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  1. Article ; Online: Multiple-dose pharmacokinetics and safety of an ibuprofen-pseudoephedrine cold suspension in children.

    Gelotte, Cathy K / Prior, Mary Jane / Pendley, Charles / Zimmerman, Brenda / Lavins, Bernard J

    Clinical pediatrics

    2010  Volume 49, Issue 7, Page(s) 678–685

    Abstract: Two studies were conducted to characterize multiple-dose pharmacokinetics and potential drug interactions of ibuprofen and pseudoephedrine combined in a suspension and to evaluate safety of this combination in children with common cold, flu, or sinusitis. ...

    Abstract Two studies were conducted to characterize multiple-dose pharmacokinetics and potential drug interactions of ibuprofen and pseudoephedrine combined in a suspension and to evaluate safety of this combination in children with common cold, flu, or sinusitis. In the pharmacokinetic study, 24 healthy children aged 4-11 years were administered ibuprofen -pseudoephedrine suspension at 7.5 and 1.125 mg/kg, respectively, every 6 hours for 5 doses. Serial blood samples were drawn over 6 hours after final dose for assessment of steady-state pharmacokinetics. In the open-label, multicenter safety study, more than 100 children aged 2-11 years experiencing symptomatic rhinitis were enrolled. Ibuprofen -pseudoephedrine suspension was administered as needed at similar mg/kg doses every 6-8 hours for up to 3 days. Subjects enrolled in the pharmacokinetic study showed no accumulation of either drug; their weight-adjusted clearances were independent of age, and results were comparable with those from previous single-ingredient studies. For ibuprofen, oral clearance (Cl/F) was 77.5 + or - 16.4 mL/kg/h and volume of distribution (Vd/F) was 0.147 + or - 0.037 L/kg. For pseudoephedrine, Cl/F was 12.3 + or - 2.2 mL/kg/min and Vd/F was 2.52 + or - 0.47 L/kg. In the safety study, adverse events were reported for 18.4% of subjects; most were mild to moderate intensity. There was little difference in incidence of adverse events among different age and weight groups. In conclusion, administration of combined ibuprofen and pseudoephedrine in children demonstrated similar pharmacokinetics when compared with reports of the pharmacokinetics for the single-ingredient products, consistent with no apparent drug interactions. The combination suspension was generally well tolerated.
    MeSH term(s) Administration, Oral ; Age Factors ; Area Under Curve ; Case-Control Studies ; Child ; Child, Preschool ; Common Cold/diagnosis ; Common Cold/drug therapy ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Drug Combinations ; Drug Interactions ; Drug-Related Side Effects and Adverse Reactions ; Female ; Humans ; Ibuprofen/administration & dosage ; Ibuprofen/pharmacokinetics ; Male ; Pseudoephedrine/administration & dosage ; Pseudoephedrine/pharmacokinetics ; Reference Values ; Rhinitis/diagnosis ; Rhinitis/drug therapy ; Suspensions/administration & dosage ; Suspensions/pharmacokinetics ; Treatment Outcome
    Chemical Substances Drug Combinations ; Suspensions ; Pseudoephedrine (7CUC9DDI9F) ; Ibuprofen (WK2XYI10QM)
    Language English
    Publishing date 2010-07
    Publishing country United States
    Document type Comparative Study ; Journal Article ; Multicenter Study ; Research Support, Non-U.S. Gov't
    ZDB-ID 207678-0
    ISSN 1938-2707 ; 0009-9228
    ISSN (online) 1938-2707
    ISSN 0009-9228
    DOI 10.1177/0009922810363153
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  2. Article ; Online: Linaclotide in Chronic Idiopathic Constipation Patients with Moderate to Severe Abdominal Bloating: A Randomized, Controlled Trial.

    Lacy, Brian E / Schey, Ron / Shiff, Steven J / Lavins, Bernard J / Fox, Susan M / Jia, Xinwei D / Blakesley, Rick E / Hao, Xinming / Cronin, Jacquelyn A / Currie, Mark G / Kurtz, Caroline B / Johnston, Jeffrey M / Lembo, Anthony J

    PloS one

    2015  Volume 10, Issue 7, Page(s) e0134349

    Abstract: 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 ... ...

