findings are consistent with the earlier studies. 3,4 The most impressive difference between our study and their study is discontinuation rate of linaclotide. We can understand that randomized controlled trial is more ideal clinical situation than daily practice.…”

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confidence: 65%

Randomized, double‐blind, placebo‐controlled study vs data in the daily practice using linaclotide in patients with irritable bowel syndrome with constipation

Fukudo

Nakajima

Fujiyama

et al. 2018

Neurogastroenterology Motil

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We would like to express sincere gratitude to the interesting comments on our paper 1 by Shearer et al. 2 It is difficult to compare both results directly because different endpoints, different patients' population, different eligible criteria, different drugs prescribed during treatment period, different criteria of adverse events, and different doses of linaclotide are present between 2 studies. However, comparison of results between 0.25 mg of linaclotide (tablet) in our study 1 and 0.29 mg of linaclotide (capsule) in their study 2 would be relatively feasible. Comparable endpoints between 2 studies are only spontaneous bowel movement (SBM), straining, and adverse events.SBM showed 3.8 (mean) at baseline vs 8.9 at 4 weeks in their study 2 and 2.71 (mean) ± 1.13 (SD) at baseline vs 5.86 ± 4.44 at 4 weeks in our study. 1 Straining scored 3.9 at baseline vs 2.0 at 4 weeks in their study 2 and 3.51 (mean) ± 0.74 (SD) at baseline vs 2.62 ± 0.97 at 4 weeks in our study. 1 Note that straining was assessed on 5-point ordinate scale (1, not at all; 2, a little bit; 3, a moderate amount; 4, a great deal; and 5, an extreme amount) in our study. 1 There was no description how they evaluate the straining. 2 In their study at 4 weeks, 56.5% patients continued linaclotide and 43.5% discontinued, 22.2% due to either lack of efficacy or being lost to follow-up, and 21.3% due to adverse events. 2 Overall adverse event rate was 39.8% including 25.9% diarrhea. 2 In our study at 12 weeks, 88.4% patients continued linaclotide and 11.6% discontinued. 1 Despite longer trial period, overall adverse event rate was 41.1% including 17.9% diarrhea. 1Overall adverse event rates were roughly comparable between 2 studies. These findings are consistent with the earlier studies. 3,4 The most impressive difference between our study and their study is discontinuation rate of linaclotide. We can understand that randomized controlled trial is more ideal clinical situation than daily practice. However, from the viewpoint of good clinical practice, basic attitude of biospychosocial model including good physicianpatient relationship which is highly recommended in Japanese IBS guideline 5 may be one of factors of low drop rate. This phenomenon was discussed in the multicultural chapter in Rome IV. 6 Future studies should also clarify potential biological factors including genealogy, gut microbiota, diet, and concomitant therapy (including the ongoing use of laxatives or other constipation-related treatments) which may affect efficacy and safety of linaclotide among different individuals. CO N FLI C T O F I NTE R E S T

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confidence: 65%

Randomized, double‐blind, placebo‐controlled study vs data in the daily practice using linaclotide in patients with irritable bowel syndrome with constipation

Fukudo

Nakajima

Fujiyama

et al. 2018

Neurogastroenterology Motil

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“…Interestingly, the correlation between aggregate measures of published studies addressing bowel patterns and pain correspond with results of a pilot study, which demonstrated a significant relationship between changes in bowel frequency and pain ratings for individual patients receiving linaclotide for constipation. 62 The described correlation between improved pain ratings were not only reported in studies of the newly introduced agents for IBS-C, [63][64][65][66][67] but were also observed in many other trials, which did not meet inclusion criteria for this analysis and examined the effects of interventions ranging from fiber supplements, 68,69 to herbal preparations, 70 biofeedback, 71 bisacodyl, 72 or osmotic laxatives. [73][74][75] While not the focus of this analysis, we noted some statistically significant, but clinically minor, differences in the endpoints between patient cohorts with constipation and IBS-C.…”

Section: Discussionmentioning

confidence: 99%

Effective Constipation Treatment Changes More Than Bowel Frequency: A Systematic Review and Meta-Analysis

Bielefeldt

Levinthal

Nusrat

2015

J Neurogastroenterol Motil

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Background/AimsThe marketing of newer agents for treatment of constipation and irritable bowel syndrome with constipation (IBS-C) emphasize improvements in abdominal pain. However, it is not clear whether this observation reflects a unique visceral analgesic effect of these agents or is a general feature of effective laxation. We sought to determine the relationship between improvements in bowel frequency and decreases in abdominal pain in clinical trials of patients with constipation or IBS-C. MethodsWe searched "PubMed" and "Embase" databanks for clinical trials in patients with constipation or IBS-C, targeting publications that provided detailed data on bowel movement frequency and pain intensity before and after an intervention. We abstracted the results and performed meta-analytic and meta-regression analyses. Results Twenty

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“…An intracellular cascade of events leads to activation of chloride secretion and thereby a net movement of water into the gut lumen, resulting in softer stool and more frequent bowel movements [27]. A feature of particular interest relates to reductions in constipation associated abdominal pain [28] and bloating [29], which can develop gradually over months from the start of treatment.…”

Section: Constipationmentioning

confidence: 99%

Treatment of gastrointestinal autonomic neuropathy

Törnblom

2015

Diabetologia

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The symptoms caused by gastrointestinal autonomic neuropathy in diabetes mellitus is important to highlight since it affects a large proportion of people with diabetes, regardless of whether this is type 1 or type 2. Gastroparesis and general signs of bowel dysfunction, such as constipation, diarrhoea and abdominal pain are most often encountered and involve both pharmacological and non-pharmacological treatment options. This mini-review summarises a presentation given at the 'Diagnosis and treatment of autonomic diabetic neuropathy in the gut' symposium at the 2015 annual meeting of the EASD. It is accompanied by another mini-review on a topic from this symposium (by Azpiroz and Malagelada,

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Linaclotide for Irritable Bowel Syndrome With Constipation: A 26-Week, Randomized, Double-blind, Placebo-Controlled Trial to Evaluate Efficacy and Safety

Cited by 384 publications

References 30 publications

Randomized, double‐blind, placebo‐controlled study vs data in the daily practice using linaclotide in patients with irritable bowel syndrome with constipation

Randomized, double‐blind, placebo‐controlled study vs data in the daily practice using linaclotide in patients with irritable bowel syndrome with constipation

Effective Constipation Treatment Changes More Than Bowel Frequency: A Systematic Review and Meta-Analysis

Treatment of gastrointestinal autonomic neuropathy

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