Study design
This trial will adopt a multicentre, double-blinded, randomized controlled trial with two parallel groups, to explore the efficiency of the TJ methodology granules combined with PPIs de-escalation for NERD. The protocol will be described in accordance with Recommendations for Interventional Trials 2013 guidelines [24]. The details of the study design are shown in Figure 1.
Study setting
This multicentre, double-blind, RCT will be conducted at six hospitals in China (Xiyuan Hospital of China Academy of Chinese Medical Sciences; Guangdong Provincial Hospital of Traditional Chinese Medicine; Wuhan No.1 Hospital; The First Affiliated Hospital of Tianjin University of Traditional Chinese Medicine; Traditional Chinese Medicine Hospital of Kunshan; Liuzhou Hospital of Traditional Chinese Medicine). A total of 174 participants will be recruited from the hospital outpatient departments, hospital websites and posters. Participants will be divided into three groups according to their different TCM syndromes, and those with the same syndrome will be divided into the intervention group and the control group at a 1:1 ratio.
Eligibility criteria
All participating patients must first be judged by TCM physicians to determine whether they meet the following inclusion and exclusion criteria.
Inclusion criteria
(1) The diagnostic criteria of NERD according to the China Consensus Opinion on Gastro-oesophageal Reflux Disease, 2014 edition and treatment with PPIs for more than 8 weeks and whose curative effect is not satisfactory; (2) The diagnostic criteria of stagnation of liver and stomach heat syndrome, spleen deficiency and dampness-heat syndrome and intermingled heat and cold syndrome in TCM; (3) Agreement to participate in the clinical trial and sign the informed consent form; (4) Age from 18 to 65 years old.
Exclusion criteria
(1) Pregnant or breastfeeding females or those who are planning pregnancy; (2) Other chronic GI diseases like RE or BE or primary diseases such as peptic ulcers, achalasia, pyloric obstructions, and oesophageal cancer that can cause gastroesophageal reflux; (3) Severe cardio-cerebrovascular system diseases, liver, kidney, hematopoietic system diseases, psychiatric diseases and tumours; (4) Anti-reflux surgery (fundoplication or endoscopic minimally invasive surgery) and other upper gastrointestinal surgery records; (5) History of allergies or drug and food allergies appearing during the trials; (6) Inability to describe self-symptoms or to cooperate with treatment; (7) Abuse of alcohol or drugs, frequent changes in the working environment and tendency to dropout; (8) Participation in other clinical trials within 4 weeks.
Dropout criteria
(1) Decision to exit the trial himself/herself; (2) Loss to follow-up; (3) Poor compliance; (4) Diagnosis with other TCM syndromes or an order to withdraw by the TCM physicians.
For the occurrence of patients presented with the above situation, we will consider making a suspension. In cases of dropout, the reason should be explained. If there are baseline pharmacodynamic data, the last main therapeutic effect index can be transferred to the final results for statistical analysis, and the CRF should be retained.
Intervention
Each centre's treatment of participants will be provided by licensed TCM physicians. TCM physicians will distribute granules to participants tailored according to their symptoms under the guidance of the TJ methodology. To reduce intervention bias, TCM physicians have conducted relevant training. Our record physicians must study and be familiar with the scales and questionnaires in this trial, and learn the skills to guide participants to complete them appropriately. The granule-distributing physicians arrange and distribute the granules accordingly. In addition to that, we have a chief physician responsible for overseeing the entire process.
Intervention group
Based on the curative effect of treating NERD in clinical practice, we selected three kinds of TCM granules based on TJ methodology. According to the different TCM syndromes, participates with stagnation of liver and stomach-heat syndrome will be treated with Tongjiang (TJ) granule, those with spleen deficiency and dampness-heat syndrome will be treated with Jianpiqinghua (JQ) granule and those with intermingled heat and cold syndrome will be treated with Wenpiqingwei (WQ) granule. TCM granules are concentrated herbal particles obtained by the mean of spray drying the hot water extract of a mixture of raw herbs. TCM granules are extracted with water to make an aqueous extract or decoction used for treatment. Each bag of granules (approximately 20g) will be dissolved in 200 ml water and taken three times a day, 1 hour after meal. Participants in all three groups cooperated with PPIs de-escalation therapy. From week 1 to week 2 of treatment, the dose of PPIs will be half of the original dose, once a day, taken before bedtime. The PPIs will be replaced with famotidine 20 mg from week 3 to week 4, taken before bedtime. From week 5 to week 6, acid-suppressive drugs will be withdrawn, and only TCM granules will be administered. There will be 6 weeks of treatment and 4 weeks of follow-up.
