The Effect of Psyllium Husk on Intestinal Microbiota in Constipated Patients and Healthy Controls.

Psyllium is a widely used treatment for constipation. It traps water in the intestine increasing stool water, easing defaecation and altering the colonic environment. We aimed to assess the impact of psyllium on faecal microbiota, whose key role in gut physiology is being increasingly recognised. We performed two randomised, placebo-controlled, double-blinded trials comparing 7 days of psyllium with a placebo (maltodextrin) in 8 healthy volunteers and 16 constipated patients respectively. We measured the patients' gastrointestnal (GI) transit, faecal water content, short-chain fatty acid (SCFA) and the stool microbiota composition. While psyllium supplement had a small but significant effect on the microbial composition of healthy adults (increasing Veillonella and decreasing Subdoligranulum), in constipated subjects there were greater effects on the microbial composition (increased Lachnospira, Faecalibacterium, Phascolarctobacterium, Veillonella and Sutterella and decreased uncultured Coriobacteria and Christensenella) and alterations in the levels of acetate and propionate. We found several taxa to be associated with altered GI transit, SCFAs and faecal water content in these patients. Significant increases in three genera known to produce butyrate, Lachnospira, Roseburia and Faecalibacterium, correlated with increased faecal water. In summary, psyllium supplementation increased stool water and this was associated with significant changes in microbiota, most marked in constipated patients.

Linaclotide in irritable bowel syndrome with constipation: A Phase 3 randomized trial in China and other regions.

BACKGROUND AND AIM: Linaclotide is a guanylate cyclase-C agonist approved in multiple countries to treat irritable bowel syndrome with constipation (IBS-C). China has unmet need for well-tolerated therapy that is effective in treating both bowel and abdominal symptoms of IBS-C. This trial evaluated linaclotide's efficacy and safety in IBS-C patients in China and other regions. METHODS: This Phase 3, double-blind trial randomized IBS-C patients to once-daily oral 290-µg linaclotide or placebo at centers in China, North America, and Oceania. Patients reported bowel and abdominal symptoms daily; adverse events were monitored. Co-primary and secondary endpoints were tested using a predefined three-step serial gatekeeping multiple comparisons procedure. RESULTS: The intent-to-treat population included 839 patients (mean age = 41 years; 82% female; 81% Asian). The trial met all co-primary and secondary endpoints. Co-primary responder criteria were met by 60.0% of linaclotide patients versus 48.8% of placebo patients for abdominal pain/discomfort (≥ 30% decrease for ≥ 6/12 weeks; P < 0.05), and 31.7% of linaclotide versus 15.4% of placebo patients for IBS degree of relief (score ≤ 2 for ≥ 6/12 weeks; P < 0.0001). Secondary 12-week change-from-baseline endpoints (spontaneous bowel movement/complete spontaneous bowel movement frequency, stool consistency, straining, abdominal pain, abdominal discomfort, and abdominal bloating) were significantly improved with linaclotide versus placebo (all P < 0.0001). Diarrhea was the most common adverse event (9.4% linaclotide, 1.2% placebo). Discontinuation rates due to diarrhea were low (0.7% linaclotide, 0.2% placebo). CONCLUSIONS: Once-daily 290-µg linaclotide improved bowel habits, abdominal symptoms, and global measures in a predominantly Chinese IBS-C population.

Two randomized trials of linaclotide for chronic constipation.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.).

Effect of linaclotide on severe abdominal symptoms in patients with irritable bowel syndrome with constipation.

BACKGROUND & AIMS: 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). METHODS: 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. RESULTS: 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%). CONCLUSIONS: 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 NUMBERS: NCT00938717, NCT00948818.

Linaclotide inhibits colonic nociceptors and relieves abdominal pain via guanylate cyclase-C and extracellular cyclic guanosine 3',5'-monophosphate.