    Abstract 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.
    MeSH term(s) Abdominal Pain/drug therapy ; Abdominal Pain/physiopathology ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Chronic Disease ; Constipation/drug therapy ; Constipation/physiopathology ; Double-Blind Method ; Female ; Gastrointestinal Agents/administration & dosage ; Gastrointestinal Agents/adverse effects ; Gastrointestinal Agents/therapeutic use ; Humans ; Male ; Middle Aged ; Peptides/administration & dosage ; Peptides/adverse effects ; Peptides/therapeutic use ; Treatment Outcome ; Young Adult
    Chemical Substances Gastrointestinal Agents ; Peptides ; linaclotide (N0TXR0XR5X)
    Language English
    Publishing date 2015
    Publishing country United States
    Document type Clinical Trial, Phase III ; Journal Article ; Multicenter Study ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0134349
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  3. Article: Comparison of adequate relief with symptom, global, and responder endpoints in linaclotide phase 3 trials in IBS-C.

    Camilleri, Michael / Lembo, Anthony J / Lavins, Bernard J / MacDougall, James E / Carson, Robyn T / Williams, Valerie Sl / Nelson, Lauren M / Shiff, Steven J / Currie, Mark G / Kurtz, Caroline B / Johnston, Jeffrey M

    United European gastroenterology journal

    2015  Volume 3, Issue 1, Page(s) 53–62

    Abstract: 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 ...

    Abstract 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.
    Language English
    Publishing date 2015-02
    Publishing country England
    Document type Journal Article
    ISSN 2050-6406
    ISSN 2050-6406
    DOI 10.1177/2050640614555946
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  4. Article: Efficacy and safety of epicutaneous ketoprofen in Transfersome (IDEA-033) versus oral celecoxib and placebo in osteoarthritis of the knee: multicentre randomised controlled trial.

    Rother, Matthias / Lavins, Bernard J / Kneer, Werner / Lehnhardt, Klaus / Seidel, Egbert J / Mazgareanu, Stefan

    Annals of the rheumatic diseases

    2007  Volume 66, Issue 9, Page(s) 1178–1183

    Abstract: Objective: To compare epicutaneous ketoprofen in Transfersome (ultra-deformable vesicles, IDEA-033) versus oral celecoxib and placebo for relief of signs and symptoms in knee osteoarthritis.: Methods: This was a multicentre, randomised, double-blind, ...