Control group
Patients will be treated with the corresponding TJ methodology granules placebo. The placebo granules consist of cyclodextrin and 5% real TJ theory granules to imitate the color and smell of the real counterpart. Both herbal granules and placebo are manufactured by China resources sanjiu medical and pharmaceutical co., ltd. (Hefei, China; Batch number: 2004902) according to the standards of the Good Manufacturing Practice. The physical properties of the placebo, such as appearance, size, colour, dose form, weight, taste, and smell, will be similar to those of the TCM granules. The PPIs de-escalation therapy will be the same as that for the intervention group.
Cointerventions
One week prior to the start of treatment, patients will be required to stop their intake of other drugs related to TCM therapies of NERD, however, acid-suppressive drugs intake will remain unchanged. During the study period, patients will be forbidden to add any drugs other than study therapies without permission. During the 1-4 weeks of the treatment period, if the participant’s symptoms increase after the reduction of PPIs according to the study protocol and cannot be tolerated, participant can temporarily use almagate suspension or almagate chewable tablets and record the combined medication. During the treatment period of 5-6 weeks, if the participant is unable to tolerate the symptoms after stopping the acid suppressive drugs, participant will be terminated from the trial and recorded, and will be treated with their original treatment therapy.
Timeline
The entire trial period will last 10 weeks (the treatment period is 6 weeks and the follow-up period will last 4 weeks). Participants will need to stop using drugs related to the treatment of NERD during pre-screening and screening, complete a physical safety examination and sign an informed consent form. At baseline, participants will need to complete the first assessment, and then randomly divided into an intervention group and a control group. During the treatment phase, TCM physicians will instruct the participants on how to take the therapy, and then evaluate compliance and outcome indicators after 2, 4 and 6 weeks of treatment. The follow-up period will last 4 weeks after the end of treatment. Details are shown in Table 1.
Sample size estimation
According to the preliminary trial results from the team and to literature reports, the average effective rate of traditional Chinese medicine treatment for NERD is 90% [25]. The literature reports that the effective rate of PPIs in the treatment of NERD is between 50% and 90% [4, 26], so we used an average of 70%. The trial intends to conduct a superiority test of two independent sample proportions, using a margin of 0.02, an alpha risk of 0.05 and a beta risk of 0.20. Assuming an attrition rate of approximately 20%. The estimated sample size is N=174, including 87 cases in the intervention group and 87 cases in the placebo group.
Randomization and blinding
In this trial, centre stratification will be used; each centre will use the block randomization method, and qualified participants will be divided into intervention and control groups in a 1: 1 ratio for grouping. The stratified randomization will be completed by a statistician through the PROC PLAN procedure in Strategic Applications Software (SAS) V.9.2, and the results of the random allocation will be published through the network central random allocation system. Groups will be placed into sealed brown envelopes, and the clinical research coordinator will number the envelopes sequentially and maintain them.
The patient's sequence number and corresponding grouping will comprise the first-level blind code and, the medicine code will comprise the second-level blind code; each patient's medicine code will be randomly assigned. All operations will be completed according to the established SOP guidelines. All codes will be kept in the Good Clinical Practice (GCP) Center of Xiyuan Hospital. The TCM practitioners and statisticians administering the treatment will be blinded to the grouping.
In the case of serious adverse events or complications in the clinical trials, blinding should be unsealed urgently, and cases of unblinding should be treated as dropout participates.
