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Trial registered on ANZCTR


Registration number
ACTRN12613000377730
Ethics application status
Approved
Date submitted
2/04/2013
Date registered
9/04/2013
Date last updated
15/04/2013
Type of registration
Retrospectively registered

Titles & IDs
Public title
A comparative study of sequential therapy and 10-day standard triple therapy for Helicobacter pylori infection
Scientific title
A comparative study of sequential therapy and 10-day standard triple therapy for Helicobacter pylori infection eradication: a randomized, open-label, multicentre trial in Chinese naive patients
Secondary ID [1] 282231 0
Nil
Universal Trial Number (UTN)
U1111-1141-2669
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Eradication of Helicobacter pylori infection 288745 0
Condition category
Condition code
Oral and Gastrointestinal 289102 289102 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
Infection 289167 289167 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Arm 1: Sequential therapy comprised esomeprazole 20 mg and amoxicillin 1 g taken twice a day for 5 days followed by esomeprazole 20 mg, clarithromycin 500 mg and tinidazole 500 mg taken twice a day for 5 days. All drugs are oral capsules or tablets.
Arm 2: 10-day standard triple therapy comprised esomeprazole 20 mg, clarithromycin 500 mg and amoxicillin 1 g taken twice a day for 10 days. All drugs are oral capsules or tablets.
Patients were asked to return within 1 to 3 days after treatment to assess the compliance with therapy. Compliance, determined by pill counts, was defined as good when more than 90% of the prescribed drugs were taken. Patients who had taken fewer than 80% of the treatment drugs (poor compliance) were excluded from per-protocol analysis.
Intervention code [1] 286841 0
Treatment: Drugs
Comparator / control treatment
10-day standard triple therapy comprised esomeprazole 20 mg, clarithromycin 500 mg and amoxicillin 1 g taken twice a day for 10 days
Control group
Active

Outcomes
Primary outcome [1] 289211 0
Eradication rates (%) of Helicobacter pylori infection associated with sequential therapy and 10-d standard triple therapy.
Patients with peptic ulcer and macroscopic gastric mucosal erosions underwent repeat upper endoscopy to determine the outcome of eradication therapy after treatment. Three gastric biopsies were taken at this visit: one from the antrum for rapid urease test and one each from the antrum and corpus for Warthin-Starry staining. Helicobacter pylori infection eradication was defined by the demonstration of a negative rapid urease test and a negative Warthin-Starry stain.
A urea breath test was used to confirm Helicobacter pylori infection status for patients without evidence of peptic ulcer or macroscopic gastric mucosal erosions after treatment. Helicobacter pylori infection was considered to be eradicated if the urea breath test result was negative.
Timepoint [1] 289211 0
At 8 to 12 weeks after treatment (participants are assessed once only)
Secondary outcome [1] 302051 0
The safety and compliance to sequential therapy and 10-d standard triple therapy.
Patients were asked to return within 1 to 3 days after treatment, to determine the incidence of side effects (safety) and to assess the compliance with therapy. Adverse events were evaluated in all patients using open-ended questions, by patient self-reports and from physical examinations. The common known or possible side effects include nausea, epigastric pain, diarrhea, itching, headache, constipation and taste alteration. Compliance, determined by pill counts, was defined as good when more than 90% of the prescribed drugs were taken. Patients who had taken fewer than 80% of the treatment drugs (poor compliance) were excluded from per-protocol analysis.
Timepoint [1] 302051 0
Within 1 to 3 days after treatment
Secondary outcome [2] 302052 0
The effects of different patterns of antibiotic resistance on Helicobacter pylori eradication and the factors that influenced eradication efficacy.
Helicobacter pylori strains were isolated from gastric mucosal samples, and in vitro antibiotic resistance to three antibiotics was tested by E-test.
The effects of different patterns of antibiotic resistance on Helicobacter pylori eradication were demonstrated by comparisons of the eradication rates in the subgroups with different resistance patterns.
Host and bacterial parameters were analyzed using univariate analysis. Variables with a P-value lower than 0.3 were included in a multivariate logistic regression analysis to identify independent factors for eradication outcome.
Timepoint [2] 302052 0
At the time of data analysis

