The impact of abdominal pain on global measures in patients with chronic idiopathic constipation, before and after treatment with linaclotide: a pooled analysis of two randomised, double-blind, placebo-controlled, phase 3 trials

Abstract

Background: Few clinical trials in chronic idiopathic constipation (CIC) patients have evaluated abdominal symptom severity and whether CIC patients with abdominal symptoms respond similarly to patients with limited abdominal symptoms.

Aims: To examine abdominal symptom severity and relationships between symptoms and global measures at baseline; compare linaclotide's effect on symptoms in subpopulations with more or less abdominal pain; and assess relationships between symptom improvement and global measures in these two subpopulations.

Methods: In two phase 3 trials, patients meeting modified Rome II CIC criteria were assigned to linaclotide 145 μg, 290 μg, or placebo once daily. Patients rated abdominal and bowel symptoms daily during 2-week pre-treatment and 12-week treatment periods. Linaclotide's effect on symptoms and global measures [constipation severity, health-related quality of life (HRQOL), treatment satisfaction] and their inter-relationships were assessed in post hoc analyses of abdominal pain subpopulations.

Results: Of 1271 CIC patients, 23%, 32%, and 43% reported moderate-to-severe abdominal pain, discomfort, and bloating, respectively, during baseline. In more-severe abdominal pain patients, abdominal symptoms were more strongly correlated than bowel symptoms with global measures, but in less-severe abdominal pain patients, abdominal and bowel symptoms were similarly correlated with global measures, at baseline and post-treatment. Linaclotide significantly improved all symptoms and global measures in both subpopulations.

Conclusions: When abdominal pain is present in CIC, abdominal and not bowel symptoms may drive patient assessments of constipation severity, HRQOL, and treatment satisfaction. Linaclotide (145 μg and 290 μg) is an effective treatment for both abdominal and bowel symptoms, even in CIC patients with more severe abdominal pain at baseline. (Clinicaltrials.gov: NCT00765882, NCT00730015).

Figure 1

Subpopulations of patients with moderate-to-severe abdominal symptoms (ITT population). Venn diagram depicting the relative sizes and overlaps of the subpopulations of patients with moderate-to-severe (≥3) abdominal pain, abdominal discomfort, and abdominal bloating at baseline in the ITT population.

Figure 2

Correlations of baseline global measures with baseline abdominal and bowel symptoms. (a) Correlations of constipation severity score at baseline with abdominal and bowel symptoms at baseline. Pearson correlation coefficients, r, absolute values shown; *P < 0.05. (b) Correlations of PAC-QOL overall score at baseline with abdominal and bowel symptoms at baseline. Pearson correlation coefficients, r, absolute values shown; *P < .05.

Figure 3

Weekly mean change from baseline in abdominal pain. (a) Mean change from baseline in abdominal pain (LOCF) by week during the 12-week treatment period, by dose group in patients who had none-to-mild abdominal pain at baseline. Abdominal pain measured on a 5-point ordinal scale (1 = none to 5 = very severe). (b) Mean change from baseline in abdominal pain (LOCF) by week during the 12-week treatment period, by dose group in patients who had moderate-to-severe abdominal pain at baseline. Abdominal pain measured on a 5-point ordinal scale (1 = none to 5 = very severe).

Figure 4

Correlation of global measures after treatment with improvement in abdominal and bowel symptoms. (a) Correlation of constipation severity (week 12 LOCF) with improvement in abdominal and bowel symptoms (baseline to week 12 LOCF). Pearson correlation coefficients, r, absolute values shown; *P < 0.05. (b) Correlation of PAC-QOL overall score (week 12) with improvement in abdominal and bowel symptoms (baseline to week 12 LOCF). Pearson correlation coefficients, r, absolute values shown; *P < 0.05. (c) Correlation of treatment satisfaction (week 12 LOCF) with improvement in abdominal and bowel symptoms (baseline to week 12 LOCF). Pearsoncorrelation coefficients, r, absolute values shown; *P < 0.05.