Determining an optimal dose of linaclotide for use in Japanese patients with irritable bowel syndrome with constipation: A phase II randomized, double‐blind, placebo‐controlled study

Fukudo, Shin; Nakajima, Atsushi; Fujiyama, Y; Kosako, Masanori; Nakagawa, Ayako; Akiho, Hiraku; Nakashima, Yoshihiro; Johnston, Jeffrey M.; Miwa, Hiroto

doi:10.1111/nmo.13275

Cited by 29 publications

(48 citation statements)

References 36 publications

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“…By contrast, results obtained in Japan have been somewhat different. A phase II study of IBS‐C patients showed 0.5 mg per day of linaclotide to be the optimal dose . A subsequent phase III study of IBS‐C patients confirmed 0.5 mg per day of linaclotide to be effective and safe .…”

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confidence: 70%

High‐dose linaclotide is effective and safe in patients with chronic constipation: A phase III randomized, double‐blind, placebo‐controlled study with a long‐term open‐label extension study in Japan

Fukudo

Miwa

Nakajima

et al. 2018

Neurogastroenterology Motil

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Background A previous phase II dose‐ranging study of linaclotide in a Japanese chronic constipation (CC) population showed that 0.5 mg was the most effective dose. This study aimed to verify the hypothesis that 0.5 mg of linaclotide is effective and safe in Japanese CC patients. Methods This was a Japanese phase III randomized, double‐blind, placebo‐controlled (part 1), and long‐term, open‐label extension (part 2) study of linaclotide. CC patients (n = 186) diagnosed using the Rome III criteria were randomly assigned to linaclotide 0.5 mg (n = 95) or placebo (n = 91) for a 4‐week double‐blind treatment period in part 1, followed by an additional 52 weeks of open‐label treatment with linaclotide in part 2. The primary efficacy endpoint was the change from baseline in weekly spontaneous bowel movement (SBM) frequency at the first week. Secondary endpoints included responder rate for complete SBM (CSBM), changes in stool consistency, and severity of straining. Key Results Part 1: Change in weekly mean SBM frequency in the first week of treatment with linaclotide (4.02) was significantly greater than that with placebo (1.48, P < 0.001). Linaclotide produced a higher CSBM responder rate (52.7%) compared to placebo (26.1%, P < 0.001). Part 2: Patients continued to show improved SBM frequency with linaclotide. Through parts 1 and 2, the most common drug‐related adverse event was mild and occasionally moderate diarrhea. Conclusions and Inferences The results of this study indicate that a linaclotide dose of 0.5 mg/day is effective and safe in Japanese CC patients.

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Section: Introductionmentioning

confidence: 70%

High‐dose linaclotide is effective and safe in patients with chronic constipation: A phase III randomized, double‐blind, placebo‐controlled study with a long‐term open‐label extension study in Japan

Fukudo

Miwa

Nakajima

et al. 2018

Neurogastroenterology Motil

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“…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.…”

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confidence: 78%

“…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. 1 Overall adverse event rates were roughly comparable between 2 studies.…”

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confidence: 99%

“…1 Despite longer trial period, overall adverse event rate was 41.1% including 17.9% diarrhea. 1 Overall adverse event rates were roughly comparable between 2 studies. These findings are consistent with the earlier studies.…”

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confidence: 99%

“…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.…”

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confidence: 99%

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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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Clinical presentation and therapeutic outcome of patients with jackhammer esophagus—a multicenter cohort study in Japan

et al. 2022

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Background Jackhammer esophagus (JE) is a hypercontractile esophageal motility disorder diagnosed using high-resolution manometry (HRM). We sought to determine the clinical presentation and therapeutic data of patients with JE in Japan. Methods The study included patients with JE, diagnosed through HRM performed for suspicious esophageal motility disorders. Demographics, esophagogastroduodenoscopy, radiology, and therapy data were collected from patient charts. Results Among the 4,412 HRM tests performed, 89 patients (61.6 ± 13.4 years; 64 males, 25 females) were diagnosed with JE (2.0%). Dysphagia was the most frequent symptom (80%), followed by chest pain (40%) and heartburn (25%). Esophagogastroduodenoscopy showed abnormal findings in 32% of patients: corkscrew/rosary beads appearance in 26%, narrowing in 11%. Eosinophilic infiltration (> 15 eosinophils/high power field) was diagnosed in 21%. Esophagography showed abnormal findings in 9% of the patients. For the initial therapy, 47 patients received medical treatment followed by peroral endoscopic myotomy (21 patients) and laparoscopic myotomy (two patients). Thirteen patients did not receive any treatment and 10 of those (77%) reported spontaneous resolution of symptoms. Patients who required invasive treatment experienced severe disability in their quality of life and greater maximal distal contractile integral than those who did not. Conclusions HRM showed that the prevalence of JE was very low (2%). Esophagogastroduodenoscopy revealed some characteristic features of JE in patients. Some patients showed improvement of symptoms without invasive treatments. Follow-up with/without medical treatment should be considered before performing invasive treatment in patients whose distal contractile integral is relatively low and the quality of life is not impaired.

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Determining an optimal dose of linaclotide for use in Japanese patients with irritable bowel syndrome with constipation: A phase II randomized, double‐blind, placebo‐controlled study

Abstract: This study suggests that a linaclotide dose of 0.5 mg may be appropriate in Japanese patients with IBS-C.

Cited by 29 publications

References 36 publications

High‐dose linaclotide is effective and safe in patients with chronic constipation: A phase III randomized, double‐blind, placebo‐controlled study with a long‐term open‐label extension study in Japan

High‐dose linaclotide is effective and safe in patients with chronic constipation: A phase III randomized, double‐blind, placebo‐controlled study with a long‐term open‐label extension study in Japan

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

Clinical presentation and therapeutic outcome of patients with jackhammer esophagus—a multicenter cohort study in Japan

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