Ethics approval and trial registration
The present study was approved by the Ethic Committee of Xiyuan Hospital of China Academy of Chinese Medical Sciences (Ethical Approval Number: 2014XL091-2). This trial was conducted following the principles of good clinical practice and the Declaration of Helsinki guidelines. The informed consent of all subjects was obtained at the time of enrollment. This was a randomized, standard clinical trial (Chinese ClinicalTrials.gov: ChiCTR-IPR-15005905).
Study population
This was a multi-center, randomized, positive drug control clinical trial, to evaluate the safety and efficacy of Chinese herbal compound prescriptions in treating chronic erosive gastritis with eight TCM syndromes. Patients were recruited from the following 6 Chinese centers: Xiyuan hospital, China Academy of Chinese Medical Sciences (Beijing), Kunshan Traditional Chinese Medicine Hospital (Kunshan), The Hospital of Shanxi University of Chinese Medicine (Taiyuan), Guangdong Provincial Hospital of Chinese Medicine (Guangzhou), Wuhan No.1 Hospital (Wuhan Integrated TCM and Western Medicine Hospital) (Wuhan), and Shenzhen Traditional Chinese Medicine Hospital (Shenzhen).
Diagnostic criteria
Diagnostic criteria of western medicine
“The Consensus on Chronic Gastritis in China in 2012” published by Members of Chinese Society of Gastroenterology, was referenced in diagnosing gastritis [23].
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Endoscopic diagnosis: atrophic gastritis is defined as a condition in which the color of the mucosa alternates between red and white, predominating with white, the rugae flatten or disappear, the blood vessels are visible, and the mucosa appears granular or nodular.
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Erosion: erosion can be categorized as either flat or bulge-shaped. Single or multiple erosive lesions of the gastric mucosa may be present in the former; the size of the lesions can vary from the size of the needle tip to a few centimeters in diameter. The latter can be characterized by a single or several verrucous lesions, enlarged folds or plump-like bulges, ranging in diameter from 5 to 10 mm, with mucosal defects or umbilical depressions on top and erosion in the center.
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Erythema: erythema is distinguished from its surrounding mucosa by a marked reddening.
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Intramucosal bleeding: there are several types of intramucosal bleeding, including spotty hemorrhaging, patchy bleeding, and non-raised red or dark red hemorrhagic spots (with or without oozing of blood; fresh or old).
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Pathological diagnosis: Pathologically, chronic gastritis with inherent gland atrophy, as shown by biopsy, can be diagnosed as atrophic gastritis, irrespective of the number of biopsy specimens and the degree of atrophy.
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Gastrointestinal symptoms: the main clinical symptoms include epigastric pain and epigastric bloating while the secondary symptoms include early satiety, postprandial fullness and bloating, and epigastric burning.
Diagnostic criteria of TCM
For TCM syndromes, “TCM Consensus on Chronic Atrophic Gastritis Diagnosis and Treatment (2009, Shenzhen)” was used, including syndrome of stagnation of liver-qi, syndrome of stagnant heat in liver and stomach, syndrome of spleen-stomach dampness-heat, syndrome of spleen-deficiency and qi-stagnation, syndrome of spleen and stomach deficiency-cold, syndrome of stomach-yin deficiency, syndrome of liver-stomach-yin deficiency, and syndrome of deficiency of qi and yin [24].
Inclusion criteria
A total of 216 patients with chronic atrophic gastritis with erosions were enrolled and divided into three groups: test group 1, test group 2, and control group, with 72 patients in each group.
Inclusion criteria were as follows: (1) participants who met the diagnostic criteria for chronic atrophic gastritis and had predominance of gastric antral atrophy; (2) patients aged 18 to 70 years; (3) patients with a gastric erosion grade 2 (3–5 erosions) or above, and gastric antral erosion is present; (4) patients with at least one of the symptoms including early satiety, postprandial fullness and bloating, epigastric pain, and epigastric burning; and (5) patients who are able and willing to provide informed consent and to attend treatment.
