Linaclotide In Patients Research Articles

Efficacy and safety of linaclotide in treatment-resistant chronic constipation: A multicenter, open-label study.

This study aimed to evaluate the efficacy and safety of linaclotide in patients with chronic constipation (CC) or irritable bowel syndrome with constipation (IBS-C) who did not respond to treatment with magnesium oxide (MgO). This study was designed as a multicenter, open-label, single-arm, exploratory study. Patients with CC or IBS-C who took MgO and those meeting the medication initiation criteria were administered linaclotide at a daily dosage of 500 μg for 12 weeks. The primary endpoint was a change in the Japanese version of the Patient Assessment of Constipation Quality of Life (JPAC-QOL) score from baseline, which was evaluated by using a paired t-test. The patients' mean age (± standard deviation) was 67.6 ± 13.82 years. The full analysis set included 61 patients. The JPAC-QOL total score was 1.60 at baseline and 0.70 at 12 weeks, with a significant mean change of -0.89 ± 0.721 (p < 0.001). Several secondary endpoints also showed improvement. The frequency of spontaneous bowel movement (SBM) and complete SBM increased by 2.70 ± 7.254 (p < 0.01) and 2.81 ± 5.254 times, respectively (p < 0.001). The Bristol Stool Form Scale, abdominal bloating severity, and straining severity scores improved by 1.33 ± 1.274 (p < 0.001), -0.16 ± 0.563 (p < 0.05), and -0.46 ± 0.795 (p < 0.001) points, respectively. The safety analysis set included 65 patients, 7 of whom had diarrhea, which improved with dose reduction and drug withdrawal. The study was conducted in an older adult population, similar to real clinical practice. Linaclotide may be an option for treating CC that shows an inadequate response to conventional therapy.

S770 Efficacy and Safety of Linaclotide in Patients With Chronic Idiopathic Constipation: A Post Hoc Analysis of Phase 3 Clinical Study Data Assessing Primary and Additional Endpoints by Race and Ethnicity, and by Age

S770 Efficacy and Safety of Linaclotide in Patients With Chronic Idiopathic Constipation: A Post Hoc Analysis of Phase 3 Clinical Study Data Assessing Primary and Additional Endpoints by Race and Ethnicity, and by Age

The gut microbiota participates in the effect of linaclotide in patients with irritable bowel syndrome with constipation (IBS-C): a multicenter, prospective, pre-post study

BackgroundInterindividual variation characterizes the relief experienced by constipation-predominant irritable bowel syndrome (IBS-C) patients following linaclotide treatment. Complex bidirectional interactions occur between the gut microbiota and various clinical drugs. To date, no established evidence has elucidated the interactions between the gut microbiota and linaclotide. We aimed to explore the impact of linaclotide on the gut microbiota and identify critical bacterial genera that might participate in linaclotide efficacy.MethodsIBS-C patients were administered a daily linaclotide dose of 290 µg over six weeks, and their symptoms were then recorded during a four-week posttreatment observational period. Pre- and posttreatment fecal samples were collected for 16S rRNA sequencing to assess alterations in the gut microbiota composition. Additionally, targeted metabolomics analysis was performed for the measurement of short-chain fatty acid (SCFA) concentrations.ResultsApproximately 43.3% of patients met the FDA responder endpoint after taking linaclotide for 6 weeks, and 85% of patients reported some relief from abdominal pain and constipation. Linaclotide considerably modified the gut microbiome and SCFA metabolism. Notably, the higher efficacy of linaclotide was associated with enrichment of the Blautia genus, and the abundance of Blautia after linaclotide treatment was higher than that in healthy volunteers. Intriguingly, a positive correlation was found for the Blautia abundance and SCFA concentrations with improvements in clinical symptoms among IBS-C patients.ConclusionThe gut microbiota, especially the genus Blautia, may serve as a significant predictive microbe for symptom relief in IBS-C patients receiving linaclotide treatment.Trial registration: This trial was registered with the Chinese Clinical Trial Registry (Chictr.org.cn, ChiCTR1900027934).

