| 【Background】H.pylori(Hp)infection plays a crucial role in the occurrence and development of chronic gastritis,gastric ulcer,duodenal ulcer,gastric mucosa-associated lymphoid tissue(MALT)lymphoma,and gastric adenocarcinoma [1].Eradication of Helicobacter pylori can cure most gastritis and gastroduodenal ulcer[2] and prevent the occurrence of gastric cancer[3] to a certain extent.Therefore,the fifth expert consensus on Hp infection in China recommended eradication treatment for all patients with known Helicobacter pylori infection[17].Proton pump inhibitor(PPI)combined with antibiotics is the main way to eradicate Hp.However,the increasing resistance of Hp bacteria to antibiotics poses a significant challenge to Hp eradication therapy.In most countries,the eradication rate of Hp with standard triple therapy(PPI combined with clarithromycin and amoxicillin/metronidazole)has dropped below 80%[5,6].Recent reports have shown that the rate of resistance of Hp to "key" antibiotics such as clarithromycin,metronidazole and levofloxacin has been increasing[7].Clarithromycin,for example,has a drug resistance rate of about 15% in Sweden and Taiwan,about 30% in Italy and Japan,and about 40% in Turkey[8].According to the previous data in China,although the resistance of Hp to amoxicillin,tetracycline and furazolidone is still less than 5%,the primary resistance rate to clarithromycin,metronidazole and levofloxacin has reached 20%-50%,40%-70%,20%-50%,respectively[9-16].Since the eradication rate of standard triple therapy in China is far less than 80%,China’s fifth Hp infection expert’s consensus has recommended the use of bismuth-containing quadruple therapy,and no longer distinguish between first-line and second-line treatment[17].However,due to concerns about the increasing antibiotic resistance of Hp,Chinese fifth Hp infection expert consensus also mentioned that some traditional Chinese medicine or probiotics may help improve the eradication rate of Hp,indicating the direction for the exploration of new solutions for Hp eradication.Previous studies have reported that berberine hydrochloride(berberine)can inhibit the growth of Hp strains in vitro[18],and inhibit the proliferation of multi-drug resistant Hp strains [19].Combination with berberine hydrochloride can significantly improve the eradication rate of Hp by standard triple therapy[23].Our research group have conducted two prospective,randomized,controlled,non-inferiority clinical trials on the berberine-containing therapies(Clinical Trials.gov registration number: NCT02296021,NCT02633930),the results showed that quadruple therapy with berberine with PPI,amoxicillin and clarithromycin and quadruple therapy with bismuth,PPI,amoxicillin and clarithromycin quadruple therapy have the similar Hp eradicate rate[21],berberine,amoxicillin combined PPI and bismuth quadruple therapy and clarithromycin,amoxicillin combined PPI and bismuth quadruple therapy have similar Hp eradicate rate[22].We also conducted a retrospective study to compare the effectiveness of berberine,amoxicillin combined with PPI and bismuth with tetracycline and furazolidone combined with PPI and bismuth for rescue eradication treatment of Hp,and the result showed that there was no significant difference in the eradication rate between the two regimens[23].On this basis,this study intends to further evaluate the efficacy and safety of berberine,amoxicillin combined with PPI and bismuth quadruple therapy in a prospective,randomized-controlled trial to provide high-level experimental evidence for the novel Hp eradication regimen.A series of meta-analyses showed that the combination of probiotics significantly increased the Hp eradication rate of the standard triple regimen and the bismuth quadruple regimen[24-26].It is generally believed that probiotics can increase the eradication rate of Hp mainly by reducing gastrointestinal side effects of antibiotics and improving patients’ treatment compliance[27].However,some studies have shown that certain probiotics alone can achieve more than 20% eradication rate of Hp[28].It provides a feasible non-antibiotic eradication therapy for Hp-infected patients who are not suitable to use antibiotics,such as some children and the elderly with low liver and kidney function.In this study,a pilot single-arm trial was conducted to compare the efficacy and safety of two probiotics,clostridium caseinate and bacillus coagulans,either used alone or in combination to eradicate Hp,so as to provide a new experimental evidence for the non-antibiotic regimen of Hp eradication.