Exclusion criteria
The exclusion criteria were as follows: (1) patients with H. pylori infection; (2) patients with type A gastritis, acute erosive gastritis, atrophic gastritis with severe dysplasia, upper gastrointestinal hemorrhage, peptic ulcer, or neoplasms of the gastrointestinal tract; (3) patients with evidence of gastrointestinal organic lesions such as pancreatitis and liver cirrhosis or those with diseases that can lead to disordered gastrointestinal motility, including hyperthyroidism, diabetes, chronic renal failure, psychiatric illness, or neurological lesions; (4) patients with significant impairments in the cardiac, hepatic, renal, hematologic, and hematopoietic systems, and tumors; (5) patients who continue any medications that may affect the function of the digestive tract, including antacids, H2-receptor antagonists, PPIs, gastrin receptor antagonists, anticholinergic drugs, prokinetics, prostaglandin analogs, or TCM therapies that have similar effects; (6) patients who had a history of alcohol drinking within 1 week; (8) pregnant and lactating women; (9) patients with known hypersensitivity to components from drugs used in this study; and (10) patients who are participating in other clinical trials.
Rejection criteria
The rejection criteria were as follows: (1) patients who are misdiagnosed or erroneously included; (2) patients who met exclusion criteria; (3) patients who did not take the drugs or were not observed for at least one time point; and (4) patients who take forbidden drugs so that efficacy cannot be determined.
Drop-out criteria
Reasons for drop-out are: (1) patients who drop out of the trial by themselves; (2) patients who are lost in the follow-up period; (3) patients who have poor compliance that affected the evaluation of efficacy and safety; and (4) patients who are withdrawn from the trial at any time by the treating physician due to other disease.
Discontinuation criteria
Discontinuation criteria were as follows: (1) patients who have clinically relevant safety concerns and serious adverse events; (2) the drugs which are insufficiently effective for further trials to be conducted; (3) major errors in clinical research protocol; and (4) administrative decision to withdraw the trial.
Randomization and intervention
Randomization
Participants will be randomized at a 2:1 ratio by the Central Randomization System of the Good Clinical Practice Unit of Xiyuan Hospital, which is an online, central randomized service. Using the patients’ dates of birth and erosion types, the investigators applied for the randomization code in the randomization system, and the randomization system emailed the investigators the results.
Interventions
Patients in the control group received aluminum plus magnesium suspension (15 ml/sachet; produced by Yangzhou Yiyang Pharmaceutical Co., Ltd.) thrice per day, 1 h after meals, 1 sachet at a time for 4 weeks.
Participants in test group 1 received Chinese herbal compound prescriptions plus Sanqi (Panax notoginseng) powder.
Participants in test group 2 received Chinese herbal compound prescriptions plus Sanqi (Panax notoginseng) powder and Zhebeimu (Fritillaria thunbergii Miq.) powder.
Chinese herbal compound prescriptions were consistent with TCM syndromes; the prescription was administered orally 1 h after meals, twice a day for 4 weeks; preprandial administration was allowed if there was a pre-meal hunger.
Powder (manufactured by Beijing Huamiao Pharmaceutical Co., Ltd.) was taken orally each day, before lunch and dinner, 3 g once, twice a day for 4 weeks. Specifically, Sanqi (Panax notoginseng) powder was administered orally at 3 g once in test group 1; Sanqi (Panax notoginseng) powder and Zhebeimu (Fritillaria thunbergii Miq.) powder were administered orally at 1.5 g once, respectively.
The TCM treatments were given as follows:
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Participants of syndrome of stagnation of liver-qi received Chaihu (Radix bupleuri)—9 g, Baishao (Paeoniae Radix Alba)- 15 g, Zhiqiao (Fructus aurantii)—12 g, Xiangfu (Cyperus rhizome)—12 g, Chenpi (Citrus reticulata)—9 g, Qingpi (Citri Reticulatae Pericarpium Viride)—9 g, Xiangyuanpi (Citrus medica)—12 g, Foshou (Citrus medica var. Sarcodactylis)—12 g, Chuanxiong (Ligusticum chuanxiong Hort)—9 g, Yanhusuo (Corydalis yanhusuo W.T. Wang)—12 g, Sharen (Amomum villosum Lour.)—6 g, and Shenggancao (Glycyrrhiza uralensis Fisch.)—6 g;
