The Effect of Rikkunshito on Gastric Accommodation and Nutrient Volume Tolerance in Functional Dyspepsia

A Placebo-controlled Study on the Effect of Rikkunshito on Gastric Accommodation and Nutrient Volume Tolerance, Quantified by Intragastric Pressure Monitoring During Intragastric Nutrient Infusion, in Functional Dyspepsia

Functional dyspepsia (FD) is a common chronic gastrointestinal (GI) disorder. Rikkunshito, a traditional Japanese Kampo medicine, has shown efficacy in improving FD symptoms in controlled trials in Japan. Its putative benefit for European patients has never been investigated. Further, its exact mechanism of action is incompletely elucidated. This study aimed to examine the effect of rikkunshito on gastric motility and GI symptom perception in FD in a randomized, placebo-controlled, cross-over study. Intragastric pressure (IGP) was assessed using high-resolution manometry as an indirect measurement of gastric accommodation and gastric motility.

Study Overview

• Status: Completed
• Conditions: Dyspepsia
• Intervention / Treatment: Drug: Rikkunshito; Drug: Placebos

Detailed Description

This randomized, placebo-controlled, double-blind, cross-over study had a total duration of 14 weeks, consisting of a two-week run-in period, two treatment phases of four weeks each and a four-week washout period separating the treatment phases to prevent carry-over effects. Study visits were held at baseline (screening) and after the run-in period, treatment phases and washout period.

To assess the effect of rikkunshito on intragastric pressure as an indirect measure for gastric motility, high-resolution manometry (HRM) was performed after the run-in period and after both treatment phases. During intragastric pressure measurement, a nutrient tolerance test was performed and symptom questionnaires were completed. Throughout the entire study, patients scored their gastrointestinal symptoms on a daily basis in the Leuven Postprandial Distress Scale (LPDS) diary. In addition, questionnaires on gastrointestinal symptoms and psychosocial state were completed each study visit.

Safety measures performed each study visit included blood pressure, heart rate and weight assessment, performing an electrocardiogram, adverse event evaluation and physical examination. Furthermore, blood samples were collected during screening and after each treatment phase to check liver and kidney function. Serum levels of potassium, creatine kinase, aspartate aminotransferase, alanine transaminase, alkaline phosphatase and gamma- glutamyltransferase were assessed. Women of childbearing potential were asked to do a pregnancy test before study enrollment and before each treatment period.

• Study Type: Interventional
• Enrollment (Actual): 34
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Vlaams-Brabant
    • Leuven, Vlaams-Brabant, Belgium, 3000
      • UZLeuven

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patients with FD-postprandial distress syndrome subtype diagnosis as per Rome IV
2. Patients must provide witnessed written informed consent prior to any study procedures being performed
3. Patients aged between 18 and 75 years inclusive
4. Male or female patients. Women of child-bearing potential agree to apply during the entire duration of the trial a highly effective method of birth control, which is defined as those which result in a low failure rate (i.e., less than 1% per year) when used constantly and correctly such as implants, injectables, combined oral contraceptive method, or some intrauterine devices (IUDs), sexual abstinence, or vasectomized partner. Women of non-childbearing potential may be included if surgically sterile (tubal ligation or hysterectomy) or postmenopausal with at least 2 year without spontaneous menses.
5. Patients who are capable to understand the study and the questionnaires, and to comply with the study requirements

Exclusion Criteria:

