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.

Published on May 1, 2018in Neurogastroenterology and Motility2.946
· DOI :10.1111/NMO.13275
Shin Fukudo54
Estimated H-index: 54
(Tohoku University),
A. Nakajima11
Estimated H-index: 11
(YCU: Yokohama City University)
+ 6 AuthorsHiroto Miwa54
Estimated H-index: 54
(Hyogo College of Medicine)
Sources
Abstract
BACKGROUND:Clinical testing to determine a suitable dose of linaclotide for Japanese patients with irritable bowel syndrome with constipation (IBS-C) was needed. METHODS:This was a randomized, double-blind, placebo-controlled, dose-finding trial. Japanese patients with IBS-C diagnosed using Rome III criteria (n = 559, men/women: 49/510) were randomly assigned to 1 of 4 linaclotide doses (0.0625, 0.125, 0.25, or 0.5 mg) or placebo for the 12-week treatment period. The primary endpoint was responder rate of global assessment of relief of IBS symptoms during 12 weeks. The secondary endpoints included responder rates of complete spontaneous bowel movement (CSBM), SBM and abdominal pain/discomfort relief and others. KEY RESULTS:The primary endpoint was 23.2%, 36.2%, 38.7%, 34.8%, and 38.3% in placebo (n = 112), 0.0625 (n = 116), 0.125 (n = 111), 0.25 (n = 112), and 0.5 (n = 107) mg of linaclotide groups with the difference from the placebo group in each linaclotide group (13.0%, 15.5%, 11.6%, 15.1%, P > .05). Monthly responder rate of global assessment of relief of IBS symptoms at month 3 (48.6%), responder rate of CSBM during 12 weeks (45.8%), and responder rate of abdominal pain/discomfort relief during 12 weeks (32.7%) in the 0.5 mg were significantly higher than those in placebo group (29.5%, P < .01; 25.9%, P < .01; and 18.8%, P < .05 respectively). The most frequent adverse event in the linaclotide groups was diarrhea. CONCLUSIONS & INFERENCES:This study suggests that a linaclotide dose of 0.5 mg may be appropriate in Japanese patients with IBS-C.
Download
📖 Papers frequently viewed together
3 Citations
9 Citations
66 Citations
References34
Newest
#1Ami D. Sperber (BGU: Ben-Gurion University of the Negev)H-Index: 31
#2Dan L. DumitrascuH-Index: 25
Last. William E. Whitehead (UNC: University of North Carolina at Chapel Hill)H-Index: 102
view all 14 authors...
Objectives The global prevalence of IBS is difficult to ascertain, particularly in light of the heterogeneity of published epidemiological studies. The aim was to conduct a literature review, by experts from around the world, of community-based studies on IBS prevalence. Design Searches were conducted using predetermined search terms and eligibility criteria, including papers in all languages. Pooled prevalence rates were calculated by combining separate population survey prevalence estimates to...
204 CitationsSource
#1Douglas A. Drossman (UNC: University of North Carolina at Chapel Hill)H-Index: 103
#2William L. HaslerH-Index: 62
514 CitationsSource
#1Carlos Fernando de Magalhães Francisconi (UFRGS: Universidade Federal do Rio Grande do Sul)H-Index: 3
#2Ami D. Sperber (BGU: Ben-Gurion University of the Negev)H-Index: 31
Last. Max Schmulson (UNAM: National Autonomous University of Mexico)H-Index: 23
view all 7 authors...
Cross-cultural factors are important in functional gastrointestinal disorders (FGIDs). In the setting of FGIDs, the aims of this review were as follows: (1) to engender interest in global aspects; (2) to gain a clearer understanding of culture, race, and ethnicity, and their effect on patient care and research; (3) to facilitate cross-cultural clinical and research competency; and (4) to improve and foster the quality and conduct of cross-cultural, multinational research. Cultural variables inev...
33 CitationsSource
#1Suguru Nishijima (UTokyo: University of Tokyo)H-Index: 5
#2Wataru Suda (UTokyo: University of Tokyo)H-Index: 33
Last. Masahira Hattori (UTokyo: University of Tokyo)H-Index: 99
view all 7 authors...
The human gut microbiome has profound influences on the host's health largely through its interference with various intestinal functions. As recent studies have suggested diversity in the human gut microbiome among human populations, it will be interesting to analyse how gut microbiome is correlated with geographical, cultural, and traditional differences. The Japanese people are known to have several characteristic features such as eating a variety of traditional foods and exhibiting a low BMI ...