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Participants of syndrome of stagnant heat in liver and stomach received Zisu (Perilla frutescens L. Britt.)—12 g, Xiangfu (Cyperus rhizome)—12 g, Chenpi (Citrus reticulata)—10 g, Zhishi (Citrus aurantium L.)—12 g, Sharen (Amomum villosum Lour.)—6 g, Longdan (Gentiana scabra Bunge)—6 g, Huanglian (Coptis chinensis Franch.)—6 g, Wuzhuyu (Evodiae Fructus)—2 g, Wuzeigu (Sepiella maindroni de Rochebrune)—30 g, Pugongying (Taraxacum mongolicum Hand.-Mazz.)—18 g, and Shenggancao (Glycyrrhiza uralensis Fisch.)—6 g;
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Participants of syndrome of spleen-stomach dampness-heat received Dangshen [Codonopsis pilosula (Franch.) Nannf.]—15 g, Cangzhu [Atractylodes lancea (Thunb.) DC.]—15 g, Banxia [Pinellia ternata (Thunb) Breit.]—9 g, Chenpi (Citrus reticulata)—12 g, Huangqin (Scutellaria baicalensis Georgi)—12 g, Peilan (Eupatorium fortunei Turcz.)—15 g, Zhishi (Fructus aurantii)—12 g, Sharen (Amomum villosum Lour.)—6 g, Baikouren (Amomum kravanh Pierre ex Gagnep.)—6 g, Huashi (talcum)—10 g, Zhebeimu (Fritillaria thunbergii Miq.)—15 g, and Zhigancao (Radix Glycyrrhizae preparata)—6 g;
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Participants of syndrome of spleen-deficiency and qi-stagnation received Huangqi (Astragali Radix)—18 g, Dangshen [Codonopsis pilosula (Franch.) Nannf.]—15 g, Baizhu (Atractylodes macrocephala Koidz.)—18 g, Fuling [Wolfiporia cocos (F.A. Wolf) Ryvarden & Gilb.]—18 g, Banxia [Pinellia ternata (Thunb) Breit.]—9 g, Muxiang (Radix Aucklandiae)—12 g, Zhiqiao (Fructus aurantii)—15 g, Sharen (Amomum villosum Lour.)—9 g, Shenqu (Massa Medicata Fermentata)—15 g, Yanhusuo (Corydalis yanhusuo W.T. Wang)—12 g, and Shenggancao (Glycyrrhiza uralensis Fisch.)—6 g;
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Participants of syndrome of spleen and stomach deficiency-cold received Zhihuangqi (Radix Astragali preparata)—18 g, Dangshen [Codonopsis pilosula (Franch.) Nannf.]—15 g, Chaobaizhu (Atractylodes macrocephala Koidz.)—15 g, Baishao (Paeoniae Radix Alba)—15 g, Fuling [Wolfiporia cocos (F.A. Wolf) Ryvarden & Gilb.]—18 g, Banxia [Pinellia ternata (Thunb) Breit.]—9 g, Zhiqiao (Fructus aurantii)—12 g, Muxiang (Radix Aucklandiae)—12 g, Chenpi (Citrus reticulata)—12 g, Ganjiang (Zingiberis Rhizoma)—9 g, and Shenggancao (Glycyrrhiza uralensis Fisch.)—6 g;
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Participants of syndrome of stomach-yin deficiency received Beishashen (Radix Glehniae)—15 g, Maidong [Ophiopogon japonicus (Linn. f.) Ker-Gawl.]—15 g, Baihe (Lilium brownii F.E.Brown var. viridulum Baker)—30 g, Wuyao [Lindera aggregata (Sims) Kosterm]—12 g, Shihu (Dendrobium nobile Lindl)—12 g, Chaobaizhu (Atractylodes macrocephala Koidz.)—15 g, Zhiqiao (Fructus aurantii)—12 g, Foshou (Citrus medica var. Sarcodactylis)- 15 g, Sharen (Amomum villosum Lour.)—6 g, Walengzi (Arcae Concha)—30 g, Baishao (Paeoniae Radix Alba)—15 g, Chaoguya (Setariae Fructus Germinatus)—15 g, Chaomaiya (Hordei Fructus Germinatus)—15 g, and Shenggancao (Glycyrrhiza uralensis Fisch.)—6 g;
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Participants of syndrome of liver-stomach-yin deficiency received Chaihu (Radix bupleuri)—9 g, Baishao (Paeoniae Radix Alba)—15 g, Danggui (Angelicae Sinensis Radix)—12 g, Goujizi (Lycium barbarum L.)—18 g, Beishashen (Radix Glehniae)—15 g, Maidong [Ophiopogon japonicus (Linn. f.) Ker-Gawl.]—15 g, Baizhu (Atractylodes macrocephala Koidz.)—15 g, Zhiqiao (Fructus aurantii)—12 g, Sharen (Amomum villosum Lour.)—6 g, Xiangyuanpi (Citrus medica)—12 g, Foshou (Citrus medica var. Sarcodactylis)—15 g, Wuzeigu (Sepiella maindroni de Rochebrune)—30 g, and Shenggancao (Glycyrrhiza uralensis Fisch.)—6 g;
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Participants of syndrome of deficiency of qi and yin received Huangqi (Astragali Radix)—15 g, Beishashen (Radix Glehniae)—15 g, Maidong [Ophiopogon japonicus (Linn. f.) Ker-Gawl.]—15 g, Shihu (Dendrobium nobile Lindl)—12 g, Baizhu (Atractylodes macrocephala Koidz.)—15 g, Fuling [Wolfiporia cocos (F.A. Wolf) Ryvarden & Gilb.]—15 g, Zhiqiao (Fructus aurantii)—12 g, Muxiang (Radix Aucklandiae)—12 g, Sharen (Amomum villosum Lour.)—9 g, Shenqu (Massa Medicata Fermentata)—15 g, and Shenggancao (Glycyrrhiza uralensis Fisch.)—6 g.
