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Single-center, randomized, double-blind, placebo-controlled parallel-group comparative study to evaluate the effects of Elobixibat on rectal sensory threshold in patients with chronic constipation over 60 years of age

Effects of Elobixibat on rectal visceral perception in constipated patients over 60 years of age

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The baseline characteristics for the FAS (Full Analysis Set) population were as follows. [Elobixibat group] Number of subjects: 9 Sex: male 5 (55.6%) / female 4 (44.4%) Age: 69.0 (66.0 to 73.0) Median (Inter-Quartile Range) Duration of chronic constipation (years) : 30.0 (5.5 to 45.0) Number of Spontaneous Bowel Movement: 2.80 (2.00 to 4.20) [Placebo group] Number of subjects: 8 Sex: male 4 (50.0%) / female 4 (50.0%) Age: 67.0 (64.0 to 69.0) Duration of chronic constipation (years) : 8.0 (3.5 to 23.0) Number of Spontaneous Bowel Movement: 3.50 (1.70 to 4.43) [Healthy adult group] Number of subjects: 9 Sex: male 7 (77.8%) / female 2 (22.2%) Age: 66.0 (63.0 to 71.0)

In this study, written informed consent was obtained from 24 chronic constipation patients and 11 healthy adults. Ten chronic constipation patients (41.7%) were enrolled in the elobixibat group,10 (41.7%) in the placebo group, and 10 healthy adults (90.9%) in the healthy adult group. All subjects completed the study without dropping out. Of the enrolled subjects, 9/10 (90.0%) in the elobixibat group, 8/10 (80.0%) in the placebo group, and 9/10 (90.0%) in the healthy adult group were adopted as FAS and Safety Analysis Set. Excluding one patient in the elobixibat group (rescue drug use within 24 hours of the rectal sensory threshold test) from the FAS, the subjects were adopted into the PPS (Per Protocol Set). Of the enrolled patients, those who were not adopted into the FAS or the Safety Analysis Set were serious nonconformance subjects. Who violated selection criterion 4 (one healthy adult) for provisional enrollment or exclusion criteria 10 (one case in the elobixibat group) or 11 (two cases in the placebo group) for enrollment. In addition to the patients who were not adopted into the PPS, there was one noncompliant patient in the elobixibat group who used rescue medication within 24 hours of the rectal sensory threshold test (one patient in the elobixibat group).

No disease or the like occurred in this study.

The main results in FAS were as follows. The change (mean +- SD) in rectal defecatory urge sensory threshold from the time of enrollment to the time of the 1-week visit/discontinuation (before and after administration, same applies hereafter) is -15.2 +- 19.0 mL in the elobixibat group (p = 0.0433; paired t-test) and 0.8 +- 18.8 mL in the placebo group (p = 0.9131; paired t-test), only the elobixibat group showed statistically significant reductions. The inter-group difference [estimated value (95% CI) ] in the amount of change in rectal defecatory urge sensory threshold before and after administration, which was the main analysis, was -15.8 (-34.05, 2.46) mL (p = 0.0899; ANCOVA) , and no statistically significant change was observed. In the secondary endpoints, there was a statistically significant decrease in rectal minimal tolerated threshold in the elobixibat group after administration, and the amount of change was significantly greater in the elobixibat group than in the placebo group. Rectal sensory threshold maximum tolerated threshold were greatly reduced in the elobixibat group, but there were no statistically significant differences between the elobixibat and placebo groups. In terms of fecal bile acids, there was a statistically significant increase in deoxycholic acid, total bile acids, and secondary bile acids in the elobixibat group after administration. Change in frequency of Spontaneous Bowel Movement during the observation period and 1 week after administration increase in spontaneous defecation frequency in both groups, and statistically significant, but there was no statistically significant difference between the elobixibat group and the placebo group in the amount of change. There was no statistically significant difference in each rectal sensory threshold between healthy adults and chronic constipation patients before administration.

Administration of patients with chronic constipation with elobixibat decreased the rectal sensory threshold and increased stool bile acids, suggesting that it may improve rectal sensation.

Jan. 31, 2024

Nov. 22, 2023

https://bmjopengastro.bmj.com/content/10/1/e001257.long

No

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https://jrct.mhlw.go.jp/latest-detail/jRCTs061200030

Manabe Noriaki

Kawasaki Medical School General Medical Center

2-6-1, Nakasange, Kita-ku, Okayama-City, Okayama

n_manabe@hkg.odn.ne.jp

Manabe Noriaki

Kawasaki Medical School General Medical Center

2-6-1, Nakasange, Kita-ku, Okayama-City, Okayama

+81-86-225-2111

n_manabe@hkg.odn.ne.jp

Complete

Dec. 01, 2020

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

Subjects who meet every those following criteria.