Exploratory, multicenter, open-label study to evaluate the effects of linaclotide in patients with chronic constipation with an insufficient response to magnesium oxide: A study protocol

BackgroundChronic constipation leads to poor quality of life, and treatment remains unsatisfactory for patients. In Japan, magnesium oxide has been commonly used as the first choice of treatment for constipation; however, there are some cases of low satisfaction with magnesium oxide treatment. Linaclotide has recently been used to treat chronic constipation. In this study, we will examine whether linaclotide improves symptoms and quality of life in patients showing insufficient response to magnesium oxide. MethodsThis is an exploratory multicenter open-label study. The target number of patients is 64: 32 patients with and 32 without abdominal symptoms. Patients with chronic idiopathic constipation or irritate bowel syndrome with constipation diagnosed according to the Rome-IV criteria are eligible. Patients prescribed 0.99–2 g/day of magnesium oxide for at least 4 weeks will be included. Those who consent to the study will continue taking magnesium oxide for 2–4 weeks, and defecation will be documented. Patients who meet the criteria will be prescribed linaclotide (0.5 mg) daily for 12 weeks. The primary endpoint is a change in the Japanese version of the Patient Assessment of Constipation Quality of Life (JPAC-QOL) score after 12 weeks of treatment. ConclusionThis is the first study to investigate the usefulness of linaclotide as a second-line treatment for chronic constipation. We will test the efficacy of treatment of constipation in patients with inadequate response to magnesium oxide. Trial registrationThis study is registered with the Japan Registry of Clinical Trials (jRCT, jRCTs031200048).

Efficacy and safety of linaclotide in patients with irritable bowel syndrome with constipation: Chinese sub-cohort analysis of a phase III, randomized, double-blind, placebo-controlled trial.

ObjectiveTo conduct a sub‐cohort analysis to evaluate the efficacy and safety of linaclotide in Chinese patients with constipation‐predominant irritable bowel syndrome (IBS‐C) using data from a completed trial (NCT01880424).MethodsIn this phase III, double‐blind, placebo‐controlled trial, IBS‐C patients were randomized to receive linaclotide (290 μg/d) or placebo for 12 weeks. Efficacy was assessed with two co‐primary responder end‐points (12‐wk abdominal pain/discomfort: ≥30% reduction in either score with neither deteriorating from baseline for ≥6 wks; 12‐wk IBS degree of relief: score ≤2 for ≥ 6 wks), seven secondary endpoints and several additional end‐points.ResultsIn total, 659 Chinese IBS‐C patients received linaclotide (n = 327) or placebo (n = 332). The 12‐week abdominal pain/discomfort end‐point was met in 62.1% and 53.3% of the linaclotide‐treated and placebo‐treated patients, respectively (odds ratio [OR] 1.43, 95% confidence interval [CI] 1.05‐1.96, P = 0.023); the 12‐week IBS degree of relief end‐point was achieved in 32.7% and 16.9% of the patients treated with linaclotide and placebo, respectively (OR 2.40, 95% CI 1.66‐3.47, P < 0.001). The linaclotide‐treated patients had a shorter time to the first spontaneous bowel movement than the placebo‐treated patients (23.6 h vs 43.7 h, P < 0.001). Linaclotide produced significantly greater improvement than placebo in all secondary end‐points from the first 2 weeks (all P < 0.001). Diarrhea was reported in 8.3% of linaclotide‐treated patients and 1.2% of placebo‐treated patients.ConclusionLinaclotide (290 μg/d) was efficacious and well‐tolerated in Chinese IBS‐C patients with a rapid onset of effect.