1. Patients with any condition which, in the opinion of the investigator, makes the patient unsuitable for entry into the study
2. Patients with an active major psychiatric condition (depression, anxiety disorder, alcohol or substance abuse). However, patients who are taking a stable dose of a single antidepressant (with the exception of amitryptiline and mirtazapine which are forbidden) during the last 3 months are eligible.
3. Females who are pregnant or lactating. Females who refuse to take appropriate contraception at the time of informed consent.
4. Men who want to donate sperm during the study and during the 4 weeks after stopping Rikkunshito.
5. Patients who received treatment for Helicobacter Pylori (HP) eradication during the last 3 months. Patients who are HP positive may enter the study provided that their endoscopy is negative. If HP status is unknown, determination of HP status will be done during run-in.
6. Patients suffering from diabetes type 1 or type 2.
7. Patients taking drugs affecting the gut secretion, mucosal integrity (non-steroidal anti-inflammatory drugs (NSAIDs), with an exception for aspirin at cardioprotective dose of max 125 mg daily), motility, and/or sensitivity. Patients taking proton pump inhibitors (PPIs) are eligible provided that FD is predominant and heartburn limited to maximum two episodes of mild intensity per week.
8. Patients with coronary heart disease, arrhythmias or taking concomitant drugs capable to prolong the QT.
9. Patients taking concomitant drugs able to induce drug-drug interaction (P450), Concomitant drugs interacting substantially with the different fractions of cytochromes (CYP3A4 and others) and with strong protein binding (Albumine, i-globulins, acid glycoproteins) are excluded.
10. Patients with a significant renal [serum creatinine >2 x upper limit of normal (ULN)], hepatic [alanine transaminase (ALT), aspartate transaminase (AST), gamma glutamyltransferase (GGT), bilirubin >2 x ULN], cardiovascular, pulmonary, endocrine, metabolic or haematological condition.
11. Patients with known hypersensitivity to the Ginseng or Ginger.
12. Patients with confirmed gastro-intestinal disease.
13. Patients with former digestive surgery affecting upper gut motility.
14. Patients affected by concomitant extra-digestive disease responsible for digestive symptoms.
15. Patients presenting with predominant symptoms of irritable bowel syndrome (IBS).
16. Patients presenting symptoms of epigastric pain syndrome (EPS) several times a week, not related to meals, according to Rome III questionnaire (score 5 or higher on question 10, in combination with clinical judgement).
17. Patients presenting daily symptoms of nausea syndrome, not related to meals, on Rome III questionnaire (score 6 on question 6 or score 5 or higher on question 9).
18. Patients presenting vomiting more than one day a month.
19. Patients presenting daily symptoms of Excessive belching according to Rome III questionnaire (score 6 on question 19, in combination with clinical judgement).
20. Patients presenting predominant gastro-esophageal reflux disease (GERD) (3 "yes" by GERD questionnaire, in combination with clinical judgement).
21. Patients not willing to take ultraviolet protective measures or patients at increased risk for phototoxicity (use of drugs like tetracyclins, amiodarone, sulphonamides, quinolones).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Rikkunshito; Rikkunshito: 2,5g dissolved in 200 mL lukewarm water, three times daily, 30min before meal intake	Drug: Rikkunshito; Rikkunshito, 2,5g dissolved in 200 mL lukewarm water, three times daily, 30min before meal intake; Other Names: TJ-43
Placebo Comparator: Placebo; Placebo: 2,5g dissolved in 200 mL lukewarm water, three times daily, 30min before meal intake	Drug: Placebos; Placebo, 2,5g dissolved in 200 mL lukewarm water, three times daily, 30min before meal intake

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gastric pressure	Contractions of the stomach and relaxation of the stomach upon food intake	Gastric pressure was measured until 2 hours after the start of the liquid meal. Liquid meal started 30 minutes after rikkunshito/placebo intake

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gastrointestinal symptoms during gastric pressure measurement	Change in subjective gastrointestinal symptom scores measured by visual analogue scale of 100 mm	every 5 minutes, up to 2 hours after administration of the liquid meal
Gastrointestinal symptoms during treatment period	change in subjective gastrointestinal symptom scores throughout both treatment arms	On a daily basis throughout the 4-week treatment arms

Collaborators and Investigators

• Sponsor: Universitaire Ziekenhuizen KU Leuven
• Collaborators: Tsumura and Company, Tokyo, Japan

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2015
• Primary Completion (Actual): October 1, 2018
• Study Completion (Actual): October 1, 2018

Study Registration Dates

• First Submitted: February 25, 2019
• First Submitted That Met QC Criteria: February 25, 2019
• First Posted (Actual): February 27, 2019

Study Record Updates

• Last Update Posted (Actual): March 1, 2019
• Last Update Submitted That Met QC Criteria: February 27, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Keywords: functional dyspepsia; gastric motility; functional dyspepsia symptoms
• Additional Relevant MeSH Terms: Signs and Symptoms, Digestive; Dyspepsia
• Other Study ID Numbers: Rikkunshito1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No