【Objectives】1.Evaluate the efficacy and safety of berberine,amoxicillin,esomeprazole and bismuth quadruple therapy for rescue treatment of Hp.2.Evaluate the efficacy and safety of clostridum butyricum capsules and bacillus coagulans tablets for Hp eradication,either alone or in combination【Methods】1.Design of experiments and research objects: We designed a multicenter,open label,non-inferiority,randomized-controlled clinical trial to assess berberine quadruple therapy efficacy and safety for rescue eradication of Hp,berberine,amoxicillin and esomeprazole,bismuth quadruple therapy group(BA)was test group,tetracycline,furazolidone,escitalopram omeprazole,bismuth quadruple therapy group(TF)was control group.The objects of research were patients with Hp eradication failure.A single-center,randomized,single-arm clinical trial was conducted to evaluate the efficacy and safety of Clostridum butyricum capsule and bacillus coagulans tablet for eradication of Hp.The capsule of clostridum butyricum alone was group A,the living tablet of bacillus coagulans alone was group B,and the combination of two drugs was group C.2.The sample size calculation: In the study of berberine quadruple therapy,according to reports in the literature,we assumed TF group eradication rate as 80%,the margin value of non-inferiority as-10%,the alpha was 0.05(one side),and beta was 0.1(unilateral).Thus,we calculated the required sample size for each group was 274 cases,considering that 20% of subjects is expected to lost to follow-up,patients in each group were expected to expand to 1.2 times,namely,329 cases in each group,a total of 658 patients.In the probiotics study,as it was a prospective single-arm clinical trial,50 patients were included in each group with reference to literature reports,and a total of 150 patients were required.3.Random method: We used the random table made by the third party for central randomization.In the study of berberine-containing quadruplet therapy,enrolled patients were randomly assigned(1:1)to BA group and TF group.In the probiotics study,enrolled patients were randomly assigned(1:1:1)to groups A,B,and C.4.Treatment course and outcome measure: In the study of berberine-containing quadruple therapy,patients in both groups received treatment for two weeks,the primary outcome was the eradication rate of Hp at 4-8 weeks after the end of treatment and the secondary outcomes included symptom improvement rate,incidence of adverse events and patient compliance at the end of treatment and 4 weeks after the end of treatment.In the probiotics study,patients in all three groups were treated for 8 weeks,with the primary outcome being the eradication rate of Hp at 1-2 weeks after the end of treatment,and the secondary outcomes were the incidence of adverse events and patient compliance.5.Criteria for Hp infection and eradication: Hp infection was determined by at least one of rapid urease test(RUT),pathological detection of Hp infection in gastric mucosal biopsy specimens,13/14 carbon urea breath test(UBT)or Hp stool antigen test(Hp SAT)positive outcome;The 13/14 carbon urea breath test or Hp stool antigen test were used to evaluate the eradication effect.6.Statistical analysis: Mean ± standard deviation(±SD)was used for statistical description of measurement data.The counting data is described by percentage.Continuous variables were analyzed by independent sample t test,and categorical variables were statistically analyzed by chi-square test or Fisher exact probability method.7.The inclusion criteria,exclusion criteria,abscess criteria and elimination criteria were established for both studies,which were reviewed by the ethics committee of Xijing hospital and registered on the Clinical Trials.gov.The registration number of the berberine-containing quadruple therapy study was NCT03609892 and the registration number of the probiotics study was NCT03857425.