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

Lacy BE, Schey R, Shiff SJ, Lavins BJ, Fox SM, Jia XD, Blakesley RE, Hao X, Cronin JA, Currie MG, Kurtz CB, Johnston JM, Lembo AJ - PLoS ONE (2015)

Bottom Line: The primary endpoint compared linaclotide 145 μg vs. placebo.AEs resulted in premature discontinuation of 5% and 9% of linaclotide 145 μg and 290 μg patients, respectively, and 6% of placebo patients.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.

View Article: PubMed Central - PubMed

Affiliation: Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus

Patient Flow Through the Trial.Screen failures who were rescreened and failed a second time during the screening period were counted once as screen failures. Screen failures who were rescreened, entered the baseline period, and then failed during the baseline period were counted once as pretreatment failures.
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pone.0134349.g001: Patient Flow Through the Trial.Screen failures who were rescreened and failed a second time during the screening period were counted once as screen failures. Screen failures who were rescreened, entered the baseline period, and then failed during the baseline period were counted once as pretreatment failures.

Mentions: Of the 1482 patients who were screened for participation in this trial, 487 patients were randomized to treatment (Fig 1). A total of 486 patients received at least one dose of study drug and were included in the safety population (153 linaclotide 145 μg, 160 linaclotide 290 μg, and 173 placebo patients); of those patients, 483 patients had at least one post-randomization entry of the primary efficacy assessment and were included in the ITT population (153 linaclotide 145 μg, 159 linaclotide 290 μg, and 171 placebo patients). A total of 369 patients (76% of patients randomized) completed the 12-week treatment period. The treatment groups were well-balanced with regard to demographics and baseline constipation symptoms (Table 1). During the pretreatment baseline period, approximately 79% of patients had no CSBMs and the mean abdominal bloating score was 7.1 on a 0–10-point NRS. Mean compliance with study-drug dosing (assessed by counting pills returned at study visits) up to the time of discontinuation or completion of the 12-week treatment period was 98% and 97% in the linaclotide 145 μg and 290 μg groups, respectively, and 98% in the placebo group. Use of fiber, bulk laxatives, or stool softeners was low during the trial (<5% of patients) and was similar across treatment groups.


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

Lacy BE, Schey R, Shiff SJ, Lavins BJ, Fox SM, Jia XD, Blakesley RE, Hao X, Cronin JA, Currie MG, Kurtz CB, Johnston JM, Lembo AJ - PLoS ONE (2015)

Patient Flow Through the Trial.Screen failures who were rescreened and failed a second time during the screening period were counted once as screen failures. Screen failures who were rescreened, entered the baseline period, and then failed during the baseline period were counted once as pretreatment failures.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4519259&req=5

pone.0134349.g001: Patient Flow Through the Trial.Screen failures who were rescreened and failed a second time during the screening period were counted once as screen failures. Screen failures who were rescreened, entered the baseline period, and then failed during the baseline period were counted once as pretreatment failures.
Mentions: Of the 1482 patients who were screened for participation in this trial, 487 patients were randomized to treatment (Fig 1). A total of 486 patients received at least one dose of study drug and were included in the safety population (153 linaclotide 145 μg, 160 linaclotide 290 μg, and 173 placebo patients); of those patients, 483 patients had at least one post-randomization entry of the primary efficacy assessment and were included in the ITT population (153 linaclotide 145 μg, 159 linaclotide 290 μg, and 171 placebo patients). A total of 369 patients (76% of patients randomized) completed the 12-week treatment period. The treatment groups were well-balanced with regard to demographics and baseline constipation symptoms (Table 1). During the pretreatment baseline period, approximately 79% of patients had no CSBMs and the mean abdominal bloating score was 7.1 on a 0–10-point NRS. Mean compliance with study-drug dosing (assessed by counting pills returned at study visits) up to the time of discontinuation or completion of the 12-week treatment period was 98% and 97% in the linaclotide 145 μg and 290 μg groups, respectively, and 98% in the placebo group. Use of fiber, bulk laxatives, or stool softeners was low during the trial (<5% of patients) and was similar across treatment groups.

Bottom Line: The primary endpoint compared linaclotide 145 μg vs. placebo.AEs resulted in premature discontinuation of 5% and 9% of linaclotide 145 μg and 290 μg patients, respectively, and 6% of placebo patients.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.

View Article: PubMed Central - PubMed

Affiliation: Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus