Efficacy and safety of a crystalline lactulose preparation (SK-1202) in Japanese patients with chronic constipation: a randomized, double-blind, placebo-controlled, dose-finding study

Kunio Kasugai,Aya Yoshikawa,Noboru Kuboyama,Shin Fukudo,Hisakazu Iwai

doi:10.1007/s00535-018-01545-7

Abstract

BackgroundClinical evidence of lactulose for chronic constipation in Japan was lacking. We performed a randomized, double-blind, placebo-controlled, dose-finding study in Japanese patients with chronic constipation to estimate the optimal clinical dose of lactulose.MethodsOverall, 250 patients were randomized to receive SK-1202 (13, 26, or 39 g/day, as crystalline lactulose dosage) or placebo twice daily (morning and evening) orally for 2 weeks. The primary endpoint was the change from baseline frequency of spontaneous bowel movements (SBMs) at Week 1. The secondary endpoints included the change from baseline of SBMs at Week 2, percentage of patients experiencing SBM within 24 and/or 48 h of the initial dose, stool consistency, and constipation severity, and adverse events were also evaluated.ResultsThe 26 and 39 g/day of SK-1202 induced significantly and dose-dependently more increase in SBM at Week 1 than placebo (p = 0.003, p < 0.001). These groups also showed significant improvements in the secondary endpoints. There were no significant differences in the incidence of adverse drug reactions (ADRs) between the placebo and SK-1202 groups. Gastrointestinal disorder was the most common ADR, and diarrhea developed in 6 patients (9.7%) treated with 39 g/day; however, the symptoms were mild in severity and resolved after follow-up, dose reduction, or dose suspension. SK-1202 was generally well tolerated up to 39 g/day.ConclusionOur results suggest that SK-1202 is useful in Japanese patients with chronic constipation, and optimal dose of SK-1202 is 26 g/day.

Highlights

Lactulose is a synthetic disaccharide composed of fructose and galactose
Our results suggest that SK-1202 is useful in Japanese patients with chronic constipation, and optimal dose of SK-1202 is 26 g/day
The change from baseline spontaneous bowel movements (SBMs) frequency at Week 1, the primary endpoint, was summarized group-wise using descriptive statistics, and pairwise comparisons between each SK-1202-treated group and the placebo group were performed from the highest dose group to the lowest dose group according to the closed testing procedure, using an analysis of covariance (ANCOVA) model including the baseline SBM frequency as a covariate

Summary

Introduction

Lactulose is a synthetic disaccharide composed of fructose and galactose. Orally administered lactulose reaches the lower gastrointestinal tract unchanged, where lactulose increases the retention of water and electrolytes by its osmotic effect. In Japan, the ‘‘Evidence-based clinical practice guideline for chronic constipation 2017’’ strongly recommended to use osmotic laxatives including lactulose with high level (A) of evidence [6]. Lactulose preparations, such as MonilacÒ (syrup/powder), have been marketed in Japan since 1979 for the treatment of pediatric constipation and to induce bowel movement/flatus expulsion after gynecological surgery. Placebo-controlled, double-blind, parallel-group study of the SK-1202 formulation containing crystalline lactulose as an active ingredient in Japanese adult patients with chronic constipation to evaluate the efficacy and safety of the drug administered twice daily for 2 weeks and to determine the optimal dose for Japanese adult patients

Methods

Study design

Results

Discussion

Compliance with ethical standards