    Abstract Objective: To compare epicutaneous ketoprofen in Transfersome (ultra-deformable vesicles, IDEA-033) versus oral celecoxib and placebo for relief of signs and symptoms in knee osteoarthritis.
    Methods: This was a multicentre, randomised, double-blind, controlled trial; 397 patients with knee osteoarthritis participated and 324 completed the trial. They were randomly assigned 110 mg epicutaneous ketoprofen in 4.8 g Transfersome plus oral placebo (n = 138), 100 mg oral celecoxib plus placebo gel (n = 132), or both placebo formulations (n = 127) twice daily for 6 weeks. Primary efficacy outcome measures were the changes from baseline to end of the study on the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index pain subscale, physical function subscale and patient global assessment (PGA) of response.
    Results: The mean WOMAC pain subscale scores in the intent to treat population were reduced by 18.2 (95% confidence interval -22.1 to -14.3), 20.3 (-24.3 to -16.2) and 9.9 (-13.9 to -5.8) in the IDEA-033, celecoxib and placebo groups, respectively, and the physical function subscale score by 14.6 (-18.1 to -11.0), 16.6 (-20.2 to -13.0) and 10.2 (-13.8 to -6.6), respectively. The mean PGA of response scores were 1.8 (1.6 to 2.1), 1.7 (1.5 to 1.9) and 1.3 (1.1 to 1.5), respectively. The differences in change between IDEA-033 and placebo were statistically significant for pain subscale (p<0.01) and PGA of response (p<0.01). Gastrointestinal adverse events for IDEA-033 were similar to placebo.
    Conclusion: IDEA-033 is superior to placebo and comparable with celecoxib in relieving pain associated with an acute flare of knee osteoarthritis.
    MeSH term(s) Administration, Cutaneous ; Administration, Oral ; Aged ; Anti-Inflammatory Agents, Non-Steroidal/administration & dosage ; Anti-Inflammatory Agents, Non-Steroidal/therapeutic use ; Celecoxib ; Disability Evaluation ; Double-Blind Method ; Drug Carriers ; Female ; Humans ; Ketoprofen/administration & dosage ; Ketoprofen/therapeutic use ; Least-Squares Analysis ; Male ; Middle Aged ; Osteoarthritis, Knee/drug therapy ; Osteoarthritis, Knee/physiopathology ; Pain Measurement ; Pyrazoles/administration & dosage ; Pyrazoles/therapeutic use ; Skin Absorption ; Sulfonamides/administration & dosage ; Sulfonamides/therapeutic use ; Treatment Outcome
    Chemical Substances Anti-Inflammatory Agents, Non-Steroidal ; Drug Carriers ; Pyrazoles ; Sulfonamides ; Ketoprofen (90Y4QC304K) ; Celecoxib (JCX84Q7J1L)
    Language English
    Publishing date 2007-09
    Publishing country England
    Document type Comparative Study ; Journal Article ; Multicenter Study ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
    ZDB-ID 7090-7
    ISSN 1468-2060 ; 0003-4967
    ISSN (online) 1468-2060
    ISSN 0003-4967
    DOI 10.1136/ard.2006.065128
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  5. Article ; Online: Effect of linaclotide on severe abdominal symptoms in patients with irritable bowel syndrome with constipation.

    Rao, Satish S C / Quigley, Eamonn M M / Shiff, Steven J / Lavins, Bernard J / Kurtz, Caroline B / MacDougall, James E / Currie, Mark G / Johnston, Jeffrey M

    Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association

    2014  Volume 12, Issue 4, Page(s) 616–623

    Abstract: 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 ... ...

    Abstract 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.
    MeSH term(s) Adolescent ; Adult ; Aged ; Aged, 80 and over ; Constipation/drug therapy ; Female ; Gastrointestinal Agents/administration & dosage ; Humans ; Irritable Bowel Syndrome/complications ; Irritable Bowel Syndrome/drug therapy ; Male ; Middle Aged ; Peptides/administration & dosage ; Placebos/administration & dosage ; Treatment Outcome ; Young Adult
    Chemical Substances Gastrointestinal Agents ; Peptides ; Placebos ; linaclotide (N0TXR0XR5X)
    Language English
    Publishing date 2014-04
    Publishing country United States
    Document type Clinical Trial, Phase III ; Journal Article ; Multicenter Study ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
    ZDB-ID 2119789-1
    ISSN 1542-7714 ; 1542-3565
    ISSN (online) 1542-7714
    ISSN 1542-3565
    DOI 10.1016/j.cgh.2013.09.022
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  6. Article ; Online: Linaclotide improves abdominal pain and bowel habits in a phase IIb study of patients with irritable bowel syndrome with constipation.

    Johnston, Jeffrey M / Kurtz, Caroline B / Macdougall, James E / Lavins, Bernard J / Currie, Mark G / Fitch, Donald A / O'Dea, Chris / Baird, Mollie / Lembo, Anthony J

    Gastroenterology

    2010  Volume 139, Issue 6, Page(s) 1877–1886.e2

    Abstract: 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 ... ...