Table 1 Timeline of the trial.
study period
|
|
screen-ing
|
base-line
|
treatment
|
follow-up
|
outcomes
|
week -1
|
week 0
|
week 1
|
week 2
|
week 3
|
week 4
|
week 5
|
week 6
|
week 8
|
week 10
|
|
Screening and enrolment
|
|
|
|
|
|
|
|
|
|
|
|
Informed consent form
|
○
|
|
|
|
|
|
|
|
|
|
|
Eligibility for study
|
○
|
|
|
|
|
|
|
|
|
|
|
Demographic and clinical details
|
○
|
|
|
|
|
|
|
|
|
|
|
Physical safety examination
|
○
|
|
|
|
|
|
|
|
|
|
|
Randomization
|
○
|
|
|
|
|
|
|
|
|
|
|
Intervention
|
|
|
|
|
|
|
|
|
|
|
|
TCM granules/placebo + PPIs de-escalation
|
|
○
|
|
○
|
|
○
|
|
|
|
|
|
Assessment
|
|
|
|
|
|
|
|
|
|
|
|
VAS of heartburn and reflux
|
|
○
|
○
|
○
|
○
|
○
|
○
|
○
|
○
|
○
|
|
Major symptoms scale
|
|
○
|
○
|
○
|
○
|
○
|
○
|
○
|
○
|
○
|
|
Minor symptoms scale
|
|
○
|
○
|
○
|
○
|
○
|
○
|
○
|
○
|
○
|
|
TCM syndromes scale
|
|
○
|
|
○
|
|
○
|
|
○
|
○
|
○
|
|
SF-36
|
|
○
|
|
○
|
|
○
|
|
○
|
○
|
○
|
|
PRO for chronic gastrointestinal diseases
|
|
○
|
|
○
|
|
○
|
|
○
|
○
|
○
|
|
SAS
|
|
○
|
|
○
|
|
○
|
|
○
|
○
|
○
|
|
SDS
|
|
○
|
|
○
|
|
○
|
|
○
|
○
|
○
|
|
GERD-HRQL
|
|
○
|
|
○
|
|
○
|
|
○
|
○
|
○
|
|
Compliance
|
|
|
○
|
○
|
○
|
○
|
○
|
○
|
|
|
|
Cointerventions
|
|
|
○
|
○
|
○
|
○
|
○
|
○
|
|
|
|
Adverse events
|
|
|
○
|
○
|
○
|
○
|
○
|
○
|
|
|
|
VAS, visual analogue scale; TCM, traditional Chinese medicine; SF-36, the MOS 36-item Short From Health Survey; PRO, Patient-Reported Outcome; SAS, Self-rating Anxiety Scale; SDS, Self-rating Depression Scale; GERD-HRQL, the Gastroesophageal Reflux Disease-Health-Related Quality-Of-Life.
|
Compliance
The patient’s compliance will be calculated as “actual dose/dose to be taken”; if the compliance is in the range of 0.7 to 1.2, it will be regarded as good compliance. Participants should return unused medicine and empty packaging at each visit, and TCM physicians will count the number of drugs and granules returned and keep a record of lost and unreturned medicines.
Ethics and dissemination
Patient consent
The trial is approved by the Ethical Review Committee of Xiyuan Hospital of China Academy of Chinese Medical Sciences. For eligible participants, a TCM physician will provide written informed consent forms. After the physician communicates the details of the study, participants willing to participate in the trial will sign an informed consent form. Participates and the TCM physician will each keep a copy of the form.
Confidentiality
All materials related to the trial will be safely stored in the restricted access location. All participant case reports and electronic charts will be kept confidential, and only authorized researchers will be able to access the paper version and electronic data set.
Outcomes and analysis
Participants in both the intervention group and control group will be encouraged to complete the treatment in 6 weeks, and follow-up will continue for 4 weeks. The following outcome indicators will be used to evaluate efficacy and safety. Demographic and clinical details of participants will be collected at the beginning of the trial. Physical safety examinations will be conducted at the beginning and end of the study, including: (1) routine tests of blood, urine and stool, faecal occult blood; (2) liver function tests (ALT, AST) and, kidney function tests (Cr, BUN); and (3) electrocardiograms. Outcome indicators for efficacy evaluation will include the following: (1) a visual analogue scale (VAS) for heartburn and regurgitation; (2) a major symptoms scale; (3) PPIs withdrawal rate and symptoms recurrence rate; (4) a minor symptoms scale; (5) the MOS 36-item Short From Health Survey (SF-36); (6) the Patient-Reported Outcome (PRO) scale for chronic gastrointestinal diseases; (7) Self-Rating Anxiety Scale (SAS); (8) Self-rating depression scale (SDS); (9) the Gastroesophageal Reflux Disease-Health-Related Quality-Of-Life (GERD-HRQL) scale; (10) the TCM syndromes scale. Scales and questionnaires will be completed at the beginning and end of the trial and at the end of each phase and follow-up. Adverse events will be observed throughout the treatment.
