Author information

2 Renji Hospital, Shanghai, China.

3 General Hospital of Shenyang Military Region of Chinese PLA, Shenyang, China.

4 Sir Run Run Shaw Hospital, Hangzhou, China.

5 Zhongshan Hospital, Shanghai, China.

6 First Affiliated Hospital of Harbin Medical University, Harbin, China.

7 Ruijin Hospital, Shanghai, China.

8 Delta Research Partners, Monroe, LA, USA.

9 Ironwood Pharmaceuticals, Inc., Cambridge, MA, USA.

10 AstraZeneca AB, Shanghai, China.

11 Duke-NUS Medical School Office of Clinical Sciences, Singapore.

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 3-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 bowelmovement/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.