Tongjiang Series Prescription Combined With PPIs Descending Ladder Withdrawal in Treating Nonerosive Reflux Disease

Phase 3

• Conditions: Nonerosive Reflux Disease
• Interventions: Drug: Tongjiang series prescription(Tongjiang granules, Jianpi Qinghua granules and Wenpi Qingwei granules); Drug: Acid inhibitors; Drug: Placebo

• Registration Number: NCT04340297
• Lead Sponsor: Xiyuan Hospital of China Academy of Chinese Medical Sciences

Brief Summary

Nonerosive Reflux Disease (NERD) is a common refractory gastrointestinal disease. Proton Pump Inhibitors (PPIs), the preferred drug, have poor response, single target and poor acid inhibition effect in some patients in clinical application. Long-term use of PPI can lead to many side effects, even dependency. The main Traditional Chinese Medicine (TCM)syndrome types of NERD are liver-stomach depression-heat syndrome, spleen deficiency damp-heat syndrome and cold-heat complicated syndrome. TCM syndrome differentiation treatment has the advantages of overall regulation and individualized treatment. The purpose of this study is to evaluate the safety and efficacy advantages of syndrome differentiation series prescription combined with PPIs descending ladder withdrawal in the treatment of patients who use PPIs for a long time that can not stop, and to solve the problems of multiple side effects and dependency caused by long-term use of PPIs.

Detailed Description

Nonerosive Reflux Disease (NERD) accounts for about 70% of Gastroesophageal Reflux Disease (GERD), which is a common refractory gastrointestinal disease. Proton Pump Inhibitors (PPIs), the preferred treatment, have the following problems in clinical use: about 50% of patients respond to PPIs only partially or not at all; PPIs has a single target, and the effect of acid suppression alone is poor; long term use of PPIs can lead to dyspepsia, fundic gland polyp, atrophic gastritis, intestinal flora disorders, and even dependency. Liver-stomach depression-heat syndrome, spleen deficiency damp-heat syndrome and cold-heat complicated syndrome account for 80%-91% of NERD's Traditional Chinese Medicine (TCM) syndrome. TCM syndrome differentiation treatment has the advantages of overall regulation and individualized treatment, but it lacks high-level evidence-based medicine evidence. On the basis of previous work, the project plans to establish sub centers in 6 Chinese hospitals, including 180 patients with NERD who meet the requirements to carry out a multicenter, randomized, double-blind, placebo-controlled clinical study, in which 90 subjects in the experimental group received the treatment of syndrome differentiation series of prescriptions combined with PPIs descending ladder withdrawal, and 90 subjects in the control group received the treatment of placebo combined with PPIs descending ladder withdrawal. The therapeutic effects were evaluated from the following aspects: the VAS score of reflow and heartburn, the rate of discontinuation of antacids, the rate of recurrence of NERD symptoms, the score of TCM syndromes and the improvement of gastrointestinal function. The purpose of this study is to evaluate the efficacy advantage and safety of Tongjiang series prescription combined with PPIs descending ladder withdrawal compared with PPIs descending ladder withdrawal alone for patients who use PPIs for a long time that can not stop, so as to obtain evidence-based medical evidence of high-quality TCM syndrome differentiation treatment of NERD, and form an effective and popularized treatment plan to solve the problems of various side effects and dependency caused by long-term use of PPIs.

Study Timeline

• Study First Submitted: 2020-04-01
• Study First Submitted QC: 2020-04-08
• Study First Posted: 2020-04-09
• Study Start: 2020-06-15
• Status Verified: 2020-07
• Last Update Submitted: 2020-07-28
• Last Update Posted: 2020-07-29
• Primary Completion: 2021-12-01
• Study Completion: 2021-12-31

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 180

Inclusion Criteria

• 1. It meets the diagnostic criteria of nonerosive reflex disease(NERD)
• 2. Patients with PPIs who are effective for more than 8 weeks and relapse after discontinuation
• 3. Age between 18 and 70 years old
• 4. It meets the diagnostic criteria of liver-stomach depression-heat syndrome, spleen deficiency damp-heat syndrome and cold-heat complicated syndrome of traditional Chinese medicine
• 5. Patients have informed consent and are willing to receive corresponding treatment