Primary outcomes
The primary outcomes are the VAS for heartburn and regurgitation and the major symptoms scale.
(1) The VAS is a line marked with 10 scales, with 0 points to 10 points at both ends. Zero points indicates no symptoms, and 10 points represents the most severe and unbearable symptoms. 0-2 is classified as “basic no symptoms”, 3-5 is classified as “mild”, 6-8 is classified as “moderate”, and 8-10 is classified as “severe” [27-29]. Patients will be given a VAS for regurgitation and heartburn daily through a diary card, and the average score of the two symptoms each week will be evaluated according to the content of the diary card. Participants were defined as responders if for at least 50% of weeks during the 6 weeks of the trial the weekly VAS score was reduced from baseline by ≥50%. We will calculate the percentage of responders. At the same time, the change in VAS score will be compared between groups.
(2) Major symptoms scale: For the main clinical symptoms of NERD, heartburn frequency, heartburn relief time, and regurgitation frequency, the scoring criteria are shown in Table 2.
Table 2 Major symptoms scale.
score
symptom
|
Mild (0)
|
Moderate (1)
|
Severe (2)
|
heartburn frequency
|
1 day a week
|
2-3 days a week
|
4-7 days a week
|
heartburn relief time
|
relieve within 1h
|
relieve within 1-3h
|
>3h does not relieve even all day
|
regurgitation frequency
|
1 day a week
|
2-3 days a week
|
4-7 days a week
|
Secondary outcomes
Secondary outcomes are the PPI withdrawal rate and symptoms recurrence rate, scales about minor symptoms, health-related quality of life, mental health and TCM syndromes.
(1) PPIs withdrawal rate and symptoms recurrence rate: During patient follow-up for the 4 weeks after the end of the treatment, according to the above scores, the number of recurrences and corresponding recurrence rates. The PPI withdrawal rate will calculated based on the number of people who no longer use PPIs at follow-up.
(2) Minor symptoms scale: Scoring the frequency and degree of clinical minor symptoms. For the frequency, 0 points indicates no symptoms, 1 points indicates < 1 day per week, 2 points indicates 1 day per week, 3 points indicates 2-3 days per week, 4 points indicates 4-5 days per week, 5points indicates 6-7 days per week. For the degree of symptoms, 1 points means no symptoms, 2 points means symptoms are mild, 3 points means symptoms are moderate, need to take medicine occasionally, 4 points means symptoms are severe, need to take medicine for long time, 5 points means symptoms are very serious, and affecting daily life, need to take medicine for long time. Details are shown in Table 3.
Table 3 Minor symptoms scale.
symptoms
|
frequency score
|
degree score
|
non cardiogenic chest pain
|
|
|
epigastric pain
|
|
|
epigastric discomfort
|
|
|
belch
|
|
|
cough
|
|
|
asthma
|
|
|
pharyngeal paraesthesia
|
|
|
total
|
|
|
(3) SF-36: As a concise health questionnaire, the SF-36 comprehensively evaluates the quality of life of the respondents from 8 dimensions including Physical Functioning (PF), Role-Physical (RP), Bodily Pain (BP), General Health (GH), Vitality (VT), Social Functioning (SF), Role-Emotiona (RE), Mental Health (MH). It also contains another health dimension: Health Transition (HT), which is used to evaluate the overall change in health in the past year [30-33].
(4) PRO: This scale is for patients with FGIDs. It contains a total of 35 items, divided into 6 dimensions (regurgitation, dyspepsia, general condition, social function, defecation, psychology) to assess the influencing factors of chronic gastrointestinal diseases. Each item is graded on a 5-point scale, with a maximum of 4 points and a minimum of 0 points. The higher the score, the more severe the symptoms [34, 35].
