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

Abstract

BackgroundAbdominal 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.MethodsThis 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.ResultsThe 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.ConclusionsOnce-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 RegistrationClinicalTrials.gov NCT01642914

Bloating is associated with worse quality of life, treatment satisfaction, and treatment responsiveness among patients with constipation‐predominant irritable bowel syndrome and functional constipation

“…[20][21][22][23][24][25][26][27][28] Additionally, patients treated with linaclotide, a minimally absorbed 14 amino acid peptide enhancing luminal fluid secretion and bowel motility, reported improvements of bloating sensations during a 12-week follow-up randomized controlled parallel group clinical trial against placebo. 29 However, the sensation of abdominal distension is often reported by patients with somatization disorders, a condition associated with a propensity to amplify the intensity and significance of bodily sensations, which in turn may be associated with greater healthcare-seeking behavior, 30 reduced treatment satisfaction, and worse responsiveness to treatment of somatic symptoms. Our study was not designed to shed light on the pathophysiological mechanisms underlying bloating, other lower GI symptoms, and PRO.…”

Bowel Disorders

“…42 Similarly, linaclotide also improved bloating symptoms in the phase 3 studies for chronic idiopathic constipation 133 and IBS-C. [44][45][46] In CC patients with predominant symptoms of bloating, linaclotide showed a significant improvement in bloating symptoms. 189 Desipramine, in conjunction with cognitive behavioral therapy, resulted in an improvement in bloating, although the effects of desipramine alone remain unclear. 190 A small, crossover-trial with citalopram showed an improvement in the number of days without bloating at 3 and 6 weeks.…”

Consensus statements on diagnosis and management of chronic idiopathic constipation in adults in Hong Kong

“…26 Two large randomised placebo-controlled trials (n=2731) have recently demonstrated the efficacy of plecanatide (3-mg and 6-mg doses) at improving CIC. 27,28 Both trials reported a significant improvement in the proportion of durable CSBM responders and a small incidence of diarrhoea. 27,28 Because prosecretory agents induce active secretion of electrolytes and fluids into the intestinal lumen, monitoring baseline renal function is advisable in selected patients who are at risk of dehydration or renal dysfunction.…”

“…27,28 Both trials reported a significant improvement in the proportion of durable CSBM responders and a small incidence of diarrhoea. 27,28 Because prosecretory agents induce active secretion of electrolytes and fluids into the intestinal lumen, monitoring baseline renal function is advisable in selected patients who are at risk of dehydration or renal dysfunction. 23 The Food and Drug Administration has classified linaclotide as a pregnancy category C drug.…”