Efficacy and safety of linaclotide for opioid-induced constipation in patients with chronic noncancer pain syndromes from a phase 2 randomized study

Abstract

Constipation is the most common adverse event (AE) of opioid therapy. This multicenter, phase 2 study evaluated the efficacy and safety of linaclotide in treating opioid-induced constipation (OIC) in patients with chronic noncancer pain syndromes (NCT02270983). Adults with OIC (<3 spontaneous bowel movements [SBMs]/week) related to chronic noncancer pain were randomized 1:1:1 to receive linaclotide 145 µg, linaclotide 290 µg, or placebo once daily for 8 weeks. The primary endpoint was change from baseline in 8-week SBM frequency rate (SBMs/week). Secondary efficacy endpoints included 6/8-week SBM 3 + 1 responders, time to first SBM, and changes from baseline in 8-week stool consistency, abdominal bloating, and straining. Additional endpoints included treatment satisfaction and adequate relief responders. In total, 254 patients were randomized: 87, 88, and 79 received linaclotide 145 µg, linaclotide 290 µg, and placebo, respectively. The mean changes from baseline in SBMs/week during the treatment period were 2.9 and 3.5 in the linaclotide 145 and 290 µg groups (P < 0.01 for both doses), respectively, vs 1.6 in the placebo group. Diarrhea, the most common AE, was generally mild, resulting in 1.1%, 5.7%, and 1.3% of patients discontinuing in the linaclotide 145 μg, linaclotide 290 μg, and placebo groups, respectively. No serious AEs related to diarrhea were reported in any treatment group. Compared with placebo, linaclotide-treated patients had significant improvements in stool consistency, straining, abdominal bloating, and treatment satisfaction scores (P < 0.05). Linaclotide significantly improved OIC symptoms and was well tolerated in patients with chronic noncancer pain.

Conflict of interest statement

D.M. Brenner serves as a consultant, advisor, and speaker for Allergan and Ironwood Pharmaceuticals, Inc. B.D. Cash serves as a consultant, advisor, and speaker for Allergan and Salix Pharmaceuticals and as a consultant for Ironwood Pharmaceuticals, Inc. C.E. Argoff serves as a consultant for Shionoghi, Inc and as a speaker for DSI. S.M. Fox, W. Bochenek, and P. D'Astoli are employees of, and hold stock and stock options in, Allergan plc. R.E. Blakesley is a former employee of, and holds stock in, Allergan plc. C.R. O'Dea is an employee of, and holds stock and stock options in, Ironwood Pharmaceuticals, Inc. D.S. Reasner is a former employee of, and holds stock in, Ironwood Pharmaceuticals, Inc.

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Figures

Figure 1.

(A) Change from baseline in 8-week SBM frequency ratea; (B) distribution of change from baseline in the 8-week SBM frequency rate. All analyses were conducted in the ITT population. aData are presented as least squares mean ± SD. P values were calculated from analysis of covariance model t-tests comparing specified treatment groups, controlling for geographic region and baseline value. **P < 0.01; ****P < 0.0001. ITT, intent-to-treat; LIN, linaclotide; SBM, spontaneous bowel movement.

Figure 2.

(A) 6-/8-week SBM 3 + 1 respondersa; (B) change from baseline in 8-week bowel function symptoms. Daily assessment of stool consistency for each bowel movement was performed using the 7-point Bristol Stool Form Scale (1 = separate hard lumps like nuts [difficult to pass]; 7 = watery, no solid pieces [entirely liquid]); straining for each bowel movement was assessed using a 5-point (1-5) scale, abdominal bloating using an 11-point (0-10) numerical rating scale, and weekly assessment of opioid-induced constipation severity using a 5-point (1-5) ordinal rating scale, with higher scores indicating greater symptom severity for straining, abdominal bloating, and opioid-induced constipation. All analyses were conducted in the ITT population. aData are presented as the proportion of patients in each group who met the weekly SBM 3 + 1 responder criteria for ≥6 of the 8 weeks of the treatment period. P values were calculated from analysis of covariance model t-tests comparing specified treatment groups, controlling for geographic region and baseline value. *P ≤ 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. ITT, intent-to-treat; LIN, linaclotide; SBM, spontaneous bowel movement.

Figure 3.

(A) 6-/8- + last 3-/4-week SBM 3 + 1 respondersa; change from baseline in weekly (B) SBM frequency, (C) OIC severity scores, (D) treatment satisfaction, and (E) 6-/8-week adequate relief of OIC symptom responseb. All analyses were conducted in the ITT population. Data are presented as least squares mean ± SD. P values were calculated using mixed-effect model for repeated measures t-tests comparing specified treatment groups, controlling for week, geographic region, and baseline value, with treatment group-by-week and baseline value-by-week as interaction terms; P values for adequate relief responder rates were calculated using Cochran–Mantel–Haenszel tests comparing specified treatment groups, controlling for geographic region. *P ≤ 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. Weekly assessments of OIC severity and treatment satisfaction were performed using a 5-point (1-5) ordinal rating scale, with higher scores indicating greater OIC severity and greater satisfaction. aData are presented as the proportion of patients in each group who met the weekly SBM 3 + 1 responder criteria for ≥6 of the 8 weeks and ≥3 of the last 4 weeks of the treatment period. bData are presented as the proportion of patients in each group who reported adequate relief of OIC symptoms for ≥6 weeks of the 8-week treatment period. BL, baseline; ITT, intent-to-treat; LIN, linaclotide; OIC, opioid-induced constipation; SBM, spontaneous bowel movement.