Linaclotide (Linzess) significantly alleviated abdominal symptoms in irritable bowel syndrome (IBS) patients with predominant constipation compared with placebo, researchers found in a randomized study.
Using an abdominal score that averaged abdominal bloating, discomfort, and pain on an 11-point scale, the average overall change from baseline was -1.9 for patients treated with linaclotide and -1.2 for those assigned placebo (P<0.0001), reported Lin Chang, MD, of the University of California Los Angeles, and colleagues.
At 12 weeks, the change from baseline weekly abdominal score was -2.35 in the linaclotide group and -1.48 in the placebo group (P<0.0001), the authors wrote in the American Journal of Gastroenterology.
The abdominal score responder rate, meaning they achieved at least a 2-point decrease in abdominal score for at least 6 of the 12 weeks of treatment, was 40.5% for linaclotide and 23.4% for the placebo group (OR 2.20, 95% CI 1.55-3.12).
This was the first large randomized trial to assess the efficacy of a treatment for IBS with predominant constipation using this new abdominal score assessment.
“During patients’ conversations with their doctors, there is often an unfortunate but avoidable communication gap in which patients only describe their ‘constipation’ without discussing specific symptoms such as abdominal bloating, pain and/or discomfort,” said Chang in a statement.
The FDA approved linaclotide, a guanylate cyclase-C agonist, in 2012 for chronic idiopathic constipation and a subtype of IBS characterized by constipation and abdominal pain. Linaclotide functions to increase luminal secretions, promoting analgesic effects, thereby resulting in improved bowel transit and stool formation, the authors said.
A previous study suggested IBS patients with predominant constipation present with more severe and frequent abdominal pain compared to other IBS subtypes, but the authors noted no research addressed the drug’s efficacy for abdominal pain.
They added the drug was approved on a composite endpoint of improvement of abdominal pain and frequency of complete spontaneous bowel movements. However, this was prior to the development of patient-reported outcomes research that identified “key abdominal symptoms” in this population, and produced the Diary for IBS Symptoms-Constipation (DIBSS-C) outcomes instrument.
Patient relief of abdominal symptoms was assessed for discomfort, bloating, and pain by use of an 11-point scale multi-item abdominal score, derived from DIBSS-C (0 indicating no symptoms and 10 indicating the worst symptoms).
The phase IIIb study included 614 adults who had IBS with constipation from 78 centers from June 2018 to April 2019. Inclusion was based on the Rome III IBS diagnostic criteria and most met the Rome IV criteria. Patients’ stool consistency was assessed by the Bristol Stool Form Scale.
The primary endpoint was a change from the weekly abdominal score from baseline during the 3-month trial duration. Secondary endpoints examined the 12-week change from baseline abdominal score as a cumulative distribution function, as well as the abdominal score responder at weeks 6 and 12.
Patients were randomized to receive 290 μg of linaclotide or placebo. Overall, 594 patients completed 12 weeks of treatment.
Average patient age was 47, about two-thirds were white, and over 80% were women. Baseline abdominal scores for bloating, discomfort, and pain for participants were around 6 (out of 11). All participants had a stool score of about 2 (out of 7) and a constipation severity of around 3.5 (out of 5).
“Linaclotide was associated with significant reductions in individual abdominal bloating, discomfort, and pain symptoms vs placebo in the first week,” Chang and co-authors wrote, “followed by progressive reductions through 12 weeks of the treatment period and sustained in the linaclotide-treated patients who continued on linaclotide through week 16.”
There were no participants with worsening of symptoms after the trial, they added. Patients who remained on linaclotide showed a persistent treatment response, but patients who switched from linaclotide to the placebo had a declining response to treatment.
There were 31% of patients in the linaclotide group who reported an adverse event compared to 26.6% in placebo. The most common side effect was diarrhea, occurring in 1.6% of the placebo group and 4.6% of the linaclotide group.
For the endpoint of combined abdominal pain and constipation response, the linaclotide group won out as well (29.4% vs 16.9%, P<0.001).
The authors recommended this new abdominal score be used in additional clinical trials.
Limitations of this study include its smaller size, as more data are needed to confirm results on a greater scale. This trial also only specifically evaluated one subtype of IBS patients.
“Results from this trial may help physicians and patients have a more comprehensive discussion about these bothersome symptoms and ways to manage them,” Chang said in a statement.
Funding was provided by Ironwood Pharmaceuticals, Allergan, and AbbVie. Additional support came from Urovant.
Chang disclosed receiving support from Arena, stock in ModifyHealth, and consultant work for IM HealthScience, Arena, Shire, and Takeda. Co-authors reported financial relationships with Ironwood Pharmaceuticals, AbbVie, Urovant, Alfasigma, Arena Pharmaceuticals, Viver, Salix Pharmaceuticals, Takeda, Medtronic, Salix Pharmaceuticals, Allakos, and the Speakers Bureau. Some co-authors reported past or current employment with AbbVie and Ironwood Pharmaceuticals.