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A newly approved option for pediatric patients with functional constipation significantly increased the frequency of bowel movements and improved other burdensome symptoms as well, according to a pivotal phase III trial.

Among children ages 6 years and older, linaclotide (Linzess) doubled the increase in weekly spontaneous bowel movements (SBMs) over 12 weeks compared with placebo (least squares mean [LSM] change 2.22 vs 1.05, P<0.0001).

Fully 57% of patients in the treatment group experienced an SBM within the first 48 hours of receiving the drug, reported Julie Khlevner, MD, of Columbia University in New York City, and colleagues in .

Linaclotide, a guanylate cyclase C agonist, was approved by the FDA in June 2023 for pediatric patients ages 6 years and up based on initial results from this multicenter trial as well as data from trials in adults with chronic idiopathic constipation.

"In the present study, the additional data showing improvements in stool consistency, complete SBM frequency, and straining suggest that linaclotide might address a range of symptoms associated with functional constipation in pediatric patients aged 6-17 years, not just SBM frequency," Khlevner's group wrote.

"Functional constipation symptoms are burdensome," the researchers explained, "affecting quality of life and leading to absenteeism from school, and can also affect families."

Stool consistency, as measured with the pediatric Bristol Stool Form Scale and reported by patients or their caregivers, significantly improved from baseline in the treatment group compared with placebo (LSM difference of 0.42 on the 7-point scale, P=0.0001).

The frequency of complete SBMs (an SBM associated with a sense of complete evacuation) was also significantly improved from baseline in the treatment group compared with placebo (LSM difference 0.96, P<0.0001).

In addition, the treatment group showed significantly greater improvement from baseline over placebo in straining with bowel movements (LSM difference -0.44, P<0.0001) and in overall abdominal bloating (LSM difference -0.16, P=0.027).

The most frequent treatment-emergent adverse event in the linaclotide group was diarrhea, reported in 4% of patients (vs 2% in the placebo group), including one 17-year-old female patient with severe diarrhea and dehydration requiring hospital admission and IV rehydration.

Khlevner and colleagues conducted the randomized, double-blind study at 64 clinic or hospital sites in seven countries among 328 patients ages 6 years and older who met modified Rome III criteria for functional constipation. They were randomly assigned 1:1 to receive either oral linaclotide 72 μg or placebo once daily for 12 weeks. Patients or their caregivers recorded information on bowel movements every morning and evening in an electronic diary.

Patients were also assessed at eight clinical visits during the study period. The primary endpoint was frequency of SBMs. Secondary endpoints included stool consistency, straining with bowel movements, and sense of complete bowel movements.

Silvia Salvatore, MD, of the University of Insubria in Varese, Italy, commented on the study in an . "This new paediatric study is of the upmost clinical importance," Salvatore wrote, "as constipation is one of the most frequent functional gastrointestinal disorders (now defined as disorders of gut-brain interaction) in children, affecting approximately 13% worldwide, with relevant health and economic impacts."

Osmotic and stimulant laxatives, which are recommended treatment options, have been reported to lack efficacy in more than 20% of patients, she noted.

A limitation of the study, however, was its relatively short duration, Salvatore added, which means long-term effects were not evaluated. "Post-marketing surveillance and a large, academic, real-world study, not sponsored by pharmaceutical companies, are needed to confirm the efficacy and safety of linaclotide," she said.

Studies that evaluate the efficacy of linaclotide in subgroups of pediatric patients, such as younger versus older patients or females versus males, might also yield useful information, Salvatore said. Previous studies in adults suggested female patients benefit more from linaclotide than males, she noted, but Khlevner and colleagues did not analyze their results by gender.

"Further prospective, controlled studies are needed to identify which patients are most likely to benefit from linaclotide therapy and whether linaclotide will improve the quality of life of children with functional constipation and be economically sustainable for families," Salvatore said.

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