Eligibility
Key inclusion criteria
Consecutive patients with dyspepsia who had been referred for upper endoscopy at four tertiary hospitals in Beijing, Shanghai, Wuhan and Guangzhou were included in the study. Patients with positive Helicobacter pylori cultures were recruited into the study. None of the patients had previously received treatment for Helicobacter pylori infection.
Minimum age
18 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients who had received proton pump inhibitor, H2-receptor blockers, bismuth salts or antibiotics in the previous 4 weeks were excluded from entering the study. None of the patients had a history of gastrointestinal malignancy, previous gastric or esophageal surgery, Zollinger-Ellison syndrome, severe concomitant cardiovascular, respiratory, hematological, renal, hepatic or neurological diseases. Women who were pregnant or lactating were excluded from the study, as were those known to be allergic to any of the study drugs.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Patients were enrolled by the medical personnel of the gastrointestinal unit after assessment of inclusion and exclusion criteria and provided written informed consent. Patients were interviewed to obtain demographic data and medical history, and randomly assigned to one of two treatment groups. Allocation was concealed with an opaque envelope. The envelope was opened by the investigator when the patient was eligible for the study and had provided written informed consent. The patients were randomly assigned to treatment in a 1:1 ratio within 2 weeks of a positive culture result. Treatment allocation was not blinded.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A computer-generated randomization chart (SAS version 8.0; SAS Institute, Inc., Cary, NC) stratified according to center, was constructed using a block design (block size of four) provided by an independent statistician and was used to determine treatment allocation.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The sample size was calculated based on the results from a published pooled-data analysis available at the time when the study was designed. Based on a 93.4% eradication rate for sequential therapy and a 79.6% eradication rate for 10-day standard triple therapy, it was calculated that at least 126 patients per treatment arm would be required to provide 90% power to detect statistically significant difference between treatments at a two-sided probability level of 95%. At least 139 patients were into each group to account for a 10% withdrawal rate.
Statistical analysis was performed using SPSS for Windows (version 16, SPSS Inc., Chicago, IL, USA). The primary outcome variable was the Helicobacter pylori eradication rate with sequential therapy and 10-d standard triple therapy, evaluated using both intention-to-treat and per-protocol analyses. Secondary outcomes were eradication rates in subgroups of patients with clarithromycin resistance and metronidazole resistance.
Between group differences were evaluated using Student’s t test for continuous variables and Pearson Chi-square or Fisher’s exact test for categorical variables. Host and bacterial parameters were analyzed using univariate analysis. Variables with a P-value lower than 0.3 were included in a multivariate logistic regression analysis to identify independent factors for eradication outcome. Odds ratios and 95% confidence intervals for unsuccessful eradication were calculated in relation to the different variables. The frequency of adverse events and compliance was compared between regimens. Values of P<0.05 were considered to be statistically significant.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/03/2008
Actual
3/03/2008
Date of last participant enrolment
Anticipated
31/12/2010
Actual
10/12/2010
Date of last data collection
Anticipated
Actual
Sample size
Target
280
Accrual to date
Final
Recruitment outside Australia
Country [1] 4967 0
China
State/province [1] 4967 0
beijing
Country [2] 4977 0
China
State/province [2] 4977 0
Shanghai
Country [3] 4978 0
China
State/province [3] 4978 0
Wuhan
Country [4] 4979 0
China
State/province [4] 4979 0
Guangzhou

