Low-Dose Linaclotide (72 μg) for Chronic Idiopathic Constipation: A 12-Week, Randomized, Double-Blind, Placebo-Controlled Trial

Abstract

Objectives: Linaclotide is a guanylate cyclase-C agonist approved in the United States, Canada, and Mexico at a once-daily 145-μg dose for the treatment of chronic idiopathic constipation (CIC); a once-daily 72-μg dose for CIC recently received FDA approval. The trial objective was to evaluate the efficacy and safety of a 72-μg linaclotide dose in CIC patients.

Methods: This double-blind, placebo-controlled trial randomized patients with CIC (Rome III criteria) to once-daily linaclotide 72 μg or 145 μg, or placebo for 12 weeks. The primary endpoint, 12-week complete spontaneous bowel movement (CSBM) overall responder, required patients to have ≥3 CSBMs and an increase of ≥1 CSBM per week from baseline in the same week for ≥9 of 12 weeks of the treatment period. Secondary endpoints included 12-week change from baseline in bowel (SBM and CSBM frequency, stool consistency, straining) and abdominal (bloating, discomfort) symptoms, monthly CSBM responders, and 12-week CSBM responders among patients who averaged >1 SBM/week at baseline. Sustained response (12-week CSBM overall responders who met weekly criteria for 3 of the 4 final weeks (weeks 9-12) of treatment) was evaluated as an additional endpoint. Adverse events (AEs) were monitored.

Results: The intent-to-treat population included 1,223 patients (mean age=46 years, female=77%, white=71%). The primary endpoint was met by 13.4% of linaclotide 72-μg patients vs. 4.7% of placebo patients (P<0.0001, odds ratio=3.0; statistically significant controlling for multiplicity). Sustained response was achieved by 12.4% of linaclotide 72-μg patients vs. 4.2% of placebo patients (nominal P<0.0001). Linaclotide 72-μg patients met 9-of-10 secondary endpoints vs. placebo (P<0.05; abdominal discomfort, P=0.1028). Patients treated with linaclotide 145 μg also improved CIC symptoms for the primary (12.4%) and sustained responder endpoint parameters (11.4%) and for all 10 of the secondary endpoint parameters including abdominal discomfort (P<0.05). Diarrhea, the most common AE, was mild in most instances and resulted in discontinuation of 0, 2.4%, and 3.2% of patients in the placebo, linaclotide 72-μg, and linaclotide 145-μg groups, respectively.

Conclusions: Once-daily linaclotide 72 μg significantly improved CIC symptoms in both men and women with a low rate of discontinuation due to diarrhea over 12 weeks of treatment.

Conflict of interest statement

Guarantor of the article: Michael L. Hall, MD.

Specific author contributions: A.J.L., B.E.L., P.S., and W.D.C. assisted in the interpretation of data, drafting, and critical revision of the manuscript for important intellectual content; CBK, MGC, MLH, SMF, and WB assisted in the interpretation of the data and critical revision of the manuscript for important intellectual content; CRO’D assisted in the interpretation of the data and drafting of the manuscript; DSR, KT, and RB provided statistical analysis and critical revision of the manuscript for important intellectual content; NDO coordinated acquisition of the data and trial supervision.

Financial support: This trial was funded by Forest Research Institute (an affiliate of Allergan, PLC) and Ironwood Pharmaceuticals, Inc.

Potential competing interests: Kenneth Tripp, David S. Reasner, Nicholas D. Omniewski, Christopher R. O’Dea, Mark G. Currie, and Michael L. Hall are employees of, and own stock/stock options in, Ironwood Pharmaceuticals. Carolyn B. Kurtz is a former employee of, and owns stock/stock option in, Ironwood Pharmaceuticals. Wieslaw Bochenek, Susan M. Fox, and Rick Blakesley are employees of, and own stock/stock options in, Allergan PLC. Philip Schoenfeld, Brian E. Lacy, William D. Chey, and Anthony J. Lembo are paid consultants to Ironwood Pharmaceuticals and Allergan.

Figures

Figure 1

Patient flow through the trial. (a) Patients who signed an informed consent but did not qualify for inclusion into the trial base on their screening visit evaluations. Patients who were re-screened and failed the second time during the screening period were only counted once. (b) Patients who signed an informed consent, entered the baseline period, but were not randomized into the trial. Patients who were re-screened and failed the second time during the baseline period were counted only in the pretreatment failure category. Patients who were re-screened and became randomized are not counted in either of the failure categories. (c) P=0.0123 for the linaclotide 72 μg group and P=0.0002 for the linaclotide 145 μg group vs. placebo (from pairwise comparisons with the placebo group using the Fisher’s exact test). The P-values for all other comparisons were >0.05.

Figure 2

Percent of patients who were 12-week CSBM overall responders (primary endpoint) and sustained responders (additional endpoint). 12-week CSBM overall responder (primary endpoint): ≥3 CSBMs and an increase of ≥1 CSBM per week (weekly CSBM responder) for ≥9 of the 12 weeks of treatment period (P<0.0001 vs. placebo for both 72 μg and 145 μg doses, however only the 72 μg dose was evaluated under the multiple comparisons procedure (MCP)). Placebo, N=401; Linaclotide 72 μg, N=411; Linaclotide 145 μg, N=411. 12-week CSBM sustained responder (additional endpoint): 12-week CSBM overall responder who meets weekly CSBM responder criteria for ≥3 of the final 4 weeks of the treatment period (P=0.0001 and P=0.0010 vs. placebo for the 72 μg and 145 μg doses, respectively; this analysis was not controlled for multiplicity). Placebo, N=401; Linaclotide 72 μg, N=411; Linaclotide 145 μg, N=411. For both presented analyses, P-values were obtained from the CMH tests controlling for baseline SBM stratum and geographic region.

Figure 3

Weekly mean bowel and abdominal symptom scores over the 12-week Treatment Period. Mean CSBMs per week. For linaclotide 72 μg, P<0.001 for Weeks 1–9, P<0.01 for weeks 10–12; for linaclotide 145 μg, P<0.001 for all weeks. Mean stool consistency score by week based on the balanced, seven-point BSFS. For both linaclotide doses, P<0.001 for all weeks. Mean straining score by week based on a 5-point ordinal scale. For both linaclotide doses, P<0.001 for all weeks. Mean abdominal bloating score based on an 11-point NRS. For linaclotide 72 μg, P<0.05 for weeks 2, 4–9, 12; for linaclotide 145 μg, P<0.001 for weeks 3–9, P<0.05 for Weeks 1, 2 and 10–12. For the four presented analyses, P-values for linaclotide vs. placebo were obtained from an ANCOVA model with fixed effect terms for treatment group, baseline SBM stratum, and geographic region, and the baseline value as covariate.