【Results】1.Study on the efficacy and safety of berberine,amoxicillin,esomeprazole and bismuth quadruple therapy for rescue eradication of HpFrom August 2018 to August 2019,in the center of Xijing hospital,Xianyang Central Hospital,Shaanxi university of Traditional Chinese Medicine Affiliated Hospital,the Second Affiliated Hospital of Xi ’an Jiaotong University,Yan’an University Affiliated Hospital,a total of five centers,658 subjects who failed to eradicated Hp and met the criteria were consecutively enrolled and randomly assigned to BA and TF group,329 patients in each group.The baseline data of the two groups of patients were analyzed,and the distribution of each factor was balanced with no significant difference between the two groups.In BA group,19 patients were lost to follow-up,2 patients violated the protocol,and 308 patients completed the study.In TF group,23 patients were lost to follow-up,6 patients violated the protocol,and 300 patients completed the study.Primary outcome: The analysis of intention to treatment(ITT)showed that the eradication rate of Hp in group BA was 76.3%(251/329),while that in group TF was 77.5%(255/329),with no statistical difference between the two groups(P= 0.781).Per-protocol(PP)analysis showed that the eradication rate of Hp in group BA was 81.5%(251/308),while that in group TF was 85.0%(255/300),with no significant difference between the two groups(P= 0.278).Further analysis showed that the lower 95% confidence interval(CI)of the rate difference between the two groups(ITT analysis was-7.66%,PP analysis-9.43%)was greater than the preset non-inferiority margin value(-10%),indicating that the eradication rates of the two groups met the non-inferiority criteria,that is,the Hp eradication rate of the BA group were not inferior to that of the TF group.Secondary outcomes: Gastrointestinal symptoms improved significantly in 69.3% of patients in the BA group and 62.4% in the TF group at the end of the 2-week eradication treatment(P=0.105).At 4 weeks after the end of treatment,gastrointestinal symptoms were significantly improved in 84.5% of patients in the BA group and 81.2% in the TF group(P=0.365),and there was no significant difference in symptom improvement rate between the two groups.The overall incidence of adverse reactions in BA group and TF group was 19.7% and 26.1%,respectively,with significant difference(P=0.024).Compliance in the BA group and TF group was 92.7% and 90.0%,respectively,with no significant difference between the two groups(P=0.267).2.Study on the efficacy and safety of eradication of Hp by of clostridum butyricum capsules and bacillus coagulans tabletsFrom February 2019 to August 2019,150 eligible patients with primary treatment of Hp infection were successively included in the outpatient department of gastroenterology of Xijing hospital and randomly assigned to groups A,B and C,each group with 50 patients.There was no significant difference in baseline data among the three groups.In group A,12 patients were lost to follow-up,1 patient violated the protocol,and 37 patients completed the study.In group B,10 patients were lost to follow-up,2 patients violated the protocol,and 38 patients completed the study.In group C,8 patients were lost to follow-up,2 patients violated the protocol,and 40 patients completed the study.Primary outcome: In ITT analysis,the eradication rate of Hp in group A,B and C was 18%(9/50),20%(10/50)and 26%(13/50),respectively with no statistical difference among the three groups(P=0.597).In the PP analysis,the Hp eradication rate of group A,B and C was 24.3%(9/37),26.3%(10/38)and 32.5%(13/40),respectively,with no statistical difference among the three groups(P=0.703).Secondary outcomes: Patients in group A,B and C had no adverse reactions during treatment.There was no significant difference in compliance among the three groups(74% vs 76% vs 80%,P>0.05).【Conclusions】1.The quadruple regimen of berberine,amoxicillin combined with PPI and bismuth was not inferior to the standard quadruple regimen of tetracycline,furazolidone combined with PPI and bismuth when applied to the rescue eradication therapy of Hp,which is an optional therapy for rescue eradication therapy of Hp in this region.2.Clostridum butyricum capsule and bacillus coagulans tablet both had a certain success rate of Hp eradication,which can be used as an alternative to non-antibiotic Hp eradication treatment in this region.3.The two clinical trials in this study were aimed at Hp-infected patients in northwest of China,and further randomized controlled trials were needed to verify whether the results can be applied to other regions.This study did not test the antibiotic resistance of patients with Hp,and there may be some bias in patient selection,which may affect the reliability of the test results.In addition,the probiotics trial in this study was an exploratory pilot clinical trial,and the results needed to be further evaluated in a prospective randomized controlled trial. |
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