Dataset Information

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.

ABSTRACT:

Background

Clinical 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.

Methods

Overall, 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.

Results

The 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?ConclusionOur results suggest that SK-1202 is useful in Japanese patients with chronic constipation, and optimal dose of SK-1202 is 26 g/day.

SUBMITTER: Kasugai K

PROVIDER: S-EPMC6536483 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Publications

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.

Kasugai Kunio K Iwai Hisakazu H Kuboyama Noboru N Yoshikawa Aya A Fukudo Shin S

Journal of gastroenterology 20190114 6

<h4>Background</h4>Clinical 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.<h4>Methods</h4>Overall, 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 cha ...[more]

PMID: 30643982

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Project description:BACKGROUND:Alzheimer's disease (AD) is characterized by early and region-specific declines in cerebral glucose metabolism. Ketone bodies are produced by the body during glucose deprivation and are metabolized by the brain. An oral ketogenic compound, AC-1202, was tested in subjects with probable AD to examine if ketosis could improve cognitive performance. METHODS:Daily administration of AC-1202 was evaluated in 152 subjects diagnosed with mild to moderate AD in a US-based, 90-day, randomized, double-blind, placebo-controlled, parallel-group study. Subjects were on a normal diet and continued taking approved AD medications. Primary cognitive end points were mean change from Baseline in the AD Assessment Scale-Cognitive subscale (ADAS-Cog), and global scores in the AD Cooperative Study - Clinical Global Impression of Change (ADCS-CGIC). AC-1202 was compared to Placebo in several population groups, including: intention-to-treat (ITT), per protocol, and dosage compliant groups. Results were also stratified by APOE4 carriage status (a predefined analysis based on the epsilon 4 (E4) variant of the apolipoprotein E gene). This trial was registered with ClinicalTrials.gov, registry number NCT00142805, information available at http://clinicaltrials.gov/ct2/show/NCT00142805 RESULTS:AC-1202 significantly elevated a serum ketone body (beta-hydroxybutyrate) 2 hours after administration when compared to Placebo. In each of the population groups, a significant difference was found between AC-1202 and Placebo in mean change from Baseline in ADAS-Cog score on Day 45: 1.9 point difference, p = 0.0235 in ITT; 2.53 point difference, p = 0.0324 in per protocol; 2.6 point difference, p = 0.0215 in dosage compliant. Among participants who did not carry the APOE4 allele (E4(-)), a significant difference was found between AC-1202 and Placebo in mean change from Baseline in ADAS-Cog score on Day 45 and Day 90. In the ITT population, E4(-) participants (N = 55) administered AC-1202 had a significant 4.77 point difference in mean change from Baseline in ADAS-Cog scores at Day 45 (p = 0.0005) and a 3.36 point difference at Day 90 (p = 0.0148) compared to Placebo. In the per protocol population, E4(-) participants receiving AC-1202 (N = 37) differed from placebo by 5.73 points at Day 45 (p = 0.0027) and by 4.39 points at Day 90 (p = 0.0143). In the dosage compliant population, E4(-) participants receiving AC-1202 differed from placebo by 6.26 points at Day 45 (p = 0.0011, N = 38) and 5.33 points at Day 90 (p = 0.0063, N = 35). Furthermore, a significant pharmacologic response was observed between serum beta-hydroxybutyrate levels and change in ADAS-Cog scores in E4(-) subjects at Day 90 (p = 0.008). Adverse events occurred more frequently in AC-1202 subjects, were primarily restricted to the gastrointestinal system, and were mainly mild to moderate in severity and transient in nature. CONCLUSION:AC-1202 rapidly elevated serum ketone bodies in AD patients and resulted in significant differences in ADAS-Cog scores compared to the Placebo. Effects were most notable in APOE4(-) subjects who were dosage compliant.

Project description:OBJECTIVES:Linaclotide is a guanylate cyclase-C agonist approved in the United States, Canada, and Mexico at a once-daily 145-?g dose for the treatment of chronic idiopathic constipation (CIC); a once-daily 72-?g dose for CIC recently received FDA approval. The trial objective was to evaluate the efficacy and safety of a 72-?g linaclotide dose in CIC patients. METHODS:This double-blind, placebo-controlled trial randomized patients with CIC (Rome III criteria) to once-daily linaclotide 72??g or 145??g, 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-?g 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-?g patients vs. 4.2% of placebo patients (nominal P<0.0001). Linaclotide 72-?g patients met 9-of-10 secondary endpoints vs. placebo (P<0.05; abdominal discomfort, P=0.1028). Patients treated with linaclotide 145??g 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-?g, and linaclotide 145-?g groups, respectively. CONCLUSIONS:Once-daily linaclotide 72??g significantly improved CIC symptoms in both men and women with a low rate of discontinuation due to diarrhea over 12 weeks of treatment.

Dataset Information

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.

Background

Methods

Results

Publications

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.

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