Linaclotide Significantly Improves Quality of Life and Abdominal Symptoms

Chicago—An analysis of two phase 3 clinical trials comparing linaclotide with placebo found that a daily dose of the investigational agent significantly reduced the severity of chronic constipation and related abdominal symptoms, improving patients’ quality of life. The data from the study, which was designated a “poster of distinction,” were presented at the DDW meeting. The poster was titled Effect of Linaclotide on Quality of Life Among Patients with Chronic Constipation with Abdominal Symptoms. The authors noted that constipation is a common gastrointestinal disorder, affecting approximately 15% of Americans and often associated with severe abdominal discomfort. Cumulatively, the 2 multicenter trials enrolled 1272 adult men and women with chronic constipation. Constipation was assessed using modified Rome II criteria, which stipulates <3 episodes of defecation weekly for ≥12 weeks, with no episodes of loose stool and ≥25% of defecations involving ≥2 of the following symptoms: straining, lumpy or hard stools, incomplete evacuation, and/or a sense of anorectal obstruction. Participants were randomized to 12 weeks of placebo, linaclotide 133 mcg, or linaclotide 266 mcg, administered daily via an oral capsule.

During a 2-week pretreatment phase, participants completed the self-administered Patient Assessment of Constipation-Quality of Life (PAC-QOL) questionnaire, which includes subscales rating physical discomfort, satisfaction, worries/concern, and psychosocial discomfort; higher scores indicate worse quality of life. The PAC-QOL also asks patients to rate abdominal symptoms on a scale of 1 to 5, with 1 indicating none and 5 denoting very severe. The investigators stratified patients into 3 subgroups for a post hoc analysis according to scores ≥2 for abdominal pain (n=682), abdominal discomfort (n=868), and bloating (n=982). Some patients fell into ≥1 subgroup, with 53.6% of patients experiencing abdominal pain, 68.2% noting discomfort, and 77.2% acknowledging symptoms of bloating. Patients were well balanced between the subgroups, with similar male-to-female ratios and similar proportions of white participants. At week 12, the PAC-QOL questionnaire was repeated. Responses revealed significant improvement from baseline in overall scores (P<.05) and for all 4 subscales among patients treated with linaclotide compared with those given placebo.

Results were consistent across all 3 subgroups, regardless of the linaclotide dose used. In each subgroup, satisfaction improved the least (denoted by a smaller decline in the PAC-QOL score) in patients taking placebo compared with those taking linaclotide. In the abdominal pain subgroup, the mean satisfaction PAC-QOL score declined 0.60 points in the placebo group compared with a drop of 1.32 in the linaclotide 133-mcg and linaclotide 266-mcg groups (P≤.0001 in both comparisons). In the abdominal discomfort subgroup, the mean satisfaction PAC-QOL score declined 0.56 points in the placebo group compared with a drop of 1.37 in the linaclotide 133-mcg group and 1.28 in the linaclotide 266-mcg group (P≤.0001 in both comparisons). In the bloating subgroup, the mean satisfaction PAC-QOL score declined 0.52 points in the placebo group compared with a drop of 1.28 in the linaclotide 133-mcg and linaclotide 266-mcg groups (P≤.0001 in both comparisons). In the pain subgroup, overall PAC-QOL scores declined a mean of 0.67 in the placebo group compared with a drop of 1.07 in the linaclotide 133-mcg group (P<.0001) and 1.10 in the linaclotide 266-mcg group (P<.0001). For the abdominal subgroup, declines averaged 0.62 in the placebo arm and 1.03 in each linaclotide group (P<.00001 for both comparisons). In the bloating group, the overall mean decline was also significantly greater for patients treated with linaclotide 133 mcg and 266 mcg than for those taking placebo (−0.97 vs −0.99 vs −0.58, respectively; P<.0001).

The investigators said diarrhea was the most common adverse event with linaclotide therapy. Despite the increased rate of diarrhea, however, findings demonstrate that linaclotide significantly improved quality of life for patients compared with placebo, regardless of the patient’s predominant symptom. This study was funded by Ironwood Pharmaceuticals, Inc., and Forest Laboratories, Inc.