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Investigator-initiated phase II trial to evaluate the efficacy and safety of Acotiamide in patients with esophagogastric junction outflow obstruction

Investigator-initiated phase II trial to evaluate the efficacy and safety of Acotiamide in patients with esophagogastric junction outflow obstruction

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The study was conducted on patients with esophagogastric junction outflow obstruction (EGJOO). The subjects were 13 males and 22 females, with a larger number of females, and the proportion of females was high in all dosage groups. The median age was 64.0 years. In terms of basal lower esophageal sphincter pressure (BLESP) categories, for " less than/greater than or equal to 35 mmHg", the placebo group and 300 mg/day group were higher in the "less than 35 mmHg" category (63.6% and 58.3% respectively), while the 600 mg/day group was higher in the "greater than or equal to 35 mmHg" category (75.0%). For "less than/greater than 40 mmHg", the placebo group and 300 mg/day group were higher in the "less than 40 mmHg" category (72.7% and 58.3% respectively), while the 600 mg/day group was higher in the "greater than or equal to 40 mmHg" category (58.3%).

A total of 35 subjects were enrolled and randomly assigned, with 11 in the placebo group, 12 in the 300 mg/day group, and 12 in the 600 mg/day group. The investigational drug was administered to all 35 subjects, and all were included in the SAS, FAS, and PPS analyses. All 35 subjects completed treatment period 1. No subjects were judged to have symptoms that "disappeared" at the end of treatment period 1, therefore all 35 subjects proceeded to treatment period 2 and were administered acotiamide 600 mg/day. In treatment period 2, one subject (from the placebo group) discontinued, and 34 subjects completed treatment period 2 and the post-observation period.

Adverse drug reactions included one case each of dizziness and eczema, and the severity of both was moderate and considered non-serious. Serious adverse events included one case each of gastroenteritis and injury, and these events occurred outside the treatment period and were judged to have no causal relationship with the investigational drug. There were no deaths in this study.

The proportion of patients with improved sensation of food sticking in the chest at Week 4 of treatment period 1, which was the primary endpoint of this study, was as follows: 0.0% (0/11) in the placebo group and 12.5% (3/24) in the acotiamide group (combining 300 mg/day and 600 mg/day groups, hereinafter the same). The inter-group difference (90% confidence interval) was 12.5% (-8.6%, 27.5%), and the p-value was 0.3092, indicating no statistically significant difference (Fisher's exact test, one-sided significance level of 5%). In the 300 mg/day group, 8.3% (1/12) showed improvement, and in the 600 mg/day group, 16.7% (2/12) showed improvement. The inter-group difference in improvement rate between the 300 mg/day and 600 mg/day groups (90% confidence interval) was 8.3% (-16.1%, 32.5%). Due to the closed testing procedure, a comparison between the 300 mg/day and 600 mg/day groups was not conducted. The results of the secondary endpoints were as follows: The normalization rate of integrated relaxation pressure (IRP) at Week 4 of treatment period 1 was 0.0% (0/11) in the placebo group, 41.7% (10/24) in the acotiamide group, 50.0% (6/12) in the 300 mg/day group, and 33.3% (4/12) in the 600 mg/day group. The inter-group difference in normalization rate between the placebo and acotiamide groups (90% confidence interval) was 41.7% (17.0%, 58.2%), which was statistically significant (p=0.0107, Fisher's exact test, one-sided significance level of 5%). Regarding the change in basal lower esophageal sphincter pressure (BLESP) score at Week 4 of treatment period 1, the least squares mean inter-group difference between the placebo and acotiamide groups (90% confidence interval) was -14.30 (-25.22, -3.39) mmHg, showing a statistically significant difference between the placebo and acotiamide groups (p=0.0168).

In EGJOO patients, oral acotiamide (300 mg/day or 600 mg/day for 4 weeks) did not show a statistically significant difference from placebo in the primary endpoint of dysphagia. However, a significant difference was observed in the objective indicator of IRP normalization rate. Although treatment duration, dosage, and evaluation metrics warrant further investigation, these findings suggest potential efficacy. All observed adverse drug reactions were known events, with no clinically problematic occurrences.

