A 12-Week, Randomized, Controlled Trial With a 4-Week Randomized Withdrawal Period to Evaluate the Efficacy and Safety of Linaclotide in Irritable Bowel Syndrome With Constipation

Rao, Satish S.; Lembo, Anthony; Shiff, Steven J.; Lavins, Bernard J.; Currie, Mark G.; Jia, Xinwei D.; Shi, Kelvin; MacDougall, James E.; Shao, James; Eng, Paul; Fox, Susan M.; Schneier, Harvey; Kurtz, Caroline B.; Johnston, Jeffrey M.

doi:10.1038/ajg.2012.255

Cited by 321 publications

(402 citation statements)

References 22 publications

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“…57 The modified FDA endpoint for IBS-C was implemented in two phase III trials published last year which supported the use of linaclotide in treating IBS, a secretagogue therapy which accelerates gut motility. [58][59][60] This new endpoint incorporates a binary measure of complete spontaneous bowel movements which still does not evaluate whether a patient decides that this increase in bowel movements is an adverse event. Based on data from the linaclotide trials, this IBS-C endpoint was validated against patient rating-of-change questions asked concurrently with the drug trials.…”

Section: Recent Updates In Outcome Designmentioning

confidence: 99%

Placebo Effect in Clinical Trial Design for Irritable Bowel Syndrome

Shah¹,

Pimentel²

2014

J Neurogastroenterol Motil

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Ongoing efforts to improve clinical trial design in irritable bowel syndrome have been hindered by high placebo response rates and ineffective outcome measures. We assessed established strategies to minimize placebo effect as well as the various approaches to placebo effect which can affect trial design. These include genetic markers such as catechol-O-methyltransferase, opioidergic and dopaminergic neurobiologic theory, pre-cebo effect centered on expectancy theory, and side effect unblinding grounded on conditioning theory. We reviewed endpoints used in the study of IBS over the past decade including adequate relief and subjective global relief, emphasizing their weaknesses in fully evaluating the IBS condition, specifically their motility effects based on functional net value and relative benefit-harm based on dropouts due to adverse events. The focus of this review is to highlight ongoing efforts to improve clinical trial design which can lead to better outcomes in a real-world setting.

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Section: Recent Updates In Outcome Designmentioning

confidence: 99%

Placebo Effect in Clinical Trial Design for Irritable Bowel Syndrome

Shah¹,

Pimentel²

2014

J Neurogastroenterol Motil

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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: 66%

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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“…The second phase III trial differed in terms of its design in that patients were randomized to receive linaclotide 290 µg or placebo for a total of 12 weeks, followed by a 4-week randomized withdrawal period [Rao et al 2012]. However, inclusion criteria and endpoints were identical to the first trial.…”

Section: Phase Iib Studymentioning

confidence: 99%

“…Phase III studies Two phase III randomized, double-blind, placebocontrolled trials were published in 2012 [Chey et al 2012;Rao et al 2012]. The first of these was conducted in 102 centres in the USA and randomized 804 patients to receive linaclotide 290 µg or placebo for 26 weeks [Chey et al 2012].…”

Section: Phase Iib Studymentioning

confidence: 99%

Linaclotide: new mechanisms and new promise for treatment in constipation and irritable bowel syndrome

Sood

Ford

2013

Therapeutic Advances in Chronic Disease

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Chronic idiopathic constipation (CIC) and irritable bowel syndrome (IBS) are functional disorders of the lower gastrointestinal tract. Their prevalence in the general population is between 5% and 20%. Both disorders are chronic, with a relapsing and remitting natural history. The medical treatment of both conditions is unsatisfactory at present, and they represent a huge burden to the health service. Linaclotide is a first-in-class minimally adsorbed, 14-amino-acid peptide agonist of guanylate cyclase C. The drug acts on the intestinal enterocyte. As a consequence of this, intestinal fluid secretion is increased and intestinal transit is accelerated. The efficacy of linaclotide has been studied in both CIC and constipation-predominant IBS (IBS-C). Randomized controlled trials consistently demonstrate that the drug is effective in the treatment of CIC and IBS-C, across a wide range of continuous and dichotomous endpoints. The number needed to treat with linaclotide to prevent one patient with CIC or IBS-C failing to respond to therapy is between 5 and 8 in studies that have reported these data. Overall, in the majority of trials, total numbers of adverse events have been no more frequent with linaclotide, but rates of diarrhoea have been consistently higher. While the drug is clearly effective in the treatment of CIC, there are other evidence-based therapies available, and head-to-head efficacy and cost-effectiveness studies are therefore required to further delineate the role of linaclotide in the treatment of the condition. In IBS-C there are no other licensed therapies available, and linaclotide therefore represents a novel treatment with great promise.

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A 12-Week, Randomized, Controlled Trial With a 4-Week Randomized Withdrawal Period to Evaluate the Efficacy and Safety of Linaclotide in Irritable Bowel Syndrome With Constipation

Cited by 321 publications

References 22 publications

Placebo Effect in Clinical Trial Design for Irritable Bowel Syndrome

Placebo Effect in Clinical Trial Design for Irritable Bowel Syndrome

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

Linaclotide: new mechanisms and new promise for treatment in constipation and irritable bowel syndrome

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