Exclusion Criteria

• 1. Patients with active peptic ulcer, gastrointestinal hemorrhage, severe dysplasia of gastric mucosa or suspected malignant change, achalasia or postoperative achalasia
• 2. There are other organic diseases of the digestive system (such as acute and chronic pancreatitis, cirrhosis, etc.), or systemic diseases that affect the gastrointestinal motility, such as hyperthyroidism, diabetes mellitus over 10 years, chronic renal insufficiency, spirit (the score of SAS and SDS shows severe anxiety or depression), nervous system diseases, etc
• 3. Patients with severe organ diseases such as heart, liver and kidney (such as ALT, AST more than 2 times of normal value), hematopoietic system diseases and tumors
• 4. Pregnant and lactating women
• 5. Patients with history of nervous system disease and mental disease
• 6. People with a history of allergies to all the test drugs
• 7. Subjects who are participating in other clinical trials or have participated in other clinical trials within 4 weeks

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Experimental group	Tongjiang series prescription(Tongjiang granules, Jianpi Qinghua granules and Wenpi Qingwei granules)	Tongjiang granules are taken orally in liver-stomach depression-heat syndrome, Jianpi Qinghua granules are taken orally in spleen deficiency damp-heat syndrome, Wenpi Qingwei granules are taken orally in cold-heat complicated syndrome, one bag per time, 3 times a day and 1 hour after a meal. At the same time, it was combined with acid inhibitors to reduce the steps of withdrawal treatment: in the 1-2 weeks, acid inhibitor (PPI) was reduced from the dose before entering the group to half of the dose, once a day, before going to bed; in the 3-4 weeks, acid inhibitor was changed from PPI to famotidine tablets, 20mg each time, before going to bed; in the 5-6 weeks, all acid inhibitors were stopped.
Experimental group	Acid inhibitors	Tongjiang granules are taken orally in liver-stomach depression-heat syndrome, Jianpi Qinghua granules are taken orally in spleen deficiency damp-heat syndrome, Wenpi Qingwei granules are taken orally in cold-heat complicated syndrome, one bag per time, 3 times a day and 1 hour after a meal. At the same time, it was combined with acid inhibitors to reduce the steps of withdrawal treatment: in the 1-2 weeks, acid inhibitor (PPI) was reduced from the dose before entering the group to half of the dose, once a day, before going to bed; in the 3-4 weeks, acid inhibitor was changed from PPI to famotidine tablets, 20mg each time, before going to bed; in the 5-6 weeks, all acid inhibitors were stopped.
Control group	Acid inhibitors	Tongjiang placebo granules are taken orally by patients with liver-stomach depression-heat syndrome, Jianpi Qinghua placebo granules are taken orally by patients with spleen deficiency damp-heat syndrome, Wenpi Qingwei placebo granules are taken orally by patients with cold-heat complicated syndrome, 1 bag per time, 3 times a day and 1 hour after a meal. At the same time, it was combined with acid inhibitors to reduce the steps of withdrawal treatment: in the 1-2 weeks, acid inhibitor (PPI) was reduced from the dose before entering the group to half of the dose, once a day, before going to bed; in the 3-4 weeks, acid inhibitor was changed from PPI to famotidine tablets, 20mg each time, before going to bed; in the 5-6 weeks, all acid inhibitors were stopped.
Control group	Placebo	Tongjiang placebo granules are taken orally by patients with liver-stomach depression-heat syndrome, Jianpi Qinghua placebo granules are taken orally by patients with spleen deficiency damp-heat syndrome, Wenpi Qingwei placebo granules are taken orally by patients with cold-heat complicated syndrome, 1 bag per time, 3 times a day and 1 hour after a meal. At the same time, it was combined with acid inhibitors to reduce the steps of withdrawal treatment: in the 1-2 weeks, acid inhibitor (PPI) was reduced from the dose before entering the group to half of the dose, once a day, before going to bed; in the 3-4 weeks, acid inhibitor was changed from PPI to famotidine tablets, 20mg each time, before going to bed; in the 5-6 weeks, all acid inhibitors were stopped.

