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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

Primary Endpoint.Intent-to-treat Population; Responder = patient who had ≥ 3 CSBMs and an increase of ≥ 1 CSBM from baseline, in the same week, for at least 9 of the 12 treatment-period weeks. Note: Primary endpoint for linaclotide 145 μg vs. placebo; secondary endpoint for linaclotide 290 μg vs. placebo. CSBM = complete spontaneous bowel movement; ITT = intent to treat; Lin = linaclotide; n = number of patients meeting the responder endpoint; N = number of patients in the ITT population. * P < 0.05; P values were obtained from a Cochran-Mantel-Haenszel test controlling for geographic region, comparing each linaclotide dose vs. placebo in a pairwise manner.
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pone.0134349.g002: Primary Endpoint.Intent-to-treat Population; Responder = patient who had ≥ 3 CSBMs and an increase of ≥ 1 CSBM from baseline, in the same week, for at least 9 of the 12 treatment-period weeks. Note: Primary endpoint for linaclotide 145 μg vs. placebo; secondary endpoint for linaclotide 290 μg vs. placebo. CSBM = complete spontaneous bowel movement; ITT = intent to treat; Lin = linaclotide; n = number of patients meeting the responder endpoint; N = number of patients in the ITT population. * P < 0.05; P values were obtained from a Cochran-Mantel-Haenszel test controlling for geographic region, comparing each linaclotide dose vs. placebo in a pairwise manner.

Mentions: A total of 15.7% (24 of 153 patients) in the linaclotide 145 μg group met the responder requirements of the primary endpoint, compared with 7.6% (13 of 171 patients) in the placebo group (P = 0.0264; odds ratio 2.23; 95% CI [1.09, 4.56]; Fig 2 and Table 2). For the corresponding analysis in the linaclotide 290 μg group, which was a secondary endpoint, 16.4% (26 of 159 patients) met the responder requirements (P = 0.0109 versus placebo; odds ratio 2.45; 95% CI [1.21, 4.96]). The number needed to treat (NNT) for the primary endpoint (in the linaclotide 145 μg group) was 12.4, and for the corresponding secondary endpoint (in the linaclotide 290 μg group) was 11.4. When the components of the primary endpoint were considered for the linaclotide 145 μg group, 15.7% of patients had ≥ 3 CSBMs per week for at least 9 of 12 weeks, compared with 8.2% in the placebo group (P = 0.0413); and 26.8% of patients in the linaclotide 145 μg group had an increase from baseline of ≥ 1 CSBM per week for at least 9 of 12 weeks, compared with 16.4% in the placebo group (P = 0.0243).


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)

Primary Endpoint.Intent-to-treat Population; Responder = patient who had ≥ 3 CSBMs and an increase of ≥ 1 CSBM from baseline, in the same week, for at least 9 of the 12 treatment-period weeks. Note: Primary endpoint for linaclotide 145 μg vs. placebo; secondary endpoint for linaclotide 290 μg vs. placebo. CSBM = complete spontaneous bowel movement; ITT = intent to treat; Lin = linaclotide; n = number of patients meeting the responder endpoint; N = number of patients in the ITT population. * P < 0.05; P values were obtained from a Cochran-Mantel-Haenszel test controlling for geographic region, comparing each linaclotide dose vs. placebo in a pairwise manner.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0134349.g002: Primary Endpoint.Intent-to-treat Population; Responder = patient who had ≥ 3 CSBMs and an increase of ≥ 1 CSBM from baseline, in the same week, for at least 9 of the 12 treatment-period weeks. Note: Primary endpoint for linaclotide 145 μg vs. placebo; secondary endpoint for linaclotide 290 μg vs. placebo. CSBM = complete spontaneous bowel movement; ITT = intent to treat; Lin = linaclotide; n = number of patients meeting the responder endpoint; N = number of patients in the ITT population. * P < 0.05; P values were obtained from a Cochran-Mantel-Haenszel test controlling for geographic region, comparing each linaclotide dose vs. placebo in a pairwise manner.
Mentions: A total of 15.7% (24 of 153 patients) in the linaclotide 145 μg group met the responder requirements of the primary endpoint, compared with 7.6% (13 of 171 patients) in the placebo group (P = 0.0264; odds ratio 2.23; 95% CI [1.09, 4.56]; Fig 2 and Table 2). For the corresponding analysis in the linaclotide 290 μg group, which was a secondary endpoint, 16.4% (26 of 159 patients) met the responder requirements (P = 0.0109 versus placebo; odds ratio 2.45; 95% CI [1.21, 4.96]). The number needed to treat (NNT) for the primary endpoint (in the linaclotide 145 μg group) was 12.4, and for the corresponding secondary endpoint (in the linaclotide 290 μg group) was 11.4. When the components of the primary endpoint were considered for the linaclotide 145 μg group, 15.7% of patients had ≥ 3 CSBMs per week for at least 9 of 12 weeks, compared with 8.2% in the placebo group (P = 0.0413); and 26.8% of patients in the linaclotide 145 μg group had an increase from baseline of ≥ 1 CSBM per week for at least 9 of 12 weeks, compared with 16.4% in the placebo group (P = 0.0243).

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