BACKGROUND & AIMS: Linaclotide is a minimally absorbed agonist of guanylate cyclase-C (GUCY2C or GC-C) that reduces symptoms associated with irritable bowel syndrome with constipation (IBS-C). Little is known about the mechanism by which linaclotide reduces abdominal pain in patients with IBS-C. METHODS: We determined the effects of linaclotide on colonic sensory afferents in healthy mice and those with chronic visceral hypersensitivity. We assessed pain transmission by measuring activation of dorsal horn neurons in the spinal cord in response to noxious colorectal distention. Levels of Gucy2c messenger RNA were measured in tissues from mice using quantitative reverse transcription polymerase chain reaction and in situ hybridization. We used human intestinal cell lines to measure release of cyclic guanosine-3',5'-monophosphate (cGMP) by linaclotide. We performed a post-hoc analysis of data from a phase III, double-blind, parallel-group study in which 805 patients with IBS-C were randomly assigned to groups given an oral placebo or 290 µg linaclotide once daily for 26 weeks. We quantified changes in IBS-C symptoms, including abdominal pain. RESULTS: In mice, linaclotide inhibited colonic nociceptors with greater efficacy during chronic visceral hypersensitivity. Intra-colonic administration of linaclotide reduced signaling of noxious colorectal distention to the spinal cord. The colonic mucosa, but not neurons, was found to express linaclotide's target, GC-C. The downstream effector of GC-C, cGMP, was released after administration of linaclotide and also inhibited nociceptors. The effects of linaclotide were lost in Gucy2c(-/-) mice and prevented by inhibiting cGMP transporters or removing the mucosa. During 26 weeks of linaclotide administration, a significantly greater percentage of patients (70%) had at least a 30% reduction in abdominal pain compared with patients given placebo (50%). CONCLUSIONS: We have identified an analgesic mechanism of linaclotide: it activates GC-C expressed on mucosal epithelial cells, resulting in the production and release of cGMP. This extracellular cGMP acts on and inhibits nociceptors, thereby reducing nociception. We also found that linaclotide reduces chronic abdominal pain in patients with IBS-C.

Linaclotide for irritable bowel syndrome with constipation: a 26-week, randomized, double-blind, placebo-controlled trial to evaluate efficacy and safety.

OBJECTIVES: Linaclotide is a minimally absorbed peptide guanylate cyclase-C agonist. The objective of this trial was to determine the efficacy and safety of linaclotide treatment in patients with irritable bowel syndrome with constipation (IBS-C) over 26 weeks. METHODS: This phase 3, double-blind, parallel-group, placebo-controlled trial randomized IBS-C patients to placebo or 290 µg of oral linaclotide once daily for a 26-week treatment period. The primary and the secondary efficacy assessments were evaluated over the first 12 weeks of treatment. Primary end points included the Food and Drug Administration's (FDA's) end point for IBS-C (responder: a patient who reported (i) improvement of ≥ 30 % from baseline in average daily worst abdominal pain score and (ii) increase of ≥ 1 complete spontaneous bowel movement (CSBM) from baseline, both in the same week for ≥ 6 / 12 weeks) and three other primary end points, based on improvements in abdominal pain and CSBMs for 9/12 weeks. Adverse events (AEs) were monitored. RESULTS: In all, 804 patients (mean age = 44 years, female = 90 % , white = 78 % ) were evaluated; 33.7 % of linaclotide-treated patients were FDA end point responders, vs. 13.9 % of placebo-treated patients ( P < 0.0001) (number needed to treat = 5.1, 95 % confidence interval (CI): 3.9, 7.1). The pain responder criterion of the FDA end point was met by 48.9 % of linaclotide-treated patients vs. 34.5 % of placebo-treated patients (number needed to treat = 7.0, 95 % CI: 4.7, 13.1), and the CSBM responder criterion was met by 47.6 % of linaclotide-treated patients, vs. 22.6 % of placebo patients (number needed to treat = 4.0, 95 % CI: 3.2, 5.4). Remaining primary end points ( P < 0.0001) and all secondary end points ( P < 0.001), including abdominal pain, abdominal bloating, and bowel symptoms (SBM and CSBM rates, Bristol Stool Form Scale (BSFS) score, and straining), were also statistically significantly improved with linaclotide vs. placebo. Statistically significant differences from placebo were observed for responder and continuous end points over 26 weeks of treatment. AE incidence was similar between treatment groups, except for diarrhea, which caused discontinuation in 4.5 % of linaclotide patients vs. 0.2 % of placebo patients. CONCLUSIONS: Linaclotide 290 µg once daily significantly improved abdominal and bowel symptoms associated with IBS-C over 26 weeks of treatment.

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 µ g 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.

Linaclotide improves abdominal pain and bowel habits in a phase IIb study of patients with irritable bowel syndrome with constipation.