(5) SAS: The SAS scale is a 20-item self-reported assessment device. Each question is scored on a Likert-type scale of 1 to 4 (based on the following replies: ‘‘a little of the time,’’ ‘‘some of the time,’’ ‘‘a good part of the time,’’ and ‘‘most of the time’’). The total score is obtained by summing the assessment of the 20 items. The total score multiplied by 1.25 gives the standard score. A standard cutoff score of 50 is usually used to diagnose anxiety. The standard score ranges are 25–49 (normal range), 50–59 (mild anxiety), 60–69 (moderate anxiety), and 70 (severe anxiety) [36, 37].
(6) SDS: The Self-rating Depression Scale (SDS) developed by Zung is a norm-referenced measure, used to screen adults for the potential presence of depressive disorders. The scale produces raw scores between 20 and 80, Zung recommended converting these to Index Scores (which ranged between 25 and 100) by the simple process of multiplying by 1.25. Zung’s recommended cut-off for identifying adults with depressive disorder was index scores of 50 and over [38]. We used in this study that an index score of 53 (raw score 42), this was more appropriate for use with Chinese populations[39].
(7) GERD–HRQL: A total of 16 items are used to evaluate the symptoms of heartburn, regurgitation and the effects of current medication on life. Each item is scored on a 6-point scale, from 0 to 5 points. A score of 0 indicates no symptoms, and a score of 5 indicates that symptoms are incapacitating when performing daily activities [40, 41].
(8) TCM syndromes scale: a 15-item scale based on the Clinical Guideline of New Drugs for Traditional Chinese Medicine. This scale evaluates the changes in TCM symptoms of the digestive tract and the whole body of the participants, including flatulence, stomachache, poor appetite, heartburn, belching, acid reflux, pharyngeal paraesthesia, thirst, distention in the lateral lower abdomen, fatigue, shortness of breath, unwillingness to speak, somatosensory heaviness, fear of cold, and loose stool. Each item is scored, with 1 being asymptomatic and 4 being severe. The higher the overall score, the more severe the overall symptoms [42].
Exploring outcomes
At baseline and after 6 weeks of treatment, faecal samples will be collected and stored at -80°C for unified testing. The experimenter will extract total DNA from the faecal samples and perform 16S rRNA sequencing. Reads will be processed to generate an operational taxonomic unit (OTU) table at 97% granularity. Through OTU analysis, the detect α-diversity, β-diversity of the faecal microbiome will be detected, and then LEfSe analysis will be used to compare and analyse the data to identify species with significant differences in abundance between groups.
Data management
We will use both written and electronic CRF. At each time point, participants will complete the CRF under the guidance of a TCM physician. The completed CRF will be entered into the Drug & Clinical Trial Data Management Platform (developed by the GCP center: http://www.xyedc.com/). The CRF data will be entered in duplicate by two trained TCM physicians. Electronic data will be permanently saved. After the study, the statisticians will be able to download the electronic data for analysis through the platform.
Statistical analysis
This trial will use intention-to-treat (ITT) analysis as the main method to evaluate the outcome results. To deal with missing outcome variables that remain to be recorded, the last record data will be carried over to the end or a multiple imputation method will be used.
Statistical analysis will be conducted using SPSS 21.0 software. The significance level is established at 0.05 and the limits of the confidence interval are 95%. Descriptive analysis and categorical variables will be described in frequency tables and as percentages or composition ratios; continuous variables will be described in terms of means and standard deviations (SDs), or medians, lower quartiles (P25), upper quartiles (P75), minimum values, and maximum values. Comparative analyse between two groups will be performed for categorical variables using the chi-squared test, Fisher’s exact probability method, the Wilcoxon rank-sum test, or the CMH test. Continuous variables that conform to a normal distribution will be compares using a t-test (for homogeneity of variance between groups, with 0.05 as the test level; if the variance is heterogeneous, the Welch-Satterthwaite t-test will be used), while those that conform to a non-normal distribution will be compared using the Wilcoxon rank-sum test or the Wilcoxon signed-rank test. Hypothesis testing will use the two-sided test uniformly, and P ≤ 0.05 will be considered statistically significant.