Efficacy and Safety of Linaclotide in Elderly Patients

The efficacy and safety of linaclotide in elderly patients are poorly understood. Herein, we aimed to assess the efficacy and safety of linaclotide in elderly patients in real-world setting. We retrospectively enrolled consecutive patients who started linaclotide therapy at Sapporo Medical University Hospital from October 1, 2017 to December 31, 2019. The efficacy and safety of linaclotide were examined in relation to various factors, including age (<65 or ≥65 years) and dose (0.25 or 0.5 mg/d). Fifty-two patients were enrolled, 60% of whom were over 65 years old and 40% were female. Thirty-six patients received a linaclotide dose of 0.25 mg/d. The most common side effect was diarrhea, but there was no difference in the incidence of diarrhea between the elderly (64.5%) and non-elderly patients (42.9%, p=0.130). No significant difference was observed with respect to improvement in constipation in the elderly (83.9%) and non-elderly patients (71.4%, p=0.318). Additionally, the difference in efficacy of linaclotide in patients who received a reduced dose (80.6%) vs. those who received the recommended dose (75.0%) was not statistically significant (p=0.719). Multivariate analysis revealed that age, gender, and dose were not associated with diarrhea induced by linaclotide treatment. However, concurrent treatment with constipation-inducing medications [odds ratio (OR) 5.79, p=0.047] and linaclotide monotherapy (OR 11.1, p=0.040) were both risk factors contributing to diarrhea. Linaclotide is effective and safe for use in elderly patients. The incidence of diarrhea may increase when linaclotide is administered alone or concurrently used with medications that cause constipation.

263 - Intestinal, Non-Intestinal, and Extra-Digestive Response to Linaclotide in Patients with Irritable Bowel Syndrome with Constipation: Results at Week 4 Predict Sustained Response

263 - Intestinal, Non-Intestinal, and Extra-Digestive Response to Linaclotide in Patients with Irritable Bowel Syndrome with Constipation: Results at Week 4 Predict Sustained Response

Optimizing the Use of Linaclotide in Patients with Constipation-Predominant Irritable Bowel Syndrome: An Expert Consensus Report.

IntroductionIrritable bowel syndrome (IBS) is a functional bowel disorder characterized by chronic or recurrent abdominal pain in association with defecation or a change in bowel habits. A predominant disorder of bowel habits, IBS is classified into three main subtypes: constipation-predominant IBS (IBS-C), diarrhea-predominant IBS (IBS-D) and IBS alternating between constipation and diarrhea (IBS-M). Linaclotide is a first-in-class, oral, once-daily guanylate cyclase-C receptor agonist (GC-CA) that is licensed for the symptomatic treatment of moderate-to-severe IBS-C in adults. This review aims to facilitate and optimize clinical practices, establishing common guidelines to monitor patients with IBS-C that are treated with linaclotide.MethodsA group of experts in functional digestive disorders was convened to review the efficacy and safety of linaclotide and to develop an updated consensus report for the treatment of patients with IBS-C. A search was performed for English, French and Spanish language articles in PubMed. On the basis of the articles identified, an initial document was drafted addressing different issues frequently raised by general practitioners and GI specialists that are related to the prescription, efficacy and safety of linaclotide. This document was then reviewed and modified by the expert panel until a final text was agreed upon and validated.ResultsBased on the evidence, the panel addressed the following recommendations: (1) Linaclotide is indicated for the treatment of moderate to severe IBS-C in adults; (2) it is recommended that patients take linaclotide continuously and not sporadically; (3) patients should be warned about the risk of diarrhea and given choices concerning how to deal with this possible side effect; (4) the absence of tachyphylaxis or potential risks implies that linaclotide treatment can be maintained for long periods of time.ConclusionsThis document seeks to lay down a set of recommendations and to identify key issues that may be useful for the clinical management of IBS-C patients treated with linaclotide.

Durability of Response of Linaclotide in the Management of Chronic Idiopathic Constipation

Introduction: Linaclotide is approved for the treatment of chronic idiopathic constipation (CIC) and IBS-C. It activates guanylate-cyclase C (GC-C) receptors on the luminal surface of enterocytes resulting in increased intestinal secretion and decreased transit time. Two phase 3 studies demonstrated that 21 days of linaclotide therapy resulted in as least 3 complete and spontaneous bowel movements (CSBM) per week and an increase of 1 CSBM per week. Since recurrence of constipation is common, the purpose of this study was to describe durability of response to linaclotide in patients with an initial response. Methods: Electronic medical records of 167 patients who began linaclotide for the management of CIC were reviewed retrospectively. To be eligible for inclusion, patients must have responded to standard dosing (145 mcg daily) for at least 4 months with appropriate follow up and documentation. Response was defined as ≥3 CSBM/week and 1 additional BM/week and a Bristol stool score (BSS) of 3-4. Patients who required dose adjustment within the first 4 months or experienced an adverse effect (AE) of treatment during initial therapy were excluded. Variables including age, gender, duration of therapy, time to follow up, response to therapy, BSS, dose and frequency of linaclotide, and AE were all recorded. Data were summarized with Microsoft excel 14.6. Paired t-test was used to compare initial and final BSS. Results: 32 of 167 patients met criteria for review. 5 were men and 27 were women. Mean age was 57 ± 18 (range 19-93). 28 patients (87.5%) exhibited sustained response with a mean follow up time of 15.3 months (range 4-36 months). BSS at the time of inclusion was 3.5 ± 0.6. BSS at the last follow up time was unchanged at 3.4 ± 0.8 (range 2-5, p = 0.55). AE were observed in 6 patients (18.7%). Three had diarrhea and 3 had discomfort or bloating. The mean time to first reported AE was 12 months (range 6-36 months). In all cases, minimal alterations in dose or frequency resulted in improvement of AE. Conclusion: CONCLUSIONS 1. 87.5% of patients in this cohort of initial responders to standard dose linaclotide demonstrated durable reponse with a mean duration of 15.3 months. 2. BSS was stable over an extended period of therapy. 3. AE occurred in 18.7% of patients, on average 12 months after starting therapy. 4. Most patients with AE responded well to changes in dose and/ or frequency of administration of linaclotide or minimal adjunctive therapy.

Mo1646 Efficacy and Safety of Linaclotide in Patients With IBS-C: Results From a Phase 3, Randomized, Double-Blind, Placebo-Controlled Trial in China and Other Regions

Mo1646 Efficacy and Safety of Linaclotide in Patients With IBS-C: Results From a Phase 3, Randomized, Double-Blind, Placebo-Controlled Trial in China and Other Regions

Sa1397 Effect of Linaclotide on Patient-Reported Confidence in Bowel Movement Success, Predictability of Bowel Movement Timing, and Treatment Satisfaction in Patients With Chronic Idiopathic Constipation and Prominent Abdominal Bloating

Objective: To evaluate the effect of linaclotide treatment on patient confidence in bowel movement (BM) success, completeness, and ease, predictability of BM timing, and on treatment satisfaction in chronic idiopathic constipation (CIC) patients with prominent abdominal bloating.Methods: Post-hoc analyses were performed on data from a phase 3b, randomized, double-blind, placebo-controlled trial of linaclotide in patients who met modified Rome II criteria for CIC and had abdominal bloating ≥5 (0-10-point numerical rating scale). Patients were randomized to linaclotide 145 μg (n=154), 290 μg (n=160), or placebo (n=173) once daily. Assessments of patient confidence included confidence in having a BM at least once every other day, producing stool when going to the bathroom with an urge to have a BM, feeling completely empty after having a BM, and occurrence of BMs without straining, each measured weekly in the two-week pretreatment period and 12-week treatment period using a 3-point Likert scale (1=Not at all; 2=Somewhat; 3=Very). Patients' ability to predict BM timing after taking study medication was measured weekly in the 12-week treatment period using a 3-point Likert scale (1=Not at all; 2=Somewhat; 3=Very). Patient satisfaction with the study medication's ability to relieve constipation symptoms was measured using a 5point Likert scale (1=Not at all; 2=A little; 3=Moderately; 4=Quite; 5=Very). Data were averaged over the pretreatment period and each of the three (4-week) study months. Treatment and time effects were analyzed (for the intent-to-treat population) within a repeatedmeasures linear model. Results: Table 1 displays the study results. No differences were observed between treatment arms for any outcomes during the pretreatment period. Prior to treatment initiation, 79% of patients reported no confidence in having successful, complete BMs without straining. There was an apparent dose-response on improvement over time across all outcomes, with statistically significant differences in improvement observed between linaclotide (both doses) and placebo (all p<0.0001). Linaclotide-treated patients had significantly greater confidence in BM frequency, completeness of evacuation, and the occurrence of BMs without straining than placebo-treated patients. Figure 1 shows results for patient confidence in BM frequency. Patients treated with linaclotide were statistically significantly more likely to be able to predict the timing of their BMs and were more satisfied with treatment than patients on placebo. Conclusions: Linaclotide treatment improves patient confidence in BM success, completeness, and ease as well as patients' ability to predict BM timing. Improvement in specific BM attributes may be an important driver of treatment satisfaction.