Observation indicators
Primary clinical outcome indicators
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The improvement in gastric mucosal erosion observed by endoscopy following the treatment: each patient underwent an endoscopy at baseline and 4 weeks after treatment initiation. The lesions in the gastric antrum, fundus and body were analyzed altogether. “Cure”, “markedly effective” and “effective” were merged to calculate efficacy rate. The endoscopy results after treatment were assessed as follows: cure (disappearance of erosions), markedly effective (the erosion score decreased by at least two points), effective (the erosion score has decreased by one point) and ineffective (no change or worse) [25];
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Changes in the pathological score of gastric mucosa (acute inflammation, chronic inflammation, atrophy, intestinal metaplasia, dysplasia) following the treatment: the total and highest pathological scores of the gastric antrum, fundus and body were compared for each group. The reduction in the aforementioned pathological scores was used to determine the pathological efficacy rate of gastric mucosa.
Throughout the study, the same expert endoscopist and experienced gastrointestinal pathologist performed all endoscopic procedures and pathologic examinations in each center. All endoscopists and pathologists were uniformly trained and qualified in a standardized manner.
Secondary outcome indicators
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Clinical symptom scores [25];
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The patient-reported outcome (PRO) instrument for chronic gastrointestinal diseases [19, 26]; (3) Safety assessments that included adverse events (AEs) and adverse drug reactions (ADRs), including any abnormalities in physical examination, blood, urine and stool routine test and electrocardiogram, liver and renal function.
Sample size estimation
The design of the study is a randomized, controlled, multi-center, clinical trial. The previous clinical literature [27,28,29] showed that the efficacy rate was 75% in the aluminum plus magnesium suspension group and 91% in the Chinese herbal compound prescriptions plus powder group.
The sample size was calculated by using a clinical research sample size calculator (CRESS V1.3) [30] with the formula of sample size for rate below (Eqs. 1 and 2).
$$ n_{c} = \frac{{\left[ {\mu_{1 - \alpha } \sqrt {\overline{p}(1 - \overline{p}(1 + 1/k)} + \mu_{1 - \beta } \sqrt {p_{T} (1 - p_{T} /k + p_{c} (1 - p_{c} } )} \right]^{2} }}{{[(p_{T} - p_{c} - \Delta ]^{2} }} $$
(1)
Based on these results, in this study, we set, a β of 0.20 (or 20%), with a one-sided α level of 0.025; the sample size was calculated as 120 cases and 60 cases in the test group and control group, respectively at a ratio of 2:1. With the dropout rate controlled within 20%, we concluded that a total of 216 patients with 144 for the test group and 72 for the control group would need to be recruited to ensure statistically significant results.
Statistical analyses
All analyses were conducted with SAS software 9.4 (SAS Institute, Cary, NC, USA). (1) Measurement data were analyzed by a t test, paired t test, rank-sum test, paired rank sum test, and median test. (2) Numerical data were analyzed by the χ2 test and Fisher exact test; ranked data were analyzed using a rank-sum test and the Cochran-Mantel–Haenszel (CMH) test. (3) Efficacy measures were strictly conducted according to the full analysis set (FAS); the CMH test was conducted for multi-center numerical data; measurement data were compared using analysis of variance (ANOVA) or rank-sum test depending on data distribution. To confounding factors that were difficult to the control prior to the treatment or without control, least-square means (LSM) and their 95% confidence intervals (CI) for results from analysis of covariance (ANCOVA) or logistic regression analysis was adopted if there was baseline imbalance between the groups. (4) Variability test was used; test level of α = 0.05, and P values less than 0.05 were considered statistically significant.
