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The goal of this clinical trial is to learn if the 14-day susceptibility-guided bismuth quadruple therapy works to treat multiple drug resistant Helicobacter pylori (H. pylori) in adults. It will also learn about the adverse effects of bismuth quadruple therapy. The main questions it aims to answer are:
Researchers will record 14-day susceptibility-guided bismuth quadruple to see if 14-day susceptibility-guided bismuth quadruple works to treat multiple drug resistant H. pylori.
Participants will:
Helicobacter pylori (H. pylori) infection is the major culprit of dyspeptic symptoms, peptic ulcer disease, gastric adenocarcinoma, and gastric mucosa-associated lymphoid tissue lymphoma. The Tokyo consensus stated that infection with H. pylori should be regarded as a pathogenic infectious disease rather than commensals only and should be eradicated.
H. pylori eradication regimen evolved with the increase of resistance rate in different regions. In Taiwan, clarithromycin resistance rate is arising from 9.5% in 2009 to around 14-17% in 2016 when conducting the first-line therapy. As a result, Taiwan gastroenterological association consensus suggested using 14-day clarithromycin-based (hybrid, sequential, concomitant, or triple) therapy as the first-line therapy and levofloxacin-based therapy as the second line therapy according to endemic resistance rate.
After twice eradication failure, H. pylori culture for susceptibility test is strongly recommended, which guide clinician to choose appropriate susceptibility-based therapy. Progressive increased dual (clarithromycin and levofloxacin) resistance and triple (dual and metronidazole) resistance, however, made it difficult for eradication. The regimens at physicians' discretion varied a lot and the overall successful eradication rate around 60% was still unsatisfactory.
Susceptibility-guided therapy is currently the consensus recommendation for 3rd-line H. pylori eradication. Bismuth quadruple therapy could overcome either clarithromycin or metronidazole resistant strains. Several evidences of clinical randomized-controlled trials demonstrated that adding bismuth as the first line therapeutic regimen can capture additional 30-40% successful eradication rate for the resistant strain, further contributing to the overall eradication rate. Accordingly, the aim of our study was to validate the susceptibility-guided bismuth quadruple therapy in patients with multiple drug resistant H. pylori infection in terms of efficacy and side effects.
Almost more than 99.5% ingested bismuth salt can be excreted from intestinal lumen without absorption. Bismuth may be able to form complexes in bacterial wall and periplasmic space, as well as inhibits enzymes, ATP synthesis and bacterial adherence to gastric mucosa. The MIC90 of bismuth to Helicobacter pylori ranged from 4-32 ng/L and there was no resistance been reported. Lots of H. pylori virulence factors are important players to establish colonization in gastric environment in each steps. Urease activity adjusts the pericellular environment to less acidity. Flagella direct bacterial motility and chemotaxis to mucosal surface. Colonization to epithelium is facilitated by lots of adhesion-receptor interaction, including BabA to Lewis B, SabA to sialyl-Lewis X, and CagL to α5β1 integrin. Bismuth drugs may affect the urease activity in jack bean plant and Klebsiella aerogenes. Bismuth inactivates H. pylori nickel-responsive transcription factor (NikR) protein, an important regulator for nickel homeostasis and iron metabolism in H. pylori. Since nickel iron is crucial in the catalytic function of urease, it is reasonable to assuming that it may impose effect on the urease activity in H. pylori. Furthermore, a pilot study showed that nickel-free diet can enhance the H. pylori eradication rate, which was speculated due to decreased urease activity.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Bismuth-based susceptibility-guided treatment | Experimental | Participants who have triple- or quadruple-drug resistant H. pylori infection are enrolled. Participants receive one of the four regimens based on susceptibility test. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Bismuth-based susceptibility-guided treatment | Drug | The investigators design four regimes for H. pylori eradication and participants receive one of the regimens based on susceptibility test. The four regimens are PBAT for those with both amoxicillin and tetracycline susceptible H. pylori; PBAM for those with amoxicillin susceptible but tetracycline resistant H. pylori; PBMT for those with amoxicillin resistant but tetracycline susceptible H. pylori; PBMR for those with both amoxicillin and tetracycline resistant H. pylori. A is amoxicillin (1000 mg thrice daily), B is colloidal bismuth subcitrate (120 mg thrice daily), M is metronidazole (500 mg thrice daily), P is a proton pump inhibitor, i.e., esomeprazole (40 mg twice daily), R is rifabutin (150 mg twice daily), and T is tetracycline (500 mg thrice daily). The treatment duration is 14 days for all regimens. |
| Measure | Description | Time Frame |
|---|---|---|