PWE-166 Is Response To Linaclotide After 4 Weeks Of Treatment Predictive Of 12-week Improvement?

IntroductionLinaclotide is a minimally absorbed guanylate cyclase C agonist approved in the US and EU for irritable bowel syndrome with constipation (IBS-C). A question for prescribing physicians is whether to...

Effect of Linaclotide on Severe Abdominal Symptoms in Patients With Irritable Bowel Syndrome With Constipation

Patients with irritable bowel syndrome with constipation (IBS-C) have abdominal symptoms that vary in severity. Linaclotide, a guanylate cyclase-C agonist, improves abdominal and bowel symptoms in these patients. We examined the prevalence of severe abdominal symptoms in patients with IBS-C and assessed the effects of linaclotide on abdominal symptoms, global measures, and quality of life (QOL). In two phase 3 trials, patients who met modified Rome II criteria for IBS-C were randomly assigned to groups given oral, once-daily linaclotide (290 μg) or placebo for 12 weeks. During the baseline (2 weeks prior to treatment) and treatment periods, patients rated abdominal pain, discomfort, bloating, fullness, and cramping daily (from 0 = none to 10 = very severe). Linaclotide's effects on abdominal symptoms, global measures, and IBS-related QOL were assessed in subpopulations of patients who rated specific individual abdominal symptoms as severe (≥ 7.0) at baseline. In the intent-to-treat population (1602 patients; 797 receiving placebo and 805 receiving linaclotide), baseline prevalence values for severe abdominal symptoms were 44% for bloating, 44% for fullness, 32% for discomfort, 23% for pain, and 22% for cramping, with considerable overlap among symptoms. In patients with severe symptoms, linaclotide reduced all abdominal symptoms; mean changes from baseline severity scores ranged from -2.7 to -3.4 for linaclotide vs -1.4 to -1.9 for placebo (P < .0001). Linaclotide improved global measures (P < .0001) and IBS-QOL scores (P < .01) compared with placebo. Diarrhea was the most common adverse event of linaclotide in patients with severe abdominal symptoms (18.8%-21.0%). Of 5 severe abdominal symptoms assessed, bloating and fullness were most prevalent in patients with IBS-C. Linaclotide significantly improved all abdominal symptoms, global measures, and IBS-QOL in subpopulations of IBS-C patients with severe abdominal symptoms. Clinicaltrials.gov NCT00938717, NCT00948818.

Exam 2: Effects of Linaclotide in Patients With Irritable Bowel Syndrome With Constipation or Chronic Constipation: A Meta-analysis

Exam 2: Effects of Linaclotide in Patients With Irritable Bowel Syndrome With Constipation or Chronic Constipation: A Meta-analysis

Mo2054 Assessing Abdominal and Bowel Symptoms Using Adequate Relief Based Thresholds: Results From 2 Phase 3 Trials of Linaclotide in Patients With Irritable Bowel Syndrome With Constipation

Mo2054 Assessing Abdominal and Bowel Symptoms Using Adequate Relief Based Thresholds: Results From 2 Phase 3 Trials of Linaclotide in Patients With Irritable Bowel Syndrome With Constipation

