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.

• Authors: Philip Schoenfeld, Brian E Lacy, William D Chey, Anthony J Lembo, Caroline B Kurtz, David S Reasner, Wieslaw Bochenek, Kenneth Tripp, Mark G Currie, Susan M Fox, Rick E Blakesley, Christopher R OʼDea, Nicholas D Omniewski, Michael L Hall
• Journal: The American journal of gastroenterology (Am J Gastroenterol) Vol. 113 Issue 1 Pg. 105-114 (01 2018) ISSN: 1572-0241 [Electronic] United States
• PMID: 29091082 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Guanylyl Cyclase C Agonists
• Peptides
• linaclotide

Topics

• Adult
• Aged
• Chronic Disease
• Constipation (drug therapy)
• Defecation
• Diarrhea (chemically induced)
• Double-Blind Method
• Female
• Guanylyl Cyclase C Agonists (administration & dosage, therapeutic use)
• Humans
• Male
• Medication Adherence
• Middle Aged
• Peptides (administration & dosage, therapeutic use)
• Treatment Outcome