Primary Outcome Measures

Name	Time	Method
Changes of visual analogue (VAS) scores of reflow, heartburn and other major symptoms	6 weeks during treatment period, 4 weeks during follow-up period	During the period of taking medicine, the patients recorded the reflow and heartburn attacks (attack times and duration) within 24 hours every day on the symptom diary card, and VAS scores were performed on the reflow and heartburn symptoms. The average score of each symptom in the past week was calculated. The decrease rate of symptom score ≥ 50% after weekly treatment was recorded as response, and the number of response weeks was more than 50% of the whole treatment period, which was considered effective.
Discontinuation rate of acid inhibitors	6 weeks of treatment	Discontinuation rate of acid inhibitors = Number of drug discontinuation/ Total number of people in each group
The change of recurrence rate of main symptoms in Nonerosive Reflux Disease	6 weeks of treatment, 4 weeks during follow-up period	The recurrence rate of the main symptoms, such as heartburn and reflux, was evaluated respectively. The recurrence rate = Number of symptom recurrence / Number of drug discontinuation.

Secondary Outcome Measures

Name	Time	Method
Changes in secondary symptom scores	6 weeks during treatment period, 4 weeks during follow-up period	Secondary symptoms such as non cardiogenic chest pain, epigastric pain, burning sensation of epigastrium, belching, cough, asthma and foreign body sensation in pharynx were recorded and scored. Symptom frequency: none: 0 point; \< 1 day / week: 1 point; 1 day / week: 2 points; 2-3 days / week: 3 points; 4-5 days / week: 4 points; 6-7 days / week: 5 points. Symptom degree: the symptom is not obvious, requiring the doctor's warning: 1 point; the symptom is obvious, affecting daily life, occasionally taking medicine: 3 points; the symptom is very obvious, affecting daily life, requiring long-term taking medicine: 5 points; between 1 point and 3 points, 2 points; between 3 points and 5 points, 4 points.
Changes of Traditional Chinese Medicine syndrome score	Baseline, 2 weeks, 4 weeks and 6 weeks during treatment period, 2 weeks and 4 weeks during follow-up period	Before and after treatment and during follow-up, TCM syndrome scores were recorded. Symptoms are divided into four grades: asymptomatic; mild: mild, not affecting daily life; moderate: moderate, partially affecting daily life; severe: severe, affecting daily life, hard to stick to work. According to the weight of syndrome main and secondary symptoms, the main symptoms are 0 points, 2 points, 4 points and 6 points respectively, and the secondary symptoms are 0 points, 1 point, 2 points and 3 points respectively.
Changes of Gastroesophageal Reflux Disease-Health Related Quality of Life (GERD-HRQL) scale scores	Baseline, 2 weeks, 4 weeks and 6 weeks during treatment period, 2 weeks and 4 weeks during follow-up period	The gastroesophageal Reflux Disease-Health Related Quality of Life (GERD-HRQL) scale score was evaluated before and after treatment and during follow-up. The scoring standard is the same as the international standard.
The change of the score of chronic gastrointestinal disease patient reported outcome (PRO) scale	Baseline, 2 weeks, 4 weeks and 6 weeks during treatment period, 2 weeks and 4 weeks during follow-up period	Before and after treatment and during the follow-up period, the chronic gastrointestinal disease patient reported outcome (PRO) scale score was evaluated. The scoring standard is the same as the international standard.
The change of Self-rating anxiety scale (SAS) score	Baseline, 2 weeks, 4 weeks and 6 weeks during treatment period, 2 weeks and 4 weeks during follow-up period	The anxiety was evaluated before and after treatment and during follow-up. The scoring standard is the same as the international standard.
The change of Self-rating depression scale (SDS) score	Baseline, 2 weeks, 4 weeks and 6 weeks during treatment period, 2 weeks and 4 weeks during follow-up period	The depression was evaluated before and after treatment and during follow-up. The scoring standard is the same as the international standard.

Trial Locations

Locations (1)

Xiyuan Hospital of China Academy of Chinese Medical Sciences; 🇨🇳 Beijing, China