| The eradication rate of H. pylori | The investigators define successful eradication as a negative 13C-urea breath test or a negative H. pylori stool antigen test at 4 to 6 weeks after the completion of H. pylori eradication and discontinuation of antibiotics and proton pump inhibitors. The eradication rates are determined by intention-to-treat and per-protocol analyses. The intention-to-treat analysis evaluates all enrolled participants. The per-protocol analysis evaluates those who take >= 80% of the study medications and receive post-treatment 13C-urea breath test or an H. pylori stool antigen test. The successful rate is represented with a percentage (%). | From enrollment to the end of treatment at 6-8 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Adverse effects | Adverse events are assessed by a physician and a format questionnaire survey after the end of treatment. Serious adverse events are defined as daily activities restricted or participant unable to work. The adverse events include dizziness, skin rash, headache, unpleasant taste/bitter, abdominal pain, nausea, vomiting, diarrhea, constipation, abdominal fullness, glossitis/sore throat, darkened stool, fatigue, anorexia, chest burn, palpitation, and vaginal discharge. All adverse events are classified as none, mild (not restricting daily activities), or serious (restricting daily activities or causing inability to work). |
| Measure | Description | Time Frame |
|---|---|---|
| The sex-based eradication rate of H. pylori | The eradication rates are evaluated in females and males, respectively. The investigators define successful eradication as a negative 13C-urea breath test at least four weeks after the completion of H. pylori eradication and discontinuation of antibiotics and proton pump inhibitors. The eradication rates are determined by ITT and PP analyses. The ITT analysis evaluates all enrolled participants. The PP analysis evaluates those who take >= 80% of the study medications and receive post-treatment 13C-urea breath test. The staffs assessing antibiotic sensitivity and the 13C-urea breath test are blinded. |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Hsiu-Chi Cheng, MD, PhD | National Cheng-Kung University Hospital | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| National Cheng Kung University Hospital | Tainan | Taiwan | 704302 | Taiwan |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 17635369 | Background | Fischbach L, Evans EL. Meta-analysis: the effect of antibiotic resistance status on the efficacy of triple and quadruple first-line therapies for Helicobacter pylori. Aliment Pharmacol Ther. 2007 Aug 1;26(3):343-57. doi: 10.1111/j.1365-2036.2007.03386.x. |
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The multi-resistant H. pylori eradication rates between "bismuth-susceptibility-based regimen" and history "physicians' discretion regimen" are compared.
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| From enrollment to the end of treatment at 2 weeks |
| Adherence to medications | Adherence to medications is evaluated by questionnaire surveys after treatment completion. Adherence of medications is categorized as good (≥ 80% medication taken) or poor (< 80% medication taken). | From enrollment to the end of treatment at 2 weeks |
| From enrollment to the end of treatment at 6-8 weeks |
| The regimen-based eradication rate of H. pylori | The eradication rates are evaluated in the four regimens, respectively. The investigators define successful eradication as a negative 13C-urea breath test at least four weeks after the completion of H. pylori eradication and discontinuation of antibiotics and proton pump inhibitors. The eradication rates are determined by ITT and PP analyses. The ITT analysis evaluates all enrolled participants. The PP analysis evaluates those who take >= 80% of the study medications and receive post-treatment 13C-urea breath test. The staffs assessing antibiotic sensitivity and the 13C-urea breath test are blinded. | From enrollment to the end of treatment at 6-8 weeks |
| The resistance-number-based eradication rate of H. pylori | The eradication rates are evaluated in the subjects with triple-resistant infection and those with quadruple-resistant infection, respectively. The investigators define successful eradication as a negative 13C-urea breath test at least four weeks after the completion of H. pylori eradication and discontinuation of antibiotics and proton pump inhibitors. The eradication rates are determined by ITT and PP analyses. The ITT analysis evaluates all enrolled participants. The PP analysis evaluates those who take >= 80% of the study medications and receive post-treatment 13C-urea breath test. The staffs assessing antibiotic sensitivity and the 13C-urea breath test are blinded. | From enrollment to the end of treatment at 6-8 weeks |
| The treatment-failure-experience-based eradication rate of H. pylori | The eradication rates are evaluated in the subjects with naïve, those with once treatment failure experience, those with twice treatment failure experience, those with thrice treatment failure experience, those with four-time treatment failure experience, and those with five-time treatment failure experience, respectively. The investigators define successful eradication as a negative 13C-urea breath test at least four weeks after the completion of H. pylori eradication and discontinuation of antibiotics and proton pump inhibitors. The eradication rates are determined by ITT and PP analyses. The ITT analysis evaluates all enrolled participants. The PP analysis evaluates those who take >= 80% of the study medications and receive post-treatment 13C-urea breath test. The staffs assessing antibiotic sensitivity and the 13C-urea breath test are blinded. | From enrollment to the end of treatment at 6-8 weeks |