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

Abstract

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

To establish a treatment for GI symptoms of cystic fibrosis, it is necessary to develop a symptom evaluation tool

“…Although the mechanisms of GI symptoms in CF have not been investigated in detail, it is known that guanylyl cyclase (GC) is involved in the pathogenesis of CF, as it is known to be implicated in functional or chronic idiopathic constipation. As linaclotide—recently approved for the indication to IBS‐C and chronic idiopathic constipation in some countries including Japan 7 , 8 —blocks GC and improves complete spontaneous bowel movements, fecal condition, and abdominal pain/discomfort, this drug would be also expected to be useful in the treatment of constipation symptoms in CF. Further understanding of GI symptom generation, pathophysiological origins, and assessment method for monitoring symptoms will be necessary to apply this agent to the possible treatment of CF.…”