Functional Dyspepsia
Conditions
Keywords
Rikkunshito, Double blind, Functional dyspepsia (FD)
Brief summary
The purpose of this study is to assess the efficacy and safety of Rikkunshito compared to placebo in Japanese subjects with Functional Dyspepsia (FD).
Interventions
DRUGRikkunshito
\- Oral administration of rikkunshito (2.5 g t.i.d) before meals for 8 weeks
DRUGRikkunshito placebo
\- Oral administration of rikkunshito placebo (2.5 g t.i.d) before meals for 8 weeks
Sponsors
Osaka City University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* -Patients diagnosed with FD according to the ROME III criteria i) Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to obtaining informed consent ii) Have not received upper endoscopy within the last 6 months prior to enrollment and do not have evidence of structural/organic disease iii) Must have one or more of the following symptoms: 1. Bothersome postprandial fullness 2. Early satiation 3. Epigastric pain 4. Epigastric burning * At least one of the FD-related symptoms on the Global Overall Symptom (GOS) scale (bothersome postprandial fullness, early satiation, epigastric pain, epigastric burning) is ≥4, whereas heartburn is ≤3. * Total score of depression-related symptoms on Hospital Anxiety and Depression Score (HAD) is ≤10. * Type of visit: Outpatient * Provides voluntary informed consent after receiving adequate explanation and demonstrates thorough understanding of the nature of the study.
Exclusion criteria
* Confirmed ulcer (excluding scars) or malignant tumor in the upper GI * Suspected organic lesions in the hepato-biliary-pancreatic regions such as cholelithiasis, hepatitis, pancreatitis * History of upper GI resection * Serious complications (liver, kidney, heart, or blood disease or metabolic disease) * Less than a year since testing positive for H. pylori or have undergone a successful eradication therapy * Use of prohibited medications * Neuropsychiatric disorders * Use of or planned use of any investigational drugs * Unable to take drugs orally * History of allergic reactions to Kampo medicines * Pregnant or lactating women or those who are planning to conceive during the study period * Deemed ineligible by principal investigator or sub-investigator
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Patient's Evaluation of Symptomatic Improvement by Overall Treatment Efficacy (OTE) | 8 weeks | Patient's Evaluation of Symptomatic Improvement by OTE is classified into the following 7 categories: 1. Significantly improved 2. Improved 3. Slightly improved 4. No change 5. Slightly worse 6. Worse 7. Much worse The numbers of patients at the final evaluation (i.e, the latest evaluable time point of the all patients including discontinued patients) are shown by category. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Modified Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease (GERD) (Modified FSSG) | Baseline and Week 8 | The modified FSSG questionnaire is composed of 7 questions regarding GERD symptoms (Questions 1-7, scored from 0 to 4) ranging between 0-28, lower value represents a better outcome, and 7 questions regarding dyspeptic symptoms (Questions 8-14, each question scored from 0 to 4) ranging between 0-28, lower value represents a better outcome, and a total scores, ranging from 0 to 56, lower value represents a better outcome of the all questions (Questions 1-14). Each question was assigned a score based on the frequency of symptoms. The point scores of modified FSSG are calculated from changes from baseline in each score for all symptoms (sum of point scores from Questions 1-14), GERD symptoms, and dyspeptic symptoms at final evaluation. |
| Change From Baseline in the Patient Assessment of Upper Gastrointestinal Symptom Severity Index (PAGI-SYM) | Baseline and Week 8 | PAGI-SYM questionnaire is composed of the following 6 categories that consisted of Questions 1 to 20 (each question composed of 6 subscales, i.e., point scores from 0 to 5, lower value represents a better outcome). Subscale scores are calculated by averaging across items in each category. A total score (lower value represents a better outcome, ranging from 0 to 5) is calculated as the mean of the subscale scores. Heartburn/Regurgitation, Nausea/Vomiting, Postprandial Fullness/Early satiety, Bloating, Upper Abdominal Pain, and Lower Abdominal Pain The point scores of PAGI-SYM are calculated from changes from baseline in total score and each category score at final evaluation. |
| Change From Baseline in Global Overall Symptom (GOS) | Baseline and Week 8 | The GOS scale are calculated by a total score of a 7-point Likert scale ranging from 1 = no problem to 7 = a very severe problem over 8 questions. The point scores of GOS are calculated from changes from baseline at final evaluation. |
| Change From Baseline in Short-form Health Survey-8 (SF-8) | Baseline and week 8 | The SF-8 scores comprised of Physical component summary (PCS) scores (ranging between 5.32-70.69, higher value represents a better outcome) and Mental component summary (MCS) scores (ranging between 10.11-74.51, higher value represents a better outcome), and a total scores of PCS and MCS using a formula specified in SF-8 Scoring Algorithm. The point scores of SF-8 are calculated from changes from baseline in PCS and MCS at final evaluation. |
| Change From Baseline in Hospital Anxiety and Depression Scale (HAD) | Baseline and week 8 | The HAD is a 14-item scale with 2 subscales of depression (Question 1, 3, 5, 7, 9, 11, and 13) and anxiety (Question 2, 4, 6, 8, 10, 12, and 14). Each item on the questionnaire is scored from 0 to 3 (ranging from 0 to 21, lower value represents a better outcome). The point scores of HAD are calculated from changes from baseline in overall (sum of scores for depression and anxiety, i.e., total point score ranging from 0 to 42, lower value represents a better outcome), depression, and anxiety at final evaluation. |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Rikkunshito Placebo Rikkunshito placebo: - Oral administration of rikkunshito placebo (2.5 g t.i.d) before meals for 8 weeks | 61 |
| Rikkunshito Rikkunshito: - Oral administration of rikkunshito (2.5 g t.i.d) before meals for 8 weeks | 64 |
| Total | 125 |
Baseline characteristics
| Characteristic | Rikkunshito Placebo | Rikkunshito | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 12 Participants | 11 Participants | 23 Participants |
| Age, Categorical Between 18 and 65 years | 49 Participants | 53 Participants | 102 Participants |
| Age, Continuous Age | 50.4 years STANDARD_DEVIATION 13.7 | 50.4 years STANDARD_DEVIATION 14.9 | 50.4 years STANDARD_DEVIATION 14.3 |
| Duration of FD ≥1 year | 42 Participants | 40 Participants | 82 Participants |
| Duration of FD ≥6 months to <1 year | 19 Participants | 24 Participants | 43 Participants |
| Region of Enrollment Japan | 61 Participants | 64 Participants | 125 Participants |
| Sex: Female, Male Female | 47 Participants | 42 Participants | 89 Participants |
| Sex: Female, Male Male | 14 Participants | 22 Participants | 36 Participants |
| Subtype of functional dyspepsia (FD) Both | 20 Participants | 14 Participants | 34 Participants |
| Subtype of functional dyspepsia (FD) Epigastric pain syndrome (EPS) | 18 Participants | 24 Participants | 42 Participants |
| Subtype of functional dyspepsia (FD) Postprandial distress syndrome (PDS) | 23 Participants | 26 Participants | 49 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 63 | 0 / 65 |
| other Total, other adverse events | 5 / 63 | 7 / 65 |
| serious Total, serious adverse events | 2 / 63 | 0 / 65 |
Outcome results
Primary
Patient's Evaluation of Symptomatic Improvement by Overall Treatment Efficacy (OTE)
Patient's Evaluation of Symptomatic Improvement by OTE is classified into the following 7 categories: 1. Significantly improved 2. Improved 3. Slightly improved 4. No change 5. Slightly worse 6. Worse 7. Much worse The numbers of patients at the final evaluation (i.e, the latest evaluable time point of the all patients including discontinued patients) are shown by category.
Time frame: 8 weeks
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Rikkunshito Placebo | Patient's Evaluation of Symptomatic Improvement by Overall Treatment Efficacy (OTE) | 3=Slightly improved | 25 Participants |
| Rikkunshito Placebo | Patient's Evaluation of Symptomatic Improvement by Overall Treatment Efficacy (OTE) | 5=Slightly worse | 3 Participants |
| Rikkunshito Placebo | Patient's Evaluation of Symptomatic Improvement by Overall Treatment Efficacy (OTE) | 2=Improved | 13 Participants |
| Rikkunshito Placebo | Patient's Evaluation of Symptomatic Improvement by Overall Treatment Efficacy (OTE) | 6=Worse | 0 Participants |
| Rikkunshito Placebo | Patient's Evaluation of Symptomatic Improvement by Overall Treatment Efficacy (OTE) | 4=No change | 19 Participants |
| Rikkunshito Placebo | Patient's Evaluation of Symptomatic Improvement by Overall Treatment Efficacy (OTE) | 7=Much worse | 0 Participants |
| Rikkunshito Placebo | Patient's Evaluation of Symptomatic Improvement by Overall Treatment Efficacy (OTE) | 1=Significantly improved | 1 Participants |
| Rikkunshito | Patient's Evaluation of Symptomatic Improvement by Overall Treatment Efficacy (OTE) | 7=Much worse | 0 Participants |
| Rikkunshito | Patient's Evaluation of Symptomatic Improvement by Overall Treatment Efficacy (OTE) | 1=Significantly improved | 5 Participants |
| Rikkunshito | Patient's Evaluation of Symptomatic Improvement by Overall Treatment Efficacy (OTE) | 2=Improved | 18 Participants |
| Rikkunshito | Patient's Evaluation of Symptomatic Improvement by Overall Treatment Efficacy (OTE) | 3=Slightly improved | 26 Participants |
| Rikkunshito | Patient's Evaluation of Symptomatic Improvement by Overall Treatment Efficacy (OTE) | 4=No change | 15 Participants |
| Rikkunshito | Patient's Evaluation of Symptomatic Improvement by Overall Treatment Efficacy (OTE) | 5=Slightly worse | 0 Participants |
| Rikkunshito | Patient's Evaluation of Symptomatic Improvement by Overall Treatment Efficacy (OTE) | 6=Worse | 0 Participants |
Comparison: Comparison between groups in Rikkunshito Placebo and Rikkunshito, based on the count of participants categorized in 1 (Significantly improved) through 7 (Much worse), using the Wilcoxon (Mann-Whitney).p-value: 0.038Wilcoxon (Mann-Whitney)
Secondary
Change From Baseline in Global Overall Symptom (GOS)
The GOS scale are calculated by a total score of a 7-point Likert scale ranging from 1 = no problem to 7 = a very severe problem over 8 questions. The point scores of GOS are calculated from changes from baseline at final evaluation.
Time frame: Baseline and Week 8
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rikkunshito Placebo | Change From Baseline in Global Overall Symptom (GOS) | -4.03 units on a scale | Standard Deviation 5.08 |
| Rikkunshito | Change From Baseline in Global Overall Symptom (GOS) | -6.39 units on a scale | Standard Deviation 5.22 |
p-value: 0.034Wilcoxon (Mann-Whitney)
Secondary
Change From Baseline in Hospital Anxiety and Depression Scale (HAD)
The HAD is a 14-item scale with 2 subscales of depression (Question 1, 3, 5, 7, 9, 11, and 13) and anxiety (Question 2, 4, 6, 8, 10, 12, and 14). Each item on the questionnaire is scored from 0 to 3 (ranging from 0 to 21, lower value represents a better outcome). The point scores of HAD are calculated from changes from baseline in overall (sum of scores for depression and anxiety, i.e., total point score ranging from 0 to 42, lower value represents a better outcome), depression, and anxiety at final evaluation.
Time frame: Baseline and week 8
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rikkunshito Placebo | Change From Baseline in Hospital Anxiety and Depression Scale (HAD) | Overall | -0.34 score | Standard Deviation 4.39 |
| Rikkunshito Placebo | Change From Baseline in Hospital Anxiety and Depression Scale (HAD) | Depression | -0.05 score | Standard Deviation 2.85 |
| Rikkunshito Placebo | Change From Baseline in Hospital Anxiety and Depression Scale (HAD) | Anxiety | -0.30 score | Standard Deviation 2.26 |
| Rikkunshito | Change From Baseline in Hospital Anxiety and Depression Scale (HAD) | Overall | -2.11 score | Standard Deviation 5.05 |
| Rikkunshito | Change From Baseline in Hospital Anxiety and Depression Scale (HAD) | Depression | -0.92 score | Standard Deviation 2.61 |
| Rikkunshito | Change From Baseline in Hospital Anxiety and Depression Scale (HAD) | Anxiety | -1.19 score | Standard Deviation 3.03 |
Comparison: Change from baseline in overall point score of HADp-value: 0.036Wilcoxon (Mann-Whitney)
Comparison: Change from baseline in depression point score of HADp-value: 0.084Wilcoxon (Mann-Whitney)
Comparison: Change from baseline in anxiety point score of HADp-value: 0.022Wilcoxon (Mann-Whitney)
Secondary
Change From Baseline in Modified Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease (GERD) (Modified FSSG)
The modified FSSG questionnaire is composed of 7 questions regarding GERD symptoms (Questions 1-7, scored from 0 to 4) ranging between 0-28, lower value represents a better outcome, and 7 questions regarding dyspeptic symptoms (Questions 8-14, each question scored from 0 to 4) ranging between 0-28, lower value represents a better outcome, and a total scores, ranging from 0 to 56, lower value represents a better outcome of the all questions (Questions 1-14). Each question was assigned a score based on the frequency of symptoms. The point scores of modified FSSG are calculated from changes from baseline in each score for all symptoms (sum of point scores from Questions 1-14), GERD symptoms, and dyspeptic symptoms at final evaluation.
Time frame: Baseline and Week 8
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rikkunshito Placebo | Change From Baseline in Modified Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease (GERD) (Modified FSSG) | All symptoms | -4.99 units on a scale | Standard Deviation 5.92 |
| Rikkunshito Placebo | Change From Baseline in Modified Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease (GERD) (Modified FSSG) | GERD symptoms | -1.69 units on a scale | Standard Deviation 2.93 |
| Rikkunshito Placebo | Change From Baseline in Modified Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease (GERD) (Modified FSSG) | Dyspeptic symptoms | -3.29 units on a scale | Standard Deviation 4.25 |
| Rikkunshito | Change From Baseline in Modified Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease (GERD) (Modified FSSG) | All symptoms | -7.18 units on a scale | Standard Deviation 6.94 |
| Rikkunshito | Change From Baseline in Modified Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease (GERD) (Modified FSSG) | GERD symptoms | -2.62 units on a scale | Standard Deviation 4.07 |
| Rikkunshito | Change From Baseline in Modified Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease (GERD) (Modified FSSG) | Dyspeptic symptoms | -4.58 units on a scale | Standard Deviation 4.02 |
Comparison: Change from baseline in all symptoms of modified FSSGp-value: 0.027Wilcoxon (Mann-Whitney)
Comparison: Change from baseline in GERD symptoms of modified FSSGp-value: 0.089Wilcoxon (Mann-Whitney)
Comparison: Change from baseline in dyspeptic symptoms of modified FSSGp-value: 0.148Wilcoxon (Mann-Whitney)
Secondary
Change From Baseline in Short-form Health Survey-8 (SF-8)
The SF-8 scores comprised of Physical component summary (PCS) scores (ranging between 5.32-70.69, higher value represents a better outcome) and Mental component summary (MCS) scores (ranging between 10.11-74.51, higher value represents a better outcome), and a total scores of PCS and MCS using a formula specified in SF-8 Scoring Algorithm. The point scores of SF-8 are calculated from changes from baseline in PCS and MCS at final evaluation.
Time frame: Baseline and week 8
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rikkunshito Placebo | Change From Baseline in Short-form Health Survey-8 (SF-8) | PCS | 2.68 units on a scale | Standard Deviation 5.84 |
| Rikkunshito Placebo | Change From Baseline in Short-form Health Survey-8 (SF-8) | MCS | 0.24 units on a scale | Standard Deviation 7.72 |
| Rikkunshito | Change From Baseline in Short-form Health Survey-8 (SF-8) | PCS | 3.87 units on a scale | Standard Deviation 7.61 |
| Rikkunshito | Change From Baseline in Short-form Health Survey-8 (SF-8) | MCS | 1.81 units on a scale | Standard Deviation 6.58 |
Comparison: Change from baseline in PCS of SF-8p-value: 0.27Wilcoxon (Mann-Whitney)
Comparison: Change from baseline in MCS of SF-8p-value: 0.342Wilcoxon (Mann-Whitney)
Secondary
Change From Baseline in the Patient Assessment of Upper Gastrointestinal Symptom Severity Index (PAGI-SYM)
PAGI-SYM questionnaire is composed of the following 6 categories that consisted of Questions 1 to 20 (each question composed of 6 subscales, i.e., point scores from 0 to 5, lower value represents a better outcome). Subscale scores are calculated by averaging across items in each category. A total score (lower value represents a better outcome, ranging from 0 to 5) is calculated as the mean of the subscale scores. Heartburn/Regurgitation, Nausea/Vomiting, Postprandial Fullness/Early satiety, Bloating, Upper Abdominal Pain, and Lower Abdominal Pain The point scores of PAGI-SYM are calculated from changes from baseline in total score and each category score at final evaluation.
Time frame: Baseline and Week 8
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rikkunshito Placebo | Change From Baseline in the Patient Assessment of Upper Gastrointestinal Symptom Severity Index (PAGI-SYM) | Nausea/Vomiting | -0.15 units on a scale | Standard Deviation 0.75 |
| Rikkunshito Placebo | Change From Baseline in the Patient Assessment of Upper Gastrointestinal Symptom Severity Index (PAGI-SYM) | Bloating | -0.20 units on a scale | Standard Deviation 0.78 |
| Rikkunshito Placebo | Change From Baseline in the Patient Assessment of Upper Gastrointestinal Symptom Severity Index (PAGI-SYM) | Heartburn/Regurgitation | -0.23 units on a scale | Standard Deviation 0.48 |
| Rikkunshito Placebo | Change From Baseline in the Patient Assessment of Upper Gastrointestinal Symptom Severity Index (PAGI-SYM) | Upper Abdominal Pain | -0.56 units on a scale | Standard Deviation 1.2 |
| Rikkunshito Placebo | Change From Baseline in the Patient Assessment of Upper Gastrointestinal Symptom Severity Index (PAGI-SYM) | Postprandial Fullness/Early satiety | -0.36 units on a scale | Standard Deviation 0.74 |
| Rikkunshito Placebo | Change From Baseline in the Patient Assessment of Upper Gastrointestinal Symptom Severity Index (PAGI-SYM) | Lower Abdominal Pain | -0.31 units on a scale | Standard Deviation 1.03 |
| Rikkunshito Placebo | Change From Baseline in the Patient Assessment of Upper Gastrointestinal Symptom Severity Index (PAGI-SYM) | Total | -0.30 units on a scale | Standard Deviation 0.43 |
| Rikkunshito | Change From Baseline in the Patient Assessment of Upper Gastrointestinal Symptom Severity Index (PAGI-SYM) | Lower Abdominal Pain | -0.13 units on a scale | Standard Deviation 0.9 |
| Rikkunshito | Change From Baseline in the Patient Assessment of Upper Gastrointestinal Symptom Severity Index (PAGI-SYM) | Total | -0.47 units on a scale | Standard Deviation 0.61 |
| Rikkunshito | Change From Baseline in the Patient Assessment of Upper Gastrointestinal Symptom Severity Index (PAGI-SYM) | Heartburn/Regurgitation | -0.25 units on a scale | Standard Deviation 0.63 |
| Rikkunshito | Change From Baseline in the Patient Assessment of Upper Gastrointestinal Symptom Severity Index (PAGI-SYM) | Nausea/Vomiting | -0.33 units on a scale | Standard Deviation 0.94 |
| Rikkunshito | Change From Baseline in the Patient Assessment of Upper Gastrointestinal Symptom Severity Index (PAGI-SYM) | Postprandial Fullness/Early satiety | -0.82 units on a scale | Standard Deviation 0.98 |
| Rikkunshito | Change From Baseline in the Patient Assessment of Upper Gastrointestinal Symptom Severity Index (PAGI-SYM) | Bloating | -0.56 units on a scale | Standard Deviation 1 |
| Rikkunshito | Change From Baseline in the Patient Assessment of Upper Gastrointestinal Symptom Severity Index (PAGI-SYM) | Upper Abdominal Pain | -0.76 units on a scale | Standard Deviation 1.19 |
Comparison: Change from baseline in total score of PAGI-SYMp-value: 0.051Wilcoxon (Mann-Whitney)
Comparison: Change from baseline in Heartburn/Regurgitation of PAGI-SYMp-value: 0.947Wilcoxon (Mann-Whitney)
Comparison: Change from baseline in Nausea/Vomiting of PAGI-SYMp-value: 0.157Wilcoxon (Mann-Whitney)
Comparison: Change from baseline in Postprandial Fullness/Early satiety of PAGI-SYMp-value: 0.004Wilcoxon (Mann-Whitney)
Comparison: Change from baseline in Bloating of PAGI-SYMp-value: 0.011Wilcoxon (Mann-Whitney)
Comparison: Change from baseline in Upper Abdominal Pain of PAGI-SYMp-value: 0.245Wilcoxon (Mann-Whitney)
Comparison: Change from baseline in Lower Abdominal Pain of PAGI-SYMp-value: 0.387Wilcoxon (Mann-Whitney)