Linaclotide Improves Symptoms, Quality of Life After Non-Response to Magnesium Oxide

Atsushi Nakajima, MD, PhD

Credit: AASLD

Linaclotide is a safe and effective option for patients with chronic constipation (CC) or irritable bowel syndrome with constipation (IBS-C) who do not respond to treatment with magnesium oxide, according to findings from a recent study.¹

Findings from the multicenter, open-label, single-arm, exploratory provide novel evidence suggesting linaclotide may improve quality of life, symptoms, and treatment satisfaction in patients who show an inadequate response to conventional therapy.¹

“To our knowledge, there have been no prior investigations exploring the transition to linaclotide without a washout period for MgO, as conducted in this study,” Atsushi Nakajima, MD, PhD, a professor and chairman in the department of gastroenterology and hepatology at the Yokohama City University School of Medicine, and colleagues wrote.¹

An estimated 10% to 15% of people in the United States have IBS, and it is the most common intestinal problem leading to a gastroenterologist referral. A prevalent subtype of IBS, IBS-C typically entails having a difficult time passing stool and fewer bowel movements. Treatment for any subtype of IBS seeks to improve symptoms, and although lifestyle and dietary changes are useful for some patients, others require pharmacologic treatment.²

To evaluate the efficacy and safety of linaclotide in patients with CC or IBS-C who did not respond to treatment with magnesium oxide, investigators conducted a multicenter, open-label, single-arm, exploratory study at Yokohama City University Hospital, Kanagawa Dental University Yokohama Clinic, and NamikiKoiso-Medical Clinic. For inclusion, patients were required to be 20 to 85 years of age; diagnosed with CC or IBS-C based on Rome IV criteria; and prescribed magnesium oxide 0.99 to 2 g per day for ≥ 4 weeks. Enrollment started on July 1, 2020, and ended on November 30, 2021.¹

Medication initiation criteria included a mean Japanese version of the Patient Assessment of Constipation Quality of Life (JPAC-QOL) total score of 1.0-2.5, representing the study’s primary endpoint. The JPAC-QOL questionnaire used in the study contained 28 questions, each assigned a score of 0 to 4, with a greater score indicating a poorer quality of life. Patients meeting the medication initiation criteria were administered linaclotide at a daily dosage of 500 μg for 12 weeks, and magnesium oxide was discontinued.¹

Patients recorded abdominal symptoms, stool frequency, stool consistency, and the use of rescue medication in their diaries, which was verified by a researcher at each visit. Adverse events were also recorded in the diary and reviewed during the monitoring survey. The study’s observation period ended on December 14, 2021.¹

The primary endpoint was the change in the total JPAC-QOL score after 12 weeks of linaclotide treatment. Both the primary and secondary endpoints were assessed using questionnaires and patient-recorded diaries.¹

Among 157 patients who provided written informed consent, 92 were excluded during the screening period. Of the 65 patients who started linaclotide treatment, 4 were excluded due to protocol deviations, leaving 61 participants in the full analysis set. Among the cohort, the mean age was 67.6 (Standard deviation [SD], 13.82) years and 67.2% of patients were female.¹

At baseline, the mean total JPAC-QOL score was 1.60 and decreased to 0.70 at 12 weeks, with a mean change of −0.89 (SD, 0.721; 95% CI, −1.087 to −0.697; P <.001). In the per-protocol set, the mean total score was 1.56 at baseline and 0.66 at 12 weeks, with a mean change of −0.90 (SD, 0.764; 95% CI, −1.154 to −0.637; P <.001).¹

Investigators also observed improvements in several secondary endpoints. They noted the frequency of spontaneous bowel movement (SBM) and complete SBM increased by 2.70 (95% CI, 0.743 to 4.665; P <.01) and 2.81 (95% CI, 1.394 to 4.235; P <.001) times, respectively. Additionally, investigators called attention to improvements in Bristol Stool Form Scale score by 1.33 (95% CI, 0.968 to 1.692; P <.001), abdominal bloating severity score by −0.16 (95% CI, −0.323 to −0.002; P <.05), and straining severity score by −0.46 (95% CI, −0.689 to −0.237; P <.001).¹

To determine safety, Investigators examined the safety analysis set, which comprised the enrolled population receiving linaclotide at least once (n = 65). Adverse events after treatment potentially related to treatment were grade 2 abdominal pain in 2 cases, grade 3 diarrhea in 1 case, grade 2 diarrhea in 2 cases, and grade 1 diarrhea in 4 cases.¹

Investigators acknowledged multiple limitations to these findings, including the non-randomized, single-arm study design with a small sample size; the exploratory analysis of the efficacy of secondary endpoints since the sample size was determined based on the primary endpoint; the lack of differentiation between CC and IBS-C; the lack of tracking of the percentage of patients who continued linaclotide after 12 weeks of linaclotide administration; and the potential for bias due to use of self-reported patient responses.¹

“We demonstrated the efficacy and safety of linaclotide in patients with CC or IBS-C who had an inadequate response to magnesium oxide treatment,” investigators concluded.¹ “Further randomized controlled trials, including larger sample sizes, are necessary to validate our findings.”

References

1. ^{Yoshihara T, Kessoku T, Takatsu T, et al. Efficacy and safety of linaclotide in treatment-resistant chronic constipation: A multicenter, open-label study. Neurogastroenterology & Motility. https://doi.org/10.1111/nmo.14938}
2. ^{Mount Sinai. Irritable Bowel Syndrome. Accessed October 14, 2024. https://www.mountsinai.org/health-library/diseases-conditions/irritable-bowel-syndrome}