    Abstract 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.
    MeSH term(s) Abdominal Pain/drug therapy ; Administration, Oral ; Adolescent ; Adult ; Aged ; Constipation/drug therapy ; Defecation/drug effects ; Diarrhea/chemically induced ; Female ; Guanylate Cyclase/metabolism ; Humans ; Irritable Bowel Syndrome/drug therapy ; Male ; Middle Aged ; Peptides/administration & dosage ; Peptides/adverse effects ; Young Adult
    Chemical Substances Peptides ; Guanylate Cyclase (EC 4.6.1.2) ; linaclotide (N0TXR0XR5X)
    Language English
    Publishing date 2010-12
    Publishing country United States
    Document type Clinical Trial, Phase II ; Journal Article ; Multicenter Study ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
    ZDB-ID 80112-4
    ISSN 1528-0012 ; 0016-5085
    ISSN (online) 1528-0012
    ISSN 0016-5085
    DOI 10.1053/j.gastro.2010.08.041
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  7. Article ; Online: Linaclotide for irritable bowel syndrome with constipation: a 26-week, randomized, double-blind, placebo-controlled trial to evaluate efficacy and safety.

    Chey, William D / Lembo, Anthony J / Lavins, Bernard J / Shiff, Steven J / Kurtz, Caroline B / Currie, Mark G / MacDougall, James E / Jia, Xinwei D / Shao, James Z / Fitch, Donald A / Baird, Mollie J / Schneier, Harvey A / Johnston, Jeffrey M

    The American journal of gastroenterology

    2012  Volume 107, Issue 11, Page(s) 1702–1712

    Abstract: 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 ... ...

    Abstract 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.
    MeSH term(s) Adolescent ; Adult ; Aged ; Aged, 80 and over ; Analysis of Variance ; Constipation/drug therapy ; Double-Blind Method ; Endpoint Determination ; Female ; Humans ; Irritable Bowel Syndrome/drug therapy ; Male ; Middle Aged ; Peptides/adverse effects ; Peptides/therapeutic use ; Placebos ; Treatment Outcome
    Chemical Substances Peptides ; Placebos ; linaclotide (N0TXR0XR5X)
    Language English
    Publishing date 2012-11
    Publishing country United States
    Document type Clinical Trial, Phase III ; Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
    ZDB-ID 390122-1
    ISSN 1572-0241 ; 0002-9270
    ISSN (online) 1572-0241
    ISSN 0002-9270
    DOI 10.1038/ajg.2012.254
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  8. Article ; Online: 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.

    Rao, Satish / Lembo, Anthony J / Shiff, Steven J / Lavins, Bernard J / Currie, Mark G / Jia, Xinwei D / Shi, Kelvin / MacDougall, James E / Shao, James Z / Eng, Paul / Fox, Susan M / Schneier, Harvey A / Kurtz, Caroline B / Johnston, Jeffrey M

    The American journal of gastroenterology

    2012  Volume 107, Issue 11, Page(s) 1714–24; quiz p.1725

    Abstract: 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 ...

    Abstract 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.
    MeSH term(s) Abdominal Pain/diagnosis ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Analysis of Variance ; Constipation/drug therapy ; Double-Blind Method ; Endpoint Determination ; Female ; Humans ; Irritable Bowel Syndrome/drug therapy ; Male ; Middle Aged ; Pain Measurement ; Peptides/administration & dosage ; Peptides/adverse effects ; Peptides/therapeutic use ; Placebos ; Treatment Outcome
    Chemical Substances Peptides ; Placebos ; linaclotide (N0TXR0XR5X)
    Language English
    Publishing date 2012-09-18
    Publishing country United States
    Document type Clinical Trial, Phase III ; Journal Article ; Multicenter Study ; Randomized Controlled Trial
    ZDB-ID 390122-1
    ISSN 1572-0241 ; 0002-9270
    ISSN (online) 1572-0241
    ISSN 0002-9270
    DOI 10.1038/ajg.2012.255
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Two randomized trials of linaclotide for chronic constipation.

    Lembo, Anthony J / Schneier, Harvey A / Shiff, Steven J / Kurtz, Caroline B / MacDougall, James E / Jia, Xinwei D / Shao, James Z / Lavins, Bernard J / Currie, Mark G / Fitch, Donald A / Jeglinski, Brenda I / Eng, Paul / Fox, Susan M / Johnston, Jeffrey M

    The New England journal of medicine

    2011  Volume 365, Issue 6, Page(s) 527–536

    Abstract: 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 ... ...