194 CitationsSource
#1Paul Enck (University of Tübingen)H-Index: 63
#2Qasim Aziz (QMUL: Queen Mary University of London)H-Index: 66
Last. Robin C. Spiller (University of Nottingham)H-Index: 90
view all 14 authors...
A 28-year-old woman presents with a 7-month history of recurrent, crampy pain in the left lower abdominal quadrant, bloating with abdominal distention, and frequent, loose stools. She reports having had similar but milder symptoms since childhood. She spends long times in the bathroom because she is worried about uncontrollable discomfort and fecal soiling if she does not completely empty her bowels before leaving the house. She feels anxious and fatigued and is frustrated that her previous phys...
423 CitationsSource
#1Kenji Honkura (Tohoku University)H-Index: 5
#2Yasutake Tomata (Tohoku University)H-Index: 24
Last. Ichiro Tsuji (Tohoku University)H-Index: 93
view all 8 authors...
Abstract Background It has been suggested that constipation is associated with cardiovascular disease (CVD). The association between defecation frequency and CVD mortality in a large population has not been reported hitherto. The aim of this study was to examine whether defecation frequency is related to CVD mortality. Methods and results A total of 45,112 eligible Japanese men and women aged 40–79 years participated in the Ohsaki Cohort study. Defecation frequency was evaluated at the baseline ...
30 CitationsSource
#1Shin Fukudo (Tohoku University)H-Index: 54
#2Yoshikazu Kinoshita (Shimane University)H-Index: 61
Last. Ken Haruma (Kawasaki Medical School)H-Index: 70
view all 8 authors...
Background & Aims Previous studies have indicated that serotonin-3–receptor antagonists might have a sex-specific effect in patients with irritable bowel syndrome with diarrhea (IBS-D). Alosetron has been approved for the treatment of only women, and ramosetron has been approved for the treatment for only men. We performed a randomized, placebo-controlled, phase 3 study to determine whether ramosetron reduces symptoms of IBS-D in women. Methods We performed a prospective study of 576 female outp...
65 CitationsSource
#1Jieru E. Lin (Thomas Jefferson University)H-Index: 15
#2Francheska Colon-Gonzalez (Thomas Jefferson University)H-Index: 9
Last. Scott A. Waldman (Thomas Jefferson University)H-Index: 72
view all 13 authors...
Obesity is a well-known risk factor for colorectal cancer but precisely how it influences risks of malignancy remains unclear. During colon cancer development in humans or animals, attenuation of the colonic cell surface receptor guanylyl cyclase C (GUCY2C) that occurs due to loss of its paracrine hormone ligand guanylin contributes universally to malignant progression. In this study, we explored a link between obesity and GUCY2C silencing in colorectal cancer. Using genetically engineered mice ...
41 CitationsSource
#1Shin Fukudo (Tohoku University)H-Index: 54
#2Michio HongoH-Index: 27
Last. Ryuji UenoH-Index: 1
view all 5 authors...
Background & Aims Lubiprostone is an activator of the type 2 chloride channel that facilitates spontaneous bowel movement (SBM). We performed phase 3 studies to determine whether lubiprostone increases the frequency of SBM in patients with chronic idiopathic constipation (CIC) in Japan, and whether long-term administration of lubiprostone increases the quality of life of patients with CIC. Methods We performed a randomized, double-blind, placebo-controlled, phase 3 trial of lubiprostone. Patient...
61 CitationsSource
#1Lu Liu (PKU: Peking University)H-Index: 22
#2Haimei Li (PKU: Peking University)H-Index: 11
Last. Yufeng Wang (PKU: Peking University)H-Index: 40
view all 6 authors...
Abstract Guanylyl cyclase-C knock-out mice exhibit hyperactivity and attention deficits. We investigated seven single nucleotide polymorphisms (SNPs) of Guanylate cyclase 2C gene ( GUC2C ) in 381 ADHD trios and 382 healthy controls. Transmission disequilibrium tests (TDT), case-control studies and quantitative analyses indicated association between GUC2C with ADHD and its core symptoms.
2 CitationsSource
Cited By14
Newest
#1Michelle H. M. A. Bosman (UM: Maastricht University)H-Index: 2
#2Sigrid Elsenbruch (University of Duisburg-Essen)H-Index: 52
Last. Daniel Keszthelyi (UM: Maastricht University)H-Index: 28
view all 9 authors...
Summary Background Clinical trials in irritable bowel syndrome are associated with high placebo response rates. We aimed to identify the magnitude of the placebo response and the contributing factors to this occurrence. Methods We did a systematic review and meta-analysis with a search of MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials between April 1, 1959, and April 30, 2020. We included all randomised controlled trials that compared an active pharmacotherapeutic agent ...