Patients with chronic constipation:
<At the time of temporary registration>
1)Patients who meet every those following criteria
Subjects who have had subjective symptoms of chronic constipation for more than 6 months and have met the following criteria for the last 3 months.
1. There are two or more of the following symptoms.
-Straining among more than 25% of defecations.
-Feeling of obstruction or a feeling of fullness of the rectal anus more than 25% of defecations.
-Scybalum or hard stool among more than 25% of defecations.
-Manual maneuvers to facilitate more than 25% of defecations (stool extraction, Oppression the pelvic floor, etc.).
-Feeling of unsatisfied defecation among more than 25% of defecations.
-Defecation less than three times a week.
2. Soft stool rarely occurs when laxatives are not used.
3. Does not meet the criteria for irritable bowel syndrome (IBS).
2) Age : Over 60 years at the time of informed consent.
3) Ability to provide written informed consent.

Healthy adult subjects :
<At the time of temporary registration>
1) Subjects who have bowel movements almost every day from more than 6 months prior to informed consent.
2) Age : Over 60 years at the time of informed consent
3) Ability to provide written informed consent
4) No comorbidities

Subjects who meet any of the following criteria are not included.

Patients with chronic constipation:
<At the time of temporary registration>
1) Patients with or suspected organic constipation, outlet obstruction type constipation
2) Patients with suspected biliary obstruction or decreased bile secretion
3) Patients who not able to use rescue medication (Bisacodyl suppositories 10 mg)
4) Patients with malignant tumor
5) Patients with a medical history of hypersensitivity to Elobixibat.
6) Patients who are taking bile acid preparations (ursodeoxycholic acid, chenodeoxycholic acid), aluminum-containing preparations (sucralfate hydrate, aldioxa, etc.), cholestyramine, colestimide, digoxin, Dabigatran etexilate methanesulfonate, or midazolam
7) Patients who were considered as ineligible by the investigator/sub-investigator for any other reasons
8) Patients who have serious disease related to the kidney (creatinine>=2.00 mg/dL)or the liver (total bilirubin >=3.0 mg/dL or AST or ALT >=100 U/L) or the heart at the time of Visit-1

<At the time of registration>
9) Patients who used the rescue medication(Bisacodyl suppositories 10 mg) over three times during the 1-week observation period
10) Patients who used the rescue medication less than 72 hours after bowel movement during the 1-week observation period
11) Patients with soft stool or watery stool (Bristol Stool Form Scale type 6 or 7) due to spontaneous evacuation of stool, during the 1-week observation period
12)Patients who used prohibited medications and prohibited therapies during the 1-week observation period

Healthy adult subjects :
<At the time of temporary registration/registration>
1) Subjects who have serious disease related to the kidney (creatinine>=2.00 mg/dL)or the liver (total bilirubin >=3.0 mg/dL or AST or ALT >=100 U/L) or the heart at inspection within the past 1 year
2) Subjects who were considered as ineligible by the investigator/sub-investigator for any other reasons

<At the time of registration>
3) Subjects who recorded at least twice soft stool or watery stool (Bristol Stool Form Scale type 6 or 7) due to spontaneous evacuation of stool, during the 1-week observation period
4) Subjects who have fewer than 5 bowel movements during the 1-week observation period

Both

chronic constipation

Randomized administration of Elobixibat or placebo as study drug

chronic constipation

Elobixibat

Change in rectal defecatory urge sensory threshold (at 1-week: ml) from before administration

- Change in rectal sensory threshold, Minimum, and Maximum tolerated threshold (at 1-week: ml) from before administration
-Change in rectal sensory threshold, Minimum, Defecatory urge and Maximum tolerated threshold (at 1-week: mmHg) from before administration
-Change in percentage of rectal Minimum, Defecatory urge and Maximum tolerated threshold to rectal capacity (1 week:%) from before administration
-Change in Rectal Compliance (mL / mmHg) from before administration
-Comparison of Rectal Compliance (mL / mmHg) between healthy adults and chronic constipation patients
-Change in frequency of Spontaneous Bowel Movement (1 week: times / week) from observation period
- Change in frequency of complete Spontaneous Bowel Movement (1 week: times / week) from observation period
- Bristol Stool Form Scale
- Comparison of Rectal Sensory Threshold Test Values between Healthy Adults and Chronic Constipation Patients
- Use of rescue medication
-Changes in distribution of stool and gas by abdominal ultrasonography
- Fecal bile acid
- Subpopulation analysis by background factors
- Pattern of dosage increase or decrease
- Defecation desire due to subjective symptoms

+81-86-464-1547

Nov. 02, 2020

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