    Abstract 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.).
    MeSH term(s) Adolescent ; Adult ; Aged ; Aged, 80 and over ; Chronic Disease ; Constipation/drug therapy ; Defecation/drug effects ; Diarrhea/chemically induced ; Double-Blind Method ; Female ; Guanylate Cyclase ; Humans ; Laxatives/adverse effects ; Laxatives/therapeutic use ; Male ; Middle Aged ; Peptides/adverse effects ; Peptides/therapeutic use ; Quality of Life ; Receptors, Guanylate Cyclase-Coupled/agonists ; Withholding Treatment ; Young Adult
    Chemical Substances Laxatives ; Peptides ; Guanylate Cyclase (EC 4.6.1.2) ; Receptors, Guanylate Cyclase-Coupled (EC 4.6.1.2) ; linaclotide (N0TXR0XR5X)
    Language English
    Publishing date 2011-08-11
    Publishing country United States
    Document type Clinical Trial, Phase III ; Journal Article ; Multicenter Study ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
    ZDB-ID 207154-x
    ISSN 1533-4406 ; 0028-4793
    ISSN (online) 1533-4406
    ISSN 0028-4793
    DOI 10.1056/NEJMoa1010863
    Database MEDical Literature Analysis and Retrieval System OnLINE

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

    Castro, Joel / Harrington, Andrea M / Hughes, Patrick A / Martin, Christopher M / Ge, Pei / Shea, Courtney M / Jin, Hong / Jacobson, Sarah / Hannig, Gerhard / Mann, Elizabeth / Cohen, Mitchell B / MacDougall, James E / Lavins, Bernard J / Kurtz, Caroline B / Silos-Santiago, Inmaculada / Johnston, Jeffrey M / Currie, Mark G / Blackshaw, L Ashley / Brierley, Stuart M

    Gastroenterology

    2013  Volume 145, Issue 6, Page(s) 1334–46.e1–11

    Abstract: 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 ... ...

    Abstract 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.
    MeSH term(s) Abdominal Pain/chemically induced ; Abdominal Pain/prevention & control ; Adult ; Aged ; Aged, 80 and over ; Animals ; Caco-2 Cells ; Cell Line ; Colon/drug effects ; Colon/innervation ; Colon/pathology ; Cyclic GMP/physiology ; Disease Models, Animal ; Double-Blind Method ; Female ; Guanylate Cyclase/physiology ; Humans ; Irritable Bowel Syndrome/chemically induced ; Irritable Bowel Syndrome/prevention & control ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Middle Aged ; Natriuretic Peptides/pharmacology ; Nociceptors/drug effects ; Nociceptors/physiology ; Peptides/pharmacology ; Peptides/therapeutic use ; Receptors, Atrial Natriuretic Factor/physiology ; Receptors, Enterotoxin ; Receptors, Guanylate Cyclase-Coupled/physiology ; Receptors, Peptide/physiology ; Treatment Outcome ; Trinitrobenzenesulfonic Acid/adverse effects
    Chemical Substances Natriuretic Peptides ; Peptides ; Receptors, Peptide ; uroguanylin (152175-68-3) ; Trinitrobenzenesulfonic Acid (8T3HQG2ZC4) ; GUCY2C protein, human (EC 4.6.1.2) ; Guanylate Cyclase (EC 4.6.1.2) ; Gucy2c protein, mouse (EC 4.6.1.2) ; Receptors, Atrial Natriuretic Factor (EC 4.6.1.2) ; Receptors, Enterotoxin (EC 4.6.1.2) ; Receptors, Guanylate Cyclase-Coupled (EC 4.6.1.2) ; atrial natriuretic factor receptor C (EC 4.6.1.2) ; Cyclic GMP (H2D2X058MU) ; linaclotide (N0TXR0XR5X)
    Language English
    Publishing date 2013-12
    Publishing country United States
    Document type Clinical Trial, Phase III ; Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
    ZDB-ID 80112-4
    ISSN 1528-0012 ; 0016-5085
    ISSN (online) 1528-0012
    ISSN 0016-5085
    DOI 10.1053/j.gastro.2013.08.017
    Database MEDical Literature Analysis and Retrieval System OnLINE

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