2 CitationsSource
#1Hong Jin (Tianjin Medical University General Hospital)H-Index: 2
#2Bin Wang (Tianjin Medical University General Hospital)H-Index: 2
Last. Wei Zhao (Tianjin Medical University General Hospital)H-Index: 6
view all 8 authors...
BACKGROUND AND AIMS POEM is a rescue endoscopic therapy for patients who had previously failed surgical or endoscopic treatment. However, data regarding its effectiveness after failed pneumatic dilation (PD) and its long-term effects are limited. We aimed to retrospectively investigate the long-term outcomes in patients who had undergone POEM after failed PD. METHODS Data from 66 achalasia patients with a 2-year follow-up period were analyzed. Intraprocedural events were compared between the fir...
Source
#1Magnus Simrén (UNC: University of North Carolina at Chapel Hill)H-Index: 78
#2Jan Tack (Katholieke Universiteit Leuven)H-Index: 126
Source
#1Hiroyuki OkumuraH-Index: 3
Last. Atsushi NakajimaH-Index: 82
view all 6 authors...
This systematic literature review and network meta-analysis (NMA) indirectly compared the Japanese standard dose of linaclotide 500 μg with other oral chronic constipation (CC) treatments. PubMed, Cochrane-CENTRAL, Ichushi-Web, and ClinicalTrials.gov were systematically searched for eligible randomized controlled trials of 43 oral drugs approved globally for CC, including irritable bowel syndrome with constipation (IBS-C) and opioid-induced constipation (OIC). The mean difference (95% credible i...
Source
#1Taraneh Mousavi (Tehran University of Medical Sciences)H-Index: 3
#2Shekoufeh Nikfar (Tehran University of Medical Sciences)H-Index: 48
Last. Mohammad Abdollahi (Tehran University of Medical Sciences)H-Index: 101
view all 3 authors...
Introduction: Irritable bowel syndrome (IBS), globally affecting 11.2% of the population and imposing a direct annual cost of 1.7bn-0bn in the US, is one of the today’s major therapeutic challen...
6 CitationsSource
#1Adam D. FarmerH-Index: 4
#2James K. Ruffle (QMUL: Queen Mary University of London)H-Index: 8
Last. Anthony HobsonH-Index: 30
view all 3 authors...
BACKGROUND: Linaclotide is efficacious in the management of irritable bowel syndrome with constipation (IBS-C), yet relatively little is known regarding its effect on human gastrointestinal physiology. The primary aim of the study was to examine the effect of linaclotide on change in pH across the ileocecal junction (ICJ), a proposed measure of cecal fermentation, and its relationship to symptoms and quality of life (QoL) in IBS-C. METHODS: A total of 13 participants with Rome III IBS-C underwen...
6 CitationsSource
Source
#1Shin Fukudo (Tohoku University)H-Index: 54
#2Hiroto Miwa (Hyogo College of Medicine)H-Index: 54
Last. Toshifumi Ohkusa (Jikei University School of Medicine)H-Index: 43
view all 11 authors...
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 criteri...
9 CitationsSource
#1Shin Fukudo (Tohoku University)H-Index: 54
#2Hiroto Miwa (Hyogo College of Medicine)H-Index: 54
Last. Toshifumi Ohkusa (Jikei University School of Medicine)H-Index: 43
view all 11 authors...
BACKGROUND: Based on the previous phase II/III studies of irritable bowel syndrome with constipation (IBS-C) in Japan that demonstrated the efficacy and safety of linaclotide 0.5 mg/d, we evaluated linaclotide at doses of 0.5 mg/d and lower in the treatment of Japanese patients with chronic constipation (CC). METHODS: This was a phase II randomized, double-blind, placebo-controlled, dose-finding study of linaclotide for Japanese patients with CC (n = 382, 64 men, 318 women, age 20-75). After a b...
3 CitationsSource
#1Christopher J Black (University of Leeds)H-Index: 13
#2Nicholas E Burr (University of Leeds)H-Index: 14
Last. Alexander C. Ford (University of Leeds)H-Index: 86
view all 6 authors...
Background & Aims Several secretagogues have been approved for the treatment of irritable bowel syndrome with constipation (IBS-C). However, their relative efficacy is unclear because there have been no head-to-head randomized controlled trials. We conducted a network meta-analysis to compare their efficacies in patients with IBS-C. Methods We searched MEDLINE, EMBASE, EMBASE Classic, and the Cochrane Central Register of Controlled Trials through June 2018 to identify randomized controlled trial...
70 CitationsSource