BACKGROUND & AIMS: Linaclotide, a minimally absorbed, 14-amino acid peptide agonist of guanylate cyclase-C, has shown benefit in a proof-of-concept study for the treatment of patients with irritable bowel syndrome (IBS) with constipation (IBS-C). We assessed the efficacy and safety of linaclotide at a daily dose range of 75-600 µg in IBS-C. METHODS: We performed a randomized, double-blind, multicenter, placebo-controlled study of 420 patients with IBS-C given oral linaclotide at doses of 75, 150, 300, or 600 µg or placebo once daily for 12 weeks. End points included change from baseline in daily bowel habits, daily abdominal symptoms, and weekly global assessments, in addition to responder criteria. RESULTS: All doses of linaclotide significantly improved bowel habits, including frequency of spontaneous bowel movements and complete spontaneous bowel movements (primary end point), severity of straining, and stool consistency. Abdominal pain was significantly reduced from baseline, compared with placebo; mean changes in abdominal pain (assessed on a 5-point scale) from baseline were -0.71, -0.71, -0.90, and -0.86 for linaclotide doses of 75, 150, 300, and 600 µg, respectively, compared with -0.49 for placebo. Likewise, most doses of linaclotide significantly improved other abdominal symptoms, including discomfort and bloating, and global measures of IBS-C compared with placebo. Effects were observed within the first week and were sustained throughout 12 weeks of treatment. Except for diarrhea, the incidence of adverse events was similar between placebo and linaclotide groups. CONCLUSIONS: Linaclotide, across a wide range of doses, significantly improved symptoms of IBS-C, including abdominal pain and bowel symptoms. Diarrhea was the only dose-dependent adverse event and was usually of mild or moderate severity.

Efficacy of linaclotide for patients with chronic constipation.

BACKGROUND & AIMS: Linaclotide is a minimally absorbed peptide agonist of the guanylate cyclase-C receptor that stimulates intestinal fluid secretion and transit and reduces pain in animal models. We assessed the safety and efficacy of a range of linaclotide doses in patients with chronic constipation. METHODS: We performed a multicenter, double-blind, placebo-controlled, parallel-group study of 310 patients with chronic constipation. Patients were randomly assigned to groups given 75, 150, 300, or 600 microg oral linaclotide or placebo once daily for 4 weeks. Symptom assessments included spontaneous bowel movements (SBMs), complete SBMs, stool consistency, straining, abdominal discomfort, and bloating. Severity of constipation, adequate relief of constipation, global relief of constipation, treatment satisfaction, quality of life, adverse events, clinical laboratory data, and electrocardiogram results were assessed. RESULTS: All doses of linaclotide improved the weekly rate of SBM (primary end point) compared with placebo; the increases in overall weekly number of SBMs from baseline were 2.6, 3.3, 3.6, and 4.3 for linaclotide doses of 75, 150, 300, and 600 microg, respectively, compared with 1.5 for placebo (P < or = .05 for each pair-wise comparison of a linaclotide dose to placebo). Likewise, linaclotide significantly improved the weekly rate of complete SBM, stool consistency, straining, abdominal discomfort, bloating, global assessments, and quality of life. The most common and only dose-related adverse event was diarrhea (only 6 patients discontinued treatment because of diarrhea). CONCLUSIONS: Linaclotide therapy was associated with few adverse events and produced rapid and sustained improvement of bowel habits, abdominal symptoms, global relief, and quality of life in patients with chronic constipation.

Pilot study on the effect of linaclotide in patients with chronic constipation.

OBJECTIVES: Chronic constipation is a common gastrointestinal disorder with limited treatment options. Oral administration of linaclotide, a novel peptide agonist of guanylate cyclase-C receptors, has been shown in animal studies to stimulate intestinal fluid secretion and transit. In Phase 1 studies in healthy human volunteers, linaclotide was well-tolerated, increased bowel movement frequency, and loosened stool consistency. METHODS: This randomized, double-blind, placebo-controlled pilot study evaluated the safety, tolerability, and exploratory efficacy of oral linaclotide in 42 patients with chronic constipation. Patients were randomized to linaclotide (100, 300, or 1,000 microg) or placebo once daily for 2 weeks. Bowel habits (stool frequency, consistency, straining, completeness of evacuation) and degree of abdominal discomfort were monitored daily using an interactive voice response system. Patient-reported outcomes of severity of constipation and overall relief were evaluated weekly. RESULTS: Linaclotide treatment produced dose-dependent increases from the pretreatment baseline values in weekly complete spontaneous bowel movement frequency (range: 2.2-3.2), stool consistency scores (range: 1.1-2.6, 7-point scale), and straining scores (range: 0.4-1.5, 7-point scale); corresponding placebo increases were 1.3, 0.4, 0.4, respectively. Clinical improvements were also demonstrated in abdominal discomfort, severity of constipation, and overall relief. Compared to placebo, linaclotide 100 microg/day significantly increased spontaneous bowel movement frequency, and linaclotide 1,000 microg/day significantly improved stool consistency (P<0.05). Adverse events were primarily gastrointestinal, with diarrhea being the most common. CONCLUSIONS: In this pilot study, linaclotide treatment improved bowel habits and symptoms of patients with chronic constipation. Further randomized controlled trials are warranted.

A phase II multicenter double-blind placebo-controlled study of ethyl pyruvate in high-risk patients undergoing cardiac surgery with cardiopulmonary bypass.

OBJECTIVE: Ethyl pyruvate (EP) is an investigational drug that has been shown to protect animals in several models of critical illness including myocardial or mesenteric ischemia/reperfusion injury, sepsis, and hemorrhagic shock. The purpose of this study was to assess the safety of EP administration to patients undergoing higher-risk cardiac surgery and to obtain preliminary efficacy data for the prevention of single and multisystem organ dysfunction. DESIGN: Double-blind, randomized, placebo-controlled study. SETTING: Thirteen US hospitals. PARTICIPANTS: High-risk (Parsonnet risk score >15) patients undergoing coronary artery bypass graft and/or cardiac valvular surgery with cardiopulmonary bypass. INTERVENTIONS: Subjects were randomized to placebo or EP (7,500 mg administered intravenously starting after the induction of general anesthesia followed by 5 more doses of 7,500 mg administered every 6 hours). The mean body weight (83 kg), corresponding to a dose of 90 mg/kg at each of the 6 dosing intervals, exceeds the dose of 40 mg/kg shown to be effective in many animal models. MEASUREMENTS AND MAIN RESULTS: The primary composite endpoint consisted of any of the following occurring within 28 days postoperatively: death, mechanical ventilation >48 hours postoperatively, acute renal injury/failure using the established RIFLE criteria, or need for vasoconstrictors >48 hours postoperatively. One hundred two patients were studied (placebo n = 53 and EP n = 49). No statistically significant differences were observed between groups with regard to clinical parameters or markers of systemic inflammation. CONCLUSION: Despite positive results in numerous animal models, the administration of EP does not appear to confer any benefit to cardiac surgical patients undergoing CPB.

Safety and tolerability of linaclotide for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation: pooled Phase 3 analysis.

BACKGROUND: Linaclotide is approved for treating irritable bowel syndrome with constipation (IBS-C; 290 µg QD) and chronic idiopathic constipation (CIC; 145 µg or 72 µg QD). These analyses aimed to assess linaclotide safety in a large, pooled Phase 3 population. METHODS: In six randomized controlled trials (RCTs), patients received linaclotide (72 µg, 145 µg, 290 µg) or placebo daily for 12-26 weeks; in two long-term safety (LTS) studies, patients received open-label linaclotide for ≤78 additional weeks. Laboratory values, vital signs, and treatment-emergent adverse events (TEAEs) were assessed. RESULTS: Overall, 3853 patients received ≥1 dose of linaclotide. The most common TEAE was diarrhea (majority [90.5% in RCTs] mild/moderate). Linaclotide patients experienced 1.1 diarrhea TEAE per patient-year in the RCTs (0.2 in placebo), and 0.3 in the LTS studies. In RCTs, 6.9% linaclotide and 3.0% placebo patients discontinued due to any adverse event (AE); 4.0% linaclotide and 0.3% placebo patients discontinued due to diarrhea. In LTS studies, 9.4% patients discontinued due to any AE, and 3.8% due to diarrhea. Serious AEs (SAEs) were rare and similar across treatment groups; there were no SAEs of diarrhea. CONCLUSION: These pooled analyses of patients treated for ≤104 weeks confirm linaclotide's overall safety.

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.

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.

Dose-finding study of linaclotide in Japanese patients with chronic constipation: A phase II randomized, double-blind, and placebo-controlled study.

