Linaclotide in irritable bowel syndrome with constipation: A Phase 3 randomized trial in China and other regions

Abstract Background and Aim Linaclotide is a guanylate cyclase‐C agonist approved in multiple countries to treat irritable bowel syndrome with constipation (IBS‐C). China has unmet need for well‐tolerated therapy that is effective in treating both bowel and abdominal symptoms of IBS‐C. This trial evaluated linaclotide's efficacy and safety in IBS‐C patients in China and other regions. Methods This Phase 3, double‐blind trial randomized IBS‐C patients to once‐daily oral 290‐μg linaclotide or placebo at centers in China, North America, and Oceania. Patients reported bowel and abdominal symptoms daily; adverse events were monitored. Co‐primary and secondary endpoints were tested using a predefined three‐step serial gatekeeping multiple comparisons procedure. Results The intent‐to‐treat population included 839 patients (mean age = 41 years; 82% female; 81% Asian). The trial met all co‐primary and secondary endpoints. Co‐primary responder criteria were met by 60.0% of linaclotide patients versus 48.8% of placebo patients for abdominal pain/discomfort (≥ 30% decrease for ≥ 6/12 weeks; P < 0.05), and 31.7% of linaclotide versus 15.4% of placebo patients for IBS degree of relief (score ≤ 2 for ≥ 6/12 weeks; P < 0.0001). Secondary 12‐week change‐from‐baseline endpoints (spontaneous bowel movement/complete spontaneous bowel movement frequency, stool consistency, straining, abdominal pain, abdominal discomfort, and abdominal bloating) were significantly improved with linaclotide versus placebo (all P < 0.0001). Diarrhea was the most common adverse event (9.4% linaclotide, 1.2% placebo). Discontinuation rates due to diarrhea were low (0.7% linaclotide, 0.2% placebo). Conclusions Once‐daily 290‐μg linaclotide improved bowel habits, abdominal symptoms, and global measures in a predominantly Chinese IBS‐C population.