Funding & Sponsors
Funding source category [1] 286990 0
Government body
Name [1] 286990 0
National Science & Technology Pillar Program of 11th Five-Year Plan in China (2007BAI04B02)
Country [1] 286990 0
China
Primary sponsor type
Individual
Name
Sanren Lin
Address
Department of Gastroenterology, Peking University Third Hospital, No. 49, Garden North Road, Haidian District, Beijing, China 100191
Country
China
Secondary sponsor category [1] 285779 0
Individual
Name [1] 285779 0
Liya Zhou
Address [1] 285779 0
Department of Gastroenterology, Peking University Third Hospital, No. 49, Garden North Road, Haidian District, Beijing, China 100191
Country [1] 285779 0
China
Other collaborator category [1] 277343 0
Individual
Name [1] 277343 0
Jianzhong Zhang
Address [1] 277343 0
State Key Laboratory for Infectious Disease Prevention and Control, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, No 155, Changbai Road, Changping District, Beijing, China 102206
Country [1] 277343 0
China
Other collaborator category [2] 277344 0
Individual
Name [2] 277344 0
Minhu Chen
Address [2] 277344 0
Department of Gastroenterology, First Affiliated Hospital of SunYat-sen University, No 58, Zhongshan Second Road, Yuexiu District, Guangzhou, China 510080
Country [2] 277344 0
China
Other collaborator category [3] 277345 0
Individual
Name [3] 277345 0
Xiaohua Hou
Address [3] 277345 0
Division of Gastroenterology, Union Hospital of Tongji Medical College, Huazhong University of Technology and Science, No 1277, Jiefang Dadao Road, Hankou District, Wuhan, China 430022
Country [3] 277345 0
China
Other collaborator category [4] 277346 0
Individual
Name [4] 277346 0
Zhaoshen Li
Address [4] 277346 0
Department of Digestive Diseases, Changhai Hospital of Second Military Medical University, No 168, Changhai Road, Yangpu District, Shanghai, China 200433
Country [4] 277346 0
China

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 289041 0
The Ethics Committee of Peking University Health Science Center
Ethics committee address [1] 289041 0
Peking University Health Science Center, No 38, Xue Yuan Road, Haidian District, Beijing, China 100083
Ethics committee country [1] 289041 0
China
Date submitted for ethics approval [1] 289041 0
20/01/2007
Approval date [1] 289041 0
25/01/2007
Ethics approval number [1] 289041 0
IRB00001052-0709

Summary
Brief summary
Helicobacter pylori (H. pylori) infection is an important causal factor in a wide range of upper gastrointestinal diseases and is associated with significant morbidity and mortality. Traditionally, 10-d standard triple therapy (STT) comprising a proton pump inhibitor (PPI) plus two antibiotics (clarithromycin and amoxicillin or metronidazole) is the first-line option for empiric H. pylori eradication. However, the effectiveness of STT has declined to unacceptable levels in many regions of the world mainly due to antibiotic resistance. A novel form of sequential therapy (SQT) consisting of 5 days dual therapy (PPI plus amoxicillin) followed by 5 days triple therapy (PPI plus clarithromycin plus tinidazole or metronidazole) has recently been developed. Several systematic reviews have concluded SQT is associated with a good eradication efficacy and safety, and have shown it to be more effective than STT. Based on this evidence, SQT appears to offer an effective therapeutic option to replace STT for first-line treatment of H pylori. However, the majority of evidence supporting the use of SQT comes from Italy indicating that publication bias may compromise the data. At present, STT remains the most widely used treatment approach for H. pylori eradication in China, where there is high prevalence of H. pylori infection and high resistance rates of clarithromycin and metronidazole. It remains unknown whether the SQT regimen is suitable for Chinese patients with H. pylori infection. The primary objective of the present study was to compare the eradication rates of H. pylori infection associated with STT and SQT regimens. We also investigated the effects of different patterns of antibiotic resistance on H. pylori eradication and attempted to determine the factors that influenced eradication efficacy. The safety and compliance to each regimen were also compared.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 38918 0
Prof Liya Zhou
Address 38918 0
Department of Gastroenterology, Peking University Third Hospital, No. 49, Garden North Road, Haidian District, Beijing, China 100191
Country 38918 0
China
Phone 38918 0
+86-10-62357303
Fax 38918 0
Email 38918 0
[email protected]
Contact person for public queries
Name 38919 0
Zhiqiang Song
Address 38919 0
Department of Gastroenterology, Peking University Third Hospital, No. 49, Garden North Road, Haidian District, Beijing, China 100191
Country 38919 0
China
Phone 38919 0
+86-10-62357303
Fax 38919 0
Email 38919 0
[email protected]
Contact person for scientific queries
Name 38920 0
Zhiqiang Song
Address 38920 0
Department of Gastroenterology, Peking University Third Hospital, No. 49, Garden North Road, Haidian District, Beijing, China 100191
Country 38920 0
China
Phone 38920 0
+86-10-62357303
Fax 38920 0
Email 38920 0
[email protected]

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