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

OBJECTIVES:Linaclotide is a minimally absorbed guanylate cyclase-C agonist. The objective of this trial was to determine the efficacy and safety of linaclotide in patients with irritable bowel syndrome with constipation (IBS-C).METHODS:This phase 3, double-blind, parallel-group, placebo-controlled trial randomized IBS-C patients to placebo or 290 μg oral linaclotide once daily in a 12-week treatment period, followed by a 4-week randomized withdrawal (RW) period. There were four primary end points, the Food and Drug Administration's (FDA's) primary end point for IBS-C (responder: improvement of ≥30% in average daily worst abdominal pain score and increase by ≥1 complete spontaneous bowel movement (CSBM) from baseline (same week) for at least 50% of weeks assessed) and three other primary end points, based on improvements in abdominal pain and CSBMs for 9/12 weeks. Adverse events (AEs) were monitored.RESULTS:The trial evaluated 800 patients (mean age=43.5 years, female=90.5%, white=76.9%). The FDA end point was met by 136/405 linaclotide-treated patients (33.6%), compared with 83/395 placebo-treated patients (21.0%) (P<0.0001) (number needed to treat: 8.0, 95% confidence interval: 5.4, 15.5). A greater percentage of linaclotide patients, compared with placebo patients, reported for at least 6/12 treatment period weeks, a reduction of ≥30% in abdominal pain (50.1 vs. 37.5%, P=0.0003) and an increase of ≥1 CSBM from baseline (48.6 vs. 29.6%, P<0.0001). A greater percentage of linaclotide patients vs. placebo patients were also responders for the other three primary end points (P<0.05). Significantly greater improvements were seen in linaclotide vs. placebo patients for all secondary end points (P<0.001). During the RW period, patients remaining on linaclotide showed sustained improvement; patients re-randomized from linaclotide to placebo showed return of symptoms, but without worsening of symptoms relative to baseline. Diarrhea, the most common AE, resulted in discontinuation of 5.7% of linaclotide and 0.3% of placebo patients.CONCLUSIONS:Linaclotide significantly improved abdominal pain and bowel symptoms associated with IBS-C for at least 12 weeks; there was no worsening of symptoms compared with baseline following cessation of linaclotide during the RW period.

OC-082 26-Week efficacy and safety of once-daily oral linaclotide in patients with irritable bowel syndrome with constipation (IBS-C): a European perspective

IntroductionLinaclotide, a minimally absorbed guanylate cyclase-C receptor agonist, is an investigational drug treatment for IBS-C. As part of the European Medicines Authority submission we evaluated the efficacy and safety of...

PTU-152 Significant improvements in abdominal pain and bowel symptoms in a phase 3 trial of linaclotide in patients with irritable bowel syndrome with constipation (IBS-C): a European perspective

IntroductionLinaclotide, a minimally absorbed guanylate cyclase-C agonist, was evaluated in a Phase 3 trial. To fulfil EMA submission requirements, the efficacy, safety and effects of withdrawal of linaclotide 290 μg...

Two Randomized Trials of Linaclotide for Chronic Constipation

Linaclotide is a minimally absorbed peptide agonist of the guanylate cyclase C receptor. In two trials, we aimed to determine the efficacy and safety of linaclotide in patients with chronic constipation. We conducted two randomized, 12-week, multicenter, double-blind, parallel-group, placebo-controlled, dual-dose trials (Trials 303 and 01) involving 1276 patients with chronic constipation. Patients received either placebo or linaclotide, 145 μg or 290 μg, once daily for 12 weeks. The primary efficacy end point was three or more complete spontaneous bowel movements (CSBMs) per week and an increase of one or more CSBMs from baseline during at least 9 of the 12 weeks. Adverse events were also monitored. For Trials 303 and 01, respectively, the primary end point was reached by 21.2% and 16.0% of the patients who received 145 μg of linaclotide and by 19.4% and 21.3% of the patients who received 290 μg of linaclotide, as compared with 3.3% and 6.0% of those who received placebo (P<0.01 for all comparisons of linaclotide with placebo). Improvements in all secondary end points were significantly greater in both linaclotide groups than in the placebo groups. The incidence of adverse events was similar among all study groups, with the exception of diarrhea, which led to discontinuation of treatment in 4.2% of patients in both linaclotide groups. In these two 12-week trials, linaclotide significantly reduced bowel and abdominal symptoms in patients with chronic constipation. Additional studies are needed to evaluate the potential long-term risks and benefits of linaclotide in chronic constipation. (Funded by Ironwood Pharmaceuticals and Forest Research Institute; ClinicalTrials.gov numbers, NCT00765882 and NCT00730015.).

Efficacy and Safety of Once Daily Linaclotide in Patients With Irritable Bowel Syndrome With Constipation: A 12-Week, Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial Followed by a 4-Week Randomized Withdrawal Period

Efficacy and Safety of Once Daily Linaclotide in Patients With Irritable Bowel Syndrome With Constipation: A 12-Week, Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial Followed by a 4-Week Randomized Withdrawal Period