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 baseline period of two weeks, patients were randomized to receive placebo (n = 80), or 0.0625 mg (n = 82), 0.125 mg (n = 71), 0.25 mg (n = 73) or 0.5 mg (n = 76) of linaclotide during a two-week treatment period. The primary efficacy endpoint was change from baseline in weekly spontaneous bowel movement (SBM) frequency during the first week. Secondary endpoints included complete SBM (CSBM) responder rates and IBS-QOL. Safety and adverse events were also evaluated. KEY RESULTS: The change in SBM frequency during the first week (mean) was 3.89, 3.11, 3.87, and 3.85 for 0.0625 mg, 0.125 mg, 0.25 mg, and 0.5 mg for linaclotide, significantly higher than for placebo (1.91, P < 0.05). The CSBM responder, which is an important parameter, showed the greatest improvement at the 0.5 mg during the 2 week. The most frequent adverse event in the linaclotide groups was diarrhea. CONCLUSIONS & INFERENCES: Our results suggest that 0.0625, 0.125, 0.25, and 0.5 mg/d are effective doses of linaclotide for treating CC in Japanese patients. ClinicalTrials.gov: NCT02425722, supported by Astellas Pharma, Inc.

A randomized controlled and long-term linaclotide study of irritable bowel syndrome with constipation patients in Japan.

BACKGROUND: Clinical testing was required to verify the effect of linaclotide 0.5 mg/d in patients with irritable bowel syndrome with constipation (IBS-C) in Japan. METHODS: This was a randomized, double-blind, placebo-controlled (Part 1) and long-term, open-label extension (Part 2) study of linaclotide at 60 hospitals and clinics in Japan. Patients with IBS-C diagnosed using Rome III criteria (n = 500) were randomly assigned to linaclotide 0.5 mg (n = 249) or placebo (n = 251) for a 12-week treatment period followed by open-label treatment with linaclotide (n = 324) for an additional 40 weeks. The primary endpoints were the responder rate of global improvement of IBS symptoms and complete spontaneous bowel movement (CSBM) during 12 weeks. The secondary endpoints included responder rates of SBM and abdominal pain/discomfort relief. KEY RESULTS: Part 1: The responder rates for global improvement and for CSBM frequency were significantly higher for linaclotide compared to placebo (P < 0.001). Secondary endpoints including responder rates for SBM and abdominal pain/discomfort relief in the linaclotide group were also significantly greater than those in the placebo group. Part 2: Patients switched from placebo to linaclotide showed similar responder rates for global improvement and CSBM frequency to those in patients who continued to receive linaclotide, supporting sustained efficacy. Diarrhea was seen in 14.5% of patients; all cases were mild or moderate. CONCLUSIONS AND INFERENCES: This study suggests that a linaclotide dose of 0.5 mg is effective and safe for IBS-C patients in Japan.

Comparison of adequate relief with symptom, global, and responder endpoints in linaclotide phase 3 trials in IBS-C.

BACKGROUND: Optimal clinical trial endpoints for irritable bowel syndrome with constipation (IBS-C) are uncertain. OBJECTIVE: The objective of this article is to compare adequate relief (AR) to abdominal/bowel symptoms, global endpoints, and FDA and EMA responder criteria; and to use AR as an anchor to assess clinically meaningful change (CMC) in IBS-C symptoms. METHODS: Using pooled 12-week data from two phase 3 linaclotide clinical trials, daily abdominal/bowel symptoms and weekly global assessments were correlated with AR. Symptom CMC thresholds were estimated using AR as an anchor. Agreement between AR and FDA/EMA responder criteria was assessed. RESULTS: Correlations of AR with percentage change in abdominal symptoms, bowel symptoms, and global endpoints ranged from 0.48-0.54, 0.32-0.39, and 0.61-0.71, respectively. Using AR as an anchor, CMC thresholds were 29% improvement in abdominal pain, 29% improvement in abdominal discomfort, and 0.7/week increase in CSBMs, similar to thresholds for IBS-C responder endpoints recommended by the FDA and EMA. There was considerable agreement of weekly responder rates between AR and the FDA and EMA endpoints (on average, 70%-76% and 71%-82% of weeks with agreement, respectively). CONCLUSIONS: AR bridges IBS-C clinical trials, putting into perspective the disparate primary endpoints recommended by professional societies and regulatory authorities, and allowing researchers, practitioners, and regulators to compare trial results.

Linaclotide in Chronic Idiopathic Constipation Patients with Moderate to Severe Abdominal Bloating: A Randomized, Controlled Trial.

BACKGROUND: Abdominal bloating is a common and bothersome symptom of chronic idiopathic constipation. The objective of this trial was to evaluate the efficacy and safety of linaclotide in patients with chronic idiopathic constipation and concomitant moderate-to-severe abdominal bloating. METHODS: This Phase 3b, randomized, double-blind, placebo-controlled clinical trial randomized patients to oral linaclotide (145 or 290 µg) or placebo once daily for 12 weeks. Eligible patients met Rome II criteria for chronic constipation upon entry with an average abdominal bloating score ≥5 (self-assessment: 0 10-point numerical rating scale) during the 14-day baseline period. Patients reported abdominal symptoms (including bloating) and bowel symptoms daily; adverse events were monitored. The primary responder endpoint required patients to have ≥3 complete spontaneous bowel movements/week with an increase of ≥1 from baseline, for ≥9 of 12 weeks. The primary endpoint compared linaclotide 145 µg vs. placebo. RESULTS: The intent-to-treat population included 483 patients (mean age=47.3 years, female=91.5%, white=67.7%). The primary endpoint was met by 15.7% of linaclotide 145 µg patients vs. 7.6% of placebo patients (P<0.05). Both linaclotide doses significantly improved abdominal bloating vs. placebo (P<0.05 for all secondary endpoints, controlling for multiplicity). Approximately one-third of linaclotide patients (each group) had ≥50% mean decrease from baseline in abdominal bloating vs. 18% of placebo patients (P<0.01). Diarrhea was reported in 6% and 17% of linaclotide 145 and 290 µg patients, respectively, and 2% of placebo patients. AEs resulted in premature discontinuation of 5% and 9% of linaclotide 145 µg and 290 µg patients, respectively, and 6% of placebo patients. CONCLUSIONS: Once-daily linaclotide (145 and 290 µg) significantly improved bowel and abdominal symptoms in chronic idiopathic constipation patients with moderate-to-severe baseline abdominal bloating; in particular, linaclotide significantly improved abdominal bloating compared to placebo, an important finding given the lack of agents available to treat abdominal bloating in chronic idiopathic constipation patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT01642914.

Impact of linaclotide treatment on work productivity and activity impairment in adults with irritable bowel syndrome with constipation: results from 2 randomized, double-blind, placebo-controlled phase 3 trials.

BACKGROUND: Irritable bowel syndrome with constipation (IBS-C), a chronic functional gastrointestinal disorder, has been shown to negatively affect work productivity and impair daily activity, resulting in a substantial burden for patients and employers. Linaclotide is a first-in-class guanylate cyclase-C agonist approved for the treatment of adults with IBS-C and chronic idiopathic constipation in the United States. OBJECTIVE: To analyze the impact of treatment with linaclotide on work productivity and daily activity impairment in adults with IBS-C and estimate the indirect costs associated with this condition. METHODS: This was a post-hoc analysis of data on IBS-C-related work time missed and work and activity impairment from 2 phase 3 clinical trials that assessed the efficacy and safety of linaclotide therapy in adults with IBS-C. The Work Productivity and Activity Impairment Questionnaire for IBS-C (WPAI:IBS-C) was self-administered at baseline and at weeks 4, 8, and 12 during the 12-week treatment periods in Trials 1 and 2 and at weeks 16, 20, and 26 during the extended treatment period in Trial 2. An analysis of covariance was conducted to assess changes from baseline to all study weeks for each WPAI:IBS-C measure. Indirect costs were calculated by converting overall work productivity losses into monetary values using the human capital cost approach. RESULTS: Of the 1602 patients with IBS-C who were randomized in the 2 clinical trials, 1555 (97.1%) completed a baseline and at least 1 postbaseline WPAI:IBS-C assessment and were included in the analysis cohort; 1148 (71.7%) of these patients were employed. Once-daily treatment with linaclotide significantly reduced overall work productivity loss and daily activity impairment among patients with IBS-C at all study weeks. From baseline to week 12, compared with placebo, linaclotide significantly reduced presenteeism by 5.2%, overall work productivity loss by 6.1%, and daily activity impairment by 4.7% (all P <.01) and led to a numerically greater decrease in absenteeism. From baseline to week 26, compared with placebo, reductions with linaclotide were 5.9% for presenteeism, 7.5% for overall work productivity loss, and 6.7% for daily activity impairment (all P <.05). Reductions in overall work productivity loss from baseline to week 26 translate to 103 hours to 156 hours annually and correspond to an avoided overall work loss of $3209 to $4861 annually for an employee with IBS-C. CONCLUSION: The results of this analysis indicate that appropriate treatment of IBS-C with medications such as linaclotide can reduce work-related impairment associated with IBS-C. In addition, IBS-C therapies that effectively manage this chronic condition and improve employees' quality of life and work productivity may represent significant cost-savings for employers in the form of avoided work productivity losses.