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Linaclotide in Chronic Idiopathic Constipation Patients with Moderate to Severe Abdominal Bloating: A Randomized, Controlled Trial.
PLoS One 2015; 10(7):e0134349Plos

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.

Authors+Show Affiliations

Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States of America.University of Iowa Hospitals and Clinics, Iowa City, IA, United States of America.Forest Laboratories LLC, a subsidiary of Actavis plc, Jersey City, NJ, United States of America.Ironwood Pharmaceuticals, Cambridge, MA, United States of America.Forest Laboratories LLC, a subsidiary of Actavis plc, Jersey City, NJ, United States of America.Forest Laboratories LLC, a subsidiary of Actavis plc, Jersey City, NJ, United States of America.Forest Laboratories LLC, a subsidiary of Actavis plc, Jersey City, NJ, United States of America.Ironwood Pharmaceuticals, Cambridge, MA, United States of America.Ironwood Pharmaceuticals, Cambridge, MA, United States of America.Ironwood Pharmaceuticals, Cambridge, MA, United States of America.Ironwood Pharmaceuticals, Cambridge, MA, United States of America.Ironwood Pharmaceuticals, Cambridge, MA, United States of America.Beth Israel Deaconess Medical Center, Boston, MA, United States of America.

Pub Type(s)

Clinical Trial, Phase III
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26222318

Citation

Lacy, Brian E., et al. "Linaclotide in Chronic Idiopathic Constipation Patients With Moderate to Severe Abdominal Bloating: a Randomized, Controlled Trial." PloS One, vol. 10, no. 7, 2015, pp. e0134349.
Lacy BE, Schey R, Shiff SJ, et al. Linaclotide in Chronic Idiopathic Constipation Patients with Moderate to Severe Abdominal Bloating: A Randomized, Controlled Trial. PLoS ONE. 2015;10(7):e0134349.
Lacy, B. E., Schey, R., Shiff, S. J., Lavins, B. J., Fox, S. M., Jia, X. D., ... Lembo, A. J. (2015). Linaclotide in Chronic Idiopathic Constipation Patients with Moderate to Severe Abdominal Bloating: A Randomized, Controlled Trial. PloS One, 10(7), pp. e0134349. doi:10.1371/journal.pone.0134349.
Lacy BE, et al. Linaclotide in Chronic Idiopathic Constipation Patients With Moderate to Severe Abdominal Bloating: a Randomized, Controlled Trial. PLoS ONE. 2015;10(7):e0134349. PubMed PMID: 26222318.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Linaclotide in Chronic Idiopathic Constipation Patients with Moderate to Severe Abdominal Bloating: A Randomized, Controlled Trial. AU - Lacy,Brian E, AU - Schey,Ron, AU - Shiff,Steven J, AU - Lavins,Bernard J, AU - Fox,Susan M, AU - Jia,Xinwei D, AU - Blakesley,Rick E, AU - Hao,Xinming, AU - Cronin,Jacquelyn A, AU - Currie,Mark G, AU - Kurtz,Caroline B, AU - Johnston,Jeffrey M, AU - Lembo,Anthony J, Y1 - 2015/07/29/ PY - 2015/02/19/received PY - 2015/07/09/accepted PY - 2015/7/30/entrez PY - 2015/7/30/pubmed PY - 2016/5/14/medline SP - e0134349 EP - e0134349 JF - PloS one JO - PLoS ONE VL - 10 IS - 7 N2 - 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. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/26222318/Linaclotide_in_Chronic_Idiopathic_Constipation_Patients_with_Moderate_to_Severe_Abdominal_Bloating:_A_Randomized_Controlled_Trial_ L2 - http://dx.plos.org/10.1371/journal.pone.0134349 DB - PRIME DP - Unbound Medicine ER -