Feb. 16, 2026

https://link.springer.com/article/10.1007/s10388-026-01190-7

No

https://jrct.mhlw.go.jp/latest-detail/jRCT2071210072

Ihara Eikichi

Kyushu University Hospital

3-1-1 Maidashi Higashi-ku Fukuoka 812-8582,Japan

ihara.eikichi.167@m.kyushu-u.ac.jp

Toyosaki Kayo

Kyushu University Hospital

3-1-1 Maidashi Higashi-ku Fukuoka 812-8582,Japan

+81-92-642-6290

toyosaki.kayo.844@m.kyushu-u.ac.jp

Complete

Oct. 15, 2021

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

1) Patients over the age of 20 at the time of consent.
2) Patients diagnosed as EGJOO by HRM according to Chicago Classification ver3.0.
3) Patients who have been experiencing sensation of food sticking in chest for at least one month prior to the time of consent, and have a score of 2 ("symptomatic and slightly troubled") or higher on at least one evaluation of food sticking symptoms during the previous week of observation.
4) Patients who have undergone esophagogastroduodenoscopy and esophagography, and have been excluded from other organic diseases that may cause symptoms(e.g.reflux esophagitis, eosinophilic esophagitis, gastric ulcer, etc.) .
5) Patients who understand the contents of the clinical trial and have given written consent of their own free will.

1) Patients with clinically evident hepatic dysfunction (AST or ALT in the previous observation period is three times or more than the upper limit of the institutional standard range)
2) Patients with severe renal dysfunction or renal insufficiency (creatinine clearance of less than 30 mL/min in the previous observation period)
3) Patients with a history of hypersensitivity to any component of the investigational drug
4) Patients who have taken acotiamide orally in the month prior to obtaining consent
5) Patients with concomitant malignancy. However, patients with completely resected basal cell carcinoma, Stage I spinous cell carcinoma, intraepithelial carcinoma, intramucosal carcinoma, or superficial bladder cancer may be included the study.
6) Patients with frequent irregular dietary habits, such as not eating or binge drinking/eating.
7) Patients with a history of upper gastrointestinal surgery. However, surgeries related to endoscopic treatment including endoscopic polypectomy, endoscopic mucosal resection and endoscopic submucosal dissection are excluded.
8) Patients who have participated in other clinical trials or clinical studies, and used or are using investigational drugs, devices, or products during the 3 months prior to obtaining consent.
9) Patients with serious cardiac or hematological diseases.
10) Patients with serious drug allergies
11) Female patients who are pregnant, lactating, or of childbearing potential
12) Patients who refuse to use appropriate contraceptive methods during the study period.
13) Patients who are judged by the principal investigator or sub-investigator to be inappropriate for the study.

Both

Esophageal Gastric Junction Outflow Obstruction

Therapeutic intervention by oral medication(Treatment Period 1:acotiamide 300 mg per day or 600 mg per day or placebo, Treatment Period 2:acotiamide 600 mg per day) is carried out after baseline screening. The safety is confirmed after the end of therapeutic intervention.

Esophageal Gastric Junction Outflow Obstruction

D004931

The proportion of patients with improvement in sensation of food sticking in chest at 4 weeks in treatment period 1

<1>The following items at 4 weeks of Treatment Period 1
1) Rate of normalization of IRP by HRM from baseline
2) Change from baseline in the score of patients with improvement in sensation of food sticking in chest
3) Change in EGJOO scale score from baseline (total score, each score)
4) Change in Gastrointestinal Symptom Rating Scale (GSRS) score from baseline (total score, subscale score)
5) Amount of change in following parameters by HRM
i)Distal Contractile Integral (DCI)
ii)Basal Lower esophageal sphincter pressure(BLESP)

<2>Correlation of IRP with sensation of food sticking in chest, EGJOO scale (total score, each score), and GSRS (total score, subscale score) at 4 weeks in Treatment Period 1 and Treatment Period 2

<3>Proportion of adverse events, adverse drug reactions

+81